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  • 201. Rukh, G
    et al.
    Ahmad, S
    Ericson, U
    Hindy, G
    Stocks, Tanja
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Renström, F
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Almgren, P
    Nilsson, P M
    Melander, O
    Franks, Paul W
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Orho-Melander, M
    Inverse relationship between a genetic risk score of 31 BMI loci and weight change before and after reaching middle age2016In: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 40, no 2, p. 252-259Article in journal (Refereed)
    Abstract [en]

    BACKGROUND/OBJECTIVE: Genome-wide-association studies have identified numerous body mass index (BMI)-associated variants, but it is unclear how these relate to weight gain in adults at different ages.

    METHODS: We examined the association of a genetic risk score (GRS), consisting of 31 BMI-associated variants, with an annual weight change (AWC) and a substantial weight gain (SWG) of 10% by comparing self-reported weight at 20 years (y) with baseline weight (mean: 58 y; s.d.: 8 y) in 21407 participants from the Malmö Diet and Cancer Study (MDCS), and comparing baseline weight to weight at follow-up (mean: 73 y; s.d.: 6 y) among 2673 participants. Association between GRS and AWG and SWG was replicated in 4327 GLACIER (Gene x Lifestyle interactions And Complex traits Involved in Elevated disease Risk) participants (mean: 45 y; s.d.: 7 y) with 10 y follow-up. Cohort-specific results were pooled by fixed-effect meta-analyses.

    RESULTS: In MDCS, the GRS was associated with increased AWC (β: 0.003; s.e: 0.01; P: 7 × 10(-8)) and increased odds for SWG (odds ratio (OR) 1.01 (95% confidence interval (CI): 1.00, 1.02); P: 0.013) per risk-allele from age 20y, but unexpectedly with decreased AWC (β: -0.006; s.e: 0.002; P: 0.009) and decreased odds for SWG OR 0.96 (95% CI: 0.93, 0.98); P: 0.001) between baseline and follow-up. Effect estimates from age 20 y to baseline differed significantly from those from baseline to follow-up (P: 0.0002 for AWC and P: 0.0001 for SWG). Similar to MDCS, the GRS was associated with decreased odds for SWG OR 0.98 (95% CI: 0.96, 1.00); P: 0.029) from baseline to follow-up in GLACIER. In meta-analyses (n=7000), the GRS was associated with decreased AWC (β: -0.005; s.e.m. 0.002; P: 0.002) and decreased odds for SWG OR 0.97 (95% CI: 0.96, 0.99); P: 0.001) per risk-allele.

    CONCLUSIONS: Our results provide convincing evidence for a paradoxical inversed relationship between a high number of BMI-associated risk-alleles and less weight gain during and after middle-age, in contrast to the expected increased weight gain seen in younger age.

  • 202. Russell, Beth
    et al.
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Häggström, Christel
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
    Josephs, Debra
    Kumar, Pardeep
    Malmström, Per-Uno
    Van Hemelrijck, Mieke
    Neoadjuvant chemotherapy for muscle invasive bladder cancer: a nationwide investigation on survival2019In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 53, no 4, p. 206-212Article in journal (Refereed)
    Abstract [en]

    Objectives: Randomised controlled trials (RCTs) have investigated the use of neoadjuvant chemotherapy (NAC) and its effect on survival patients with non-metastatic muscle-invasive bladder cancer (MIBC). However, these RCTs have limited external validity and generalisability and, therefore, the current study aims to use real world evidence in the form of observational data to identify the effect that NAC may have on survival, compared to the use of radical cystectomy (RC) alone.

    Materials and methods: The study cohort (consisting of 944 patients) was selected as a target trial from the Bladder Cancer Data Base Sweden (BladderBaSe). This study calculated 5-year survival and risk of bladder cancer (BC)-specific and overall death by Cox proportional hazard models for the study cohort and a propensity score (PS) matched cohort.

    Results: Those who had received NAC had higher 5-year survival proportions and decreased risk of both overall and BC specific death (HR = 0.71, 95% CI = 0.52-0.97 and HR = 0.67, 95% CI = 0.48-0.94), respectively, as compared to patients who did not receive NAC. The PS matched cohort showed similar estimates, but with larger statistical uncertainty (Overall death: HR = 0.76, 95% CI = 0.53-1.09 and BC-specific death: HR = 0.73, 95% CI = 0.50-1.07).

    Conclusion: Results from the current observational study found similar point estimates for 5-year survival and of relative risks as previous studies. However, the results based on real world evidence had larger statistical variability, resulting in a non-statistically significant effect of NAC on survival. Future studies with detailed validated data can be used to further investigate the effect of NAC in narrower patient groups.

  • 203.
    Salzer, Jonatan
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Nyström, Maria
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Stenlund, Hans
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Wadell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Sundström, Peter
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Vitamin A and systemic inflammation as protective factors in multiple sclerosis2013In: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 19, no 8, p. 1046-1051Article in journal (Refereed)
    Abstract [en]

    Background: Vitamin A is important for the immune system, and might suppress inflammatory activity in multiple sclerosis (MS).

    Objectives: We aimed to examine if vitamin A levels were associated with MS risk in samples collected prospectively and during gestation.

    Methods: We measured Retinol Binding Protein (RBP – a surrogate marker for vitamin A) and high-sensitivity C-reactive protein (hs-CRP) levels, in (1) prospectively collected biobank blood samples from MS cases and controls, and (2) gestational samples where the offspring had later developed MS, and gestational control samples. The risk of MS was calculated using matched multivariable logistic regression adjusted for confounders.

    Results: In prospective samples, RBP levels within the second quintile (vs. the first) were associated with a lower MS risk (OR = 0.38, 95% CI 0.19–0.74). No effect on MS risk in the offspring by gestational RBP levels was found. In young subjects hs-CRP levels ≥10 mg/l in prospective samples were associated with a lower MS risk (OR = 0.36, 95% CI 0.14–0.95).

    Conclusions: Our results suggest that sub-optimal vitamin A levels may be associated with MS risk. The association between hs-CRP levels and MS risk in young subjects may support the role of the hygiene hypothesis in MS aetiology. 

  • 204.
    Salzer, Jonatan
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Nyström, Maria
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Stenlund, Hans
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Wadell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Sundström, Peter
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Epstein-Barr virus antibodies and vitamin D in prospective multiple sclerosis biobank sampels2013In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 19, no 12, p. 1587-1591Article in journal (Refereed)
    Abstract [en]

    Background: Increased antibody reactivity against Epstein-Barr Nuclear Antigen-1 (EBNA-1) has been associated with an increased risk for MS, and high levels of 25-Hydroxyvitamin D (25[OH]D) have been associated with a lower risk for MS. Interaction between these two factors has been proposed.

    Objectives: To examine the association between antibody reactivity against EBNA-1 and five EBNA-1 domains, and the risk for multiple sclerosis (MS), and to examine if these antibodies and 25(OH)D status interact regarding MS risk in prospectively collected blood samples.

    Methods: Antibody reactivity (as specified above) and 25(OH)D levels were measured using ELISAs in n=192 MS cases and n=384 matched controls. The risk for MS was analysed using matched logistic regression.

    Results: The risk for MS increased across tertiles of antibody reactivity against EBNA-1, domain EBNA-1402–502, and domain EBNA-1385–420; p trend <0.001. The risk increase was most pronounced for EBNA-1385–420. In young individuals (below median age at sampling, <26.4 years) these associations were stronger, and 25(OH)D levels correlated inversely to antibody reactivity against EBNA-1 and the EBNA-1 domains.

    Conclusions: We confirm that increased antibody reactivity against EBNA-1 is a risk factor for MS. Our findings in young individuals suggest that 25(OH)D status might influence the immune response towards Epstein-Barr virus, and thereby modulate MS risk.

  • 205. Santucci-Pereira, Julia
    et al.
    O'Malley, Colleen
    de Cicco, Ricardo Lopez
    Kirma, Nameer B.
    Huang, Tim H.
    Liu, Joseph
    Ross, Eric A.
    Slifker, Michael
    Peri, Suraj
    Russo, Irma H.
    Bordas, Pal
    Lenner, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Toniolo, Paolo
    Russo, Jose
    Pregnancy changes the DNA methylation profile of the breast in postmenopausal women2014In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, no 19Article in journal (Other academic)
  • 206. Santucci-Pereira, Julia
    et al.
    Zeleniuch-Jacquotte, Anne
    Afanasyeva, Yelena
    Zhong, Hua
    Ross, Eric A.
    Slifker, Michael
    Peri, Suraj
    de Cicco, Ricardo Lopez
    Zhai, Yubo
    Russo, Irma H.
    Nguyen, Theresa
    Sheriff, Fathima
    Arslan, Alan A.
    Bordas, Pal
    Lenner, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Ahman, Janet
    Eriksson, Anna-Stina L.
    Johansson, Robert
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Toniolo, Paolo
    Russo, Jose
    Gene expression profile induced by pregnancy in the breast of premenopausal women2014In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, no 19Article in journal (Other academic)
  • 207. Santucci-Pereira, Julia
    et al.
    Zeleniuch-Jacquotte, Anne
    Afanasyeva, Yelena
    Zhong, Hua
    Slifker, Michael
    Peri, Suraj
    Ross, Eric A
    López de Cicco, Ricardo
    Zhai, Yubo
    Nguyen, Theresa
    Sheriff, Fathima
    Russo, Irma H
    Su, Yanrong
    Arslan, Alan A
    Bordas, Pal
    Lenner, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Åhman, Janet
    Landström Eriksson, Anna Stina
    Johansson, Robert
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    Toniolo, Paolo
    Russo, Jose
    Genomic signature of parity in the breast of premenopausal women2019In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 21, no 1, article id 46Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Full-term pregnancy (FTP) at an early age confers long-term protection against breast cancer. Previously, we reported that a FTP imprints a specific gene expression profile in the breast of postmenopausal women. Herein, we evaluated gene expression changes induced by parity in the breast of premenopausal women.

    METHODS: Gene expression profiling of normal breast tissue from 30 nulliparous (NP) and 79 parous (P) premenopausal volunteers was performed using Affymetrix microarrays. In addition to a discovery/validation analysis, we conducted an analysis of gene expression differences in P vs. NP women as a function of time since last FTP. Finally, a laser capture microdissection substudy was performed to compare the gene expression profile in the whole breast biopsy with that in the epithelial and stromal tissues.

    RESULTS: Discovery/validation analysis identified 43 differentially expressed genes in P vs. NP breast. Analysis of expression as a function of time since FTP revealed 286 differentially expressed genes (238 up- and 48 downregulated) comparing all P vs. all NP, and/or P women whose last FTP was less than 5 years before biopsy vs. all NP women. The upregulated genes showed three expression patterns: (1) transient: genes upregulated after FTP but whose expression levels returned to NP levels. These genes were mainly related to immune response, specifically activation of T cells. (2) Long-term changing: genes upregulated following FTP, whose expression levels decreased with increasing time since FTP but did not return to NP levels. These were related to immune response and development. (3) Long-term constant: genes that remained upregulated in parous compared to nulliparous breast, independently of time since FTP. These were mainly involved in development/cell differentiation processes, and also chromatin remodeling. Lastly, we found that the gene expression in whole tissue was a weighted average of the expression in epithelial and stromal tissues.

    CONCLUSIONS: Genes transiently activated by FTP may have a role in protecting the mammary gland against neoplastically transformed cells through activation of T cells. Furthermore, chromatin remodeling and cell differentiation, represented by the genes that are maintained upregulated long after the FTP, may be responsible for the lasting preventive effect against breast cancer.

  • 208. Scarmo, Stephanie
    et al.
    Afanasyeva, Yelena
    Lenner, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Koenig, Karen L
    Horst, Ronald L
    Clendenen, Tess V
    Arslan, Alan A
    Chen, Yu
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Lundin, Eva
    Rinaldi, Sabina
    Toniolo, Paolo
    Shore, Roy E
    Zeleniuch-Jacquotte, Anne
    Circulating levels of 25-hydroxyvitamin D and risk of breast cancer: a nested case-control study2013In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 15, no 1, p. R15-Article in journal (Refereed)
    Abstract [en]

    Introduction: Experimental evidence suggests a protective role for circulating 25-hydroxyvitamin D (25(OH) D) in breast cancer development, but the results of epidemiological studies have been inconsistent.

    Methods: We conducted a case-control study nested within two prospective cohorts, the New York University Women's Health Study and the Northern Sweden Mammary Screening Cohort. Blood samples were collected at enrollment, and women were followed up for breast cancer ascertainment. In total, 1,585 incident breast cancer cases were individually-matched to 2,940 controls. Of these subjects, 678 cases and 1,208 controls contributed two repeat blood samples, at least one year apart. Circulating levels of 25(OH) D were measured, and multivariate odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression.

    Results: No association was observed between circulating levels of 25(OH) D and overall breast cancer risk (multivariate-adjusted model OR = 0.94, 95% CI = 0.76-1.16 for the highest vs. lowest quintile, ptrend = 0.30). The temporal reliability of 25(OH)D measured in repeat blood samples was high (intraclass correlation coefficients for season-adjusted 25(OH) D > 0.70). An inverse association between 25(OH) D levels and breast cancer risk was observed among women who were = 45 years of age (ORQ5-Q1 = 0.48, 95% CI = 0.30-0.79, ptrend = 0.01) or premenopausal at enrollment (ORQ5-Q1 = 0.67, 95% CI = 0.48-0.92, ptrend = 0.03).

    Conclusions: Circulating 25(OH) D levels were not associated with breast cancer risk overall, although we could not exclude the possibility of a protective effect in younger women. Recommendations regarding vitamin D supplementation should be based on considerations other than breast cancer prevention.

  • 209. Scelo, G
    et al.
    Hofmann, J N
    Banks, R E
    Bigot, P
    Bhatt, R S
    Cancel-Tassin, G
    Chew, S K
    Creighton, C J
    Cussenot, O
    Davis, I J
    Escudier, B
    Frayling, T M
    Häggström, Christel
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Hildebrandt, M A T
    Holcatova, I
    Johansson, M
    Linehan, W M
    McDermott, D F
    Nathanson, K L
    Ogawa, S
    Perlman, E J
    Purdue, M P
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Swanton, C
    Vasudev, N S
    Wu, X
    Znaor, A
    Brennan, P
    Chanock, S J
    International cancer seminars: a focus on kidney cancer2016In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 27, no 8, p. 1382-1385Article in journal (Refereed)
    Abstract [en]

    Recent years have seen important advances in our understanding of the etiology, biology and genetics of kidney cancer. To summarize important achievements and identify prominent research questions that remain, a workshop was organized by IARC and the US NCI. A series of 'difficult questions' were formulated, which should be given future priority in the areas of population, genomic and clinical research.Recent years have seen important advances in our understanding of the etiology, biology and genetics of kidney cancer. To summarize important achievements and identify prominent research questions that remain, a workshop was organized by IARC and the US NCI. A series of 'difficult questions' were formulated, which should be given future priority in the areas of population, genomic and clinical research.

  • 210.
    Schock, Helena
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. German Cancer Research Center, Heidelberg.
    Fortner, Renée T
    German Cancer Research Center, Heidelberg.
    Surcel, Heljä-Marja
    National Institute for Health and Welfare, Oulu, Finland.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Pukkala, Eero
    School of Public Health, University of Tampere, Finland.
    Lehtinen, Matti
    School of Public Health, University of Tampere, Finland.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Early pregnancy IGF-I and placental GH and risk of epithelial ovarian cancer: A nested case-control study2015In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 137, no 2, p. 439-447Article in journal (Refereed)
    Abstract [en]

    Insulin-like growth factor-I (IGF-I) signaling may promote ovarian tumor development by exerting mitotic, antiapoptotic and proangiogenic effects. During pregnancy, maternal production of IGF-I is regulated by placental growth hormone (GH). Parity is an established protective factor for ovarian cancer, however, no prior study has evaluated placental GH and IGF-I in pregnancy and epithelial ovarian cancer (EOC). Prior prospective studies on the association between IGF-I and EOC in nonpregnant populations were inconclusive and did not address associations in subtypes of EOC. Among members of the Finnish Maternity Cohort and the Northern Sweden Maternity Cohort, we identified 1,045 EOC cases, diagnosed after recruitment (1975-2008) and before March 2011 and 2,658 individually matched controls. Placental GH and IGF-I were measured in serum from the last pregnancy before EOC diagnosis or selection as control. We used conditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for tertiles and a doubling of hormone concentrations. Higher IGF-I was associated with a nonsignificant decrease in risk for invasive [ORT3 vs. T1 : 0.79 (0.62-1.02); ptrend  = 0.07] and endometrioid tumors [ORT3 vs. T1 : 0.55 (0.28-1.07); ptrend  = 0.07]. The protective association between higher IGF-I levels and risk of invasive EOC was stronger in analyses limited to women aged <55 years at diagnosis [ORT3 vs. T1 : 0.74 (0.57-0.96); ptrend  = 0.03]. Our study provides the first data on placental GH and IGF-I in pregnancy and EOC risk overall and by subtype. Our data suggest higher IGF-I levels in pregnancy may be associated with lower risk of invasive and endometrioid EOC.

  • 211.
    Schock, Helena
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Division of Cancer Epidemiology, German Cancer Research Center, Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
    Surcel, Helja-Marja
    Oulu, Finland.
    Zeleniuch-Jacquotte, Anne
    Umeå University, Faculty of Medicine, Department of Biobank Research. New York, USA.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Lakso, Hans-Åke
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Fortner, Renee Turzanski
    Heidelberg, Germany.
    Kaaks, Rudolf
    Heidelberg, Germany.
    Pukkala, Eero
    Helsinki, Finland; Tampere, Finland.
    Lehtinen, Matti
    Tampere, Finland.
    Toniolo, Paolo
    New York, USA; Lausanne, Switzerland.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Early pregnancy sex steroids and maternal risk of epithelial ovarian cancer2014In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 21, no 6, p. 831-844Article in journal (Refereed)
    Abstract [en]

    Well-established associations between reproductive characteristics and epithelial ovarian cancer (EOC) support an involvement of sex steroid hormones in the etiology of EOC. Limited previous studies have evaluated circulating androgens and the risk of EOC, and estrogens and progesterone have been investigated in only one of the previous studies. Furthermore, there is little data on potential heterogeneity in the association between circulating hormones and EOC by histological subgroup. Therefore, we conducted a nested case-control study within the Finnish Maternity Cohort and the Northern Sweden Maternity Cohort to investigate the associations between circulating pre-diagnostic sex steroid concentrations and the histological subtypes of EOC. We identified 1052 EOC cases among cohort members diagnosed after recruitment (1975-2008) and before March 2011. Up to three controls were individually matched to each case (n=2694). Testosterone, androstenedione, 17-hydroxyprogesterone (17-OHP), progesterone, estradiol (E-2), and sex hormone-binding globulin levels were measured in serum samples collected during the last pregnancy before EOC diagnosis. We used conditional logistic regression to estimate odds ratios (ORs) and 95% CIs. Associations between hormones and EOC differed with respect to tumor histology and invasiveness. Sex steroid concentrations were not associated with invasive serous tumors; however, doubling of testosterone and 17-OHP concentration was associated with approximately 40% increased risk of borderline serous tumors. A doubling of androgen concentrations was associated with a 50% increased risk of mucinous tumors. The risk of endometrioid tumors increased with higher E-2 concentrations (OR: 1.89 (1.20-2.98)). This large prospective study in pregnant women supports a role of sex steroid hormones in the etiology of EOC arising in the ovaries.

  • 212. Shang, Shulian
    et al.
    Liu, Mengling
    Zeleniuch-Jacquotte, Anne
    Clendenen, Tess V.
    Krogh, Vittorio
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Lu, Wenbin
    Partially linear single index Cox regression model in nested case-control studies2013In: Computational Statistics & Data Analysis, ISSN 0167-9473, E-ISSN 1872-7352, Vol. 67, p. 199-212Article in journal (Refereed)
    Abstract [en]

    The nested case-control (NCC) design is widely used in epidemiologic studies as a cost-effective subcohort sampling method to study the association between a disease and its potential risk factors. NCC data are commonly analyzed using Thomas' partial likelihood approach under the Cox proportional hazards model assumption. However, the linear modeling form in the Cox model may be insufficient for practical applications, especially when there are a large number of risk factors under investigation. In this paper, we consider a partially linear single index proportional hazards model, which includes a linear component for covariates of interest to yield easily interpretable results and a nonparametric single index component to adjust for multiple confounders effectively. We propose to approximate the nonparametric single index function by polynomial splines and estimate the parameters of interest using an iterative algorithm based on the partial likelihood. Asymptotic properties of the resulting estimators are established. The proposed methods are evaluated using simulations and applied to an NCC study of ovarian cancer. 

  • 213.
    Shi, Lin
    et al.
    Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden..
    Brunius, Carl
    Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden..
    Bergdahl, Ingvar
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Rolandsson, Olov
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Donat Vargas, Carolina
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden..
    Kiviranta, Hannu
    Environmental Health Unit, National Institute for Health and Welfare, Kuopio, Finland..
    Hanhineva, Kati
    LC-MS Metabolomics Center, Kuopio, Finland. Department of Clinical Nutrition, University of Eastern Finland, Kuopio, Finland..
    Åkesson, Agneta
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden..
    Landberg, Rikard
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden..
    Joint Analysis of Metabolite Markers of Fish Intake and Persistent Organic Pollutants in Relation to Type 2 Diabetes Risk in Swedish Adults2019In: Journal of Nutrition, ISSN 0022-3166, E-ISSN 1541-6100, Vol. 149, no 8, p. 1413-1423Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: There is conflicting evidence regarding the association between fish intake and type 2 diabetes (T2D) incidence, possibly owing to measurement errors in self-reported intake and coexposure to persistent organic pollutants (POPs) present in fish.

    OBJECTIVE: The aim of this study was to identify plasma metabolites associated with fish intake and to assess their association with T2D risk, independently of POPs, in Swedish adults.

    METHODS: In a case-control study nested in the Swedish Västerbotten Intervention Programme, fasting plasma samples from 421 matched T2D case-control pairs of men and women aged 30-60 y at baseline and 10-y follow-up samples from a subset of 149 pairs were analyzed using untargeted metabolomics. Moreover, 16 plasma POPs were analyzed for the 149 pairs who had repeated samples available. Fish-related plasma metabolites were identified using multivariate modelling and partial correlation analysis. Reproducibility of metabolites and metabolite patterns, derived via principal component analysis (PCA), was assessed by intraclass correlation. A unique component of metabolites unrelated to POPs was dissected by integrating metabolites and POPs using 2-way orthogonal partial least squares regression. ORs of T2D were estimated using conditional logistic regression.

    RESULTS: We identified 31 metabolites associated with fish intake that had poor to good reproducibility. A PCA-derived metabolite pattern strongly correlated with fish intake (ρ = 0.37, P < 0.001) but showed no association with T2D risk. Integrating fish-related metabolites and POPs led to a unique metabolite component independent of POPs, which tended to be inversely associated with T2D risk (OR: 0.75; 95% CI: 0.54, 1.02, P = 0.07). This component mainly consisted of metabolites reflecting fatty fish intake.

    CONCLUSIONS: Our results suggest that fatty fish intake may be beneficial for T2D prevention, after removing the counteractive effects of coexposure to POPs in Swedish adults. Integrating metabolite markers and POP exposures appears a promising approach to advance the understanding of associations between fish intake and T2D incidence.

  • 214. Shi, Lin
    et al.
    Brunius, Carl
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Bergdahl, Ingvar
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Lindahl, Bernt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Hanhineva, Kati
    Landberg, Rikard
    Plasma metabolites associated with healthy Nordic dietary indexes and risk of type 2 diabetes: a nested case-control study in a Swedish population2018In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 108, no 3, p. 564-575Article in journal (Refereed)
    Abstract [en]

    Background: Epidemiologic evidence on the association of a healthy Nordic diet and future type 2 diabetes (T2D) is limited. Exploring metabolites as biomarkers of healthy Nordic dietary patterns may facilitate investigation of associations between such patterns and T2D.

    Objectives: We aimed to identify metabolites related to a priori-defined healthy Nordic dietary indexes, the Baltic Sea Diet Score (BSDS) and Healthy Nordic Food Index (HNFI), and evaluate associations with the T2D risk in a case-control study nested in a Swedish population-based prospective cohort.

    Design: Plasma samples from 421 case-control pairs at baseline and samples from a subset of 151 healthy controls at a 10-y follow-up were analyzed with the use of untargeted liquid chromatography-mass spectrometry metabolomics. Index-related metabolites were identified through the use of random forest modelling followed by partial correlation analysis adjustment for lifestyle confounders. Metabolite patterns were derived via principal component analysis (PCA). ORs of T2D were estimated via conditional logistic regression. Reproducibility of metabolites was assessed by intraclass correlation (ICC) in healthy controls. Associations were also assessed for 10 metabolites previously identified as linking a healthy Nordic diet with T2D.

    Results: In total, 31 metabolites were associated with BSDS and/or HNFI (-0.19 ≤ r ≤ 0.21, 0.10 ≤ ICC ≤ 0.59). Two PCs were determined from index-related metabolites: PC1 strongly correlated to the indexes (r = 0.27 for BSDS, r = 0.25 for HNFI, ICC = 0.45) but showed no association with T2D risk. PC2 was weakly associated with the indexes, but more strongly with foods not part of the indexes, e.g., pizza, sausages, and hamburgers. PC2 was also significantly associated with T2D risk. Predefined metabolites were confirmed to be reflective of consumption of whole grains, fish, or vegetables, but not related to T2D risk.

    Conclusions: Our study did not support an association between healthy Nordic dietary indexes and T2D. However, foods such as hamburger, sausage, and pizza not covered by the indexes appeared to be more important for T2D risk in the current population.

  • 215. Shi, Lin
    et al.
    Brunius, Carl
    Lehtonen, Marko
    Auriola, Seppo
    Bergdahl, Ingvar A.
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Rolandsson, Olov
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Hanhineva, Kati
    Landberg, Rikard
    Plasma metabolites associated with type 2 diabetes in a Swedish population: a case-control study nested in a prospective cohort2018In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 61, no 4, p. 849-861Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis: The aims of the present work were to identify plasma metabolites that predict future type 2 diabetes, to investigate the changes in identified metabolites among individuals who later did or did not develop type 2 diabetes over time, and to assess the extent to which inclusion of predictive metabolites could improve risk prediction.

    Methods: We established a nested case-control study within the Swedish prospective population-based Vasterbotten Intervention Programme cohort. Using untargeted liquid chromatography-MS metabolomics, we analysed plasma samples from 503 case-control pairs at baseline (a median time of 7 years prior to diagnosis) and samples from a subset of 187 case-control pairs at 10 years of follow-up. Discriminative metabolites between cases and controls at baseline were optimally selected using a multivariate data analysis pipeline adapted for large-scale metabolomics. Conditional logistic regression was used to assess associations between discriminative metabolites and future type 2 diabetes, adjusting for several known risk factors. Reproducibility of identified metabolites was estimated by intra-class correlation over the 10 year period among the subset of healthy participants; their systematic changes over time in relation to diagnosis among those who developed type 2 diabetes were investigated using mixed models. Risk prediction performance of models made from different predictors was evaluated using area under the receiver operating characteristic curve, discrimination improvement index and net reclassification index.

    Results: We identified 46 predictive plasma metabolites of type 2 diabetes. Among novel findings, phosphatidylcholines (PCs) containing odd-chain fatty acids (C19: 1 and C17:0) and 2-hydroxyethanesulfonate were associated with the likelihood of developing type 2 diabetes; we also confirmed previously identified predictive biomarkers. Identified metabolites strongly correlated with insulin resistance and/or beta cell dysfunction. Of 46 identified metabolites, 26 showed intermediate to high reproducibility among healthy individuals. Moreover, PCs with odd-chain fatty acids, branched-chain amino acids, 3-methyl-2-oxovaleric acid and glutamate changed over time along with disease progression among diabetes cases. Importantly, we found that a combination of five of the most robustly predictive metabolites significantly improved risk prediction if added to models with an a priori defined set of traditional risk factors, but only a marginal improvement was achieved when using models based on optimally selected traditional risk factors.

    Conclusions/interpretation: Predictive metabolites may improve understanding of the pathophysiology of type 2 diabetes and reflect disease progression, but they provide limited incremental value in risk prediction beyond optimal use of traditional risk factors.

  • 216. Shui, Irene M.
    et al.
    Lindstroem, Sara
    Kibel, Adam S.
    Berndt, Sonja I.
    Campa, Daniele
    Gerke, Travis
    Penney, Kathryn L.
    Albanes, Demetrius
    Berg, Christine
    Bueno-de-Mesquita, H. Bas
    Chanock, Stephen
    Crawford, E. David
    Diver, W. Ryan
    Gapstur, Susan M.
    Gaziano, J. Michael
    Giles, Graham G.
    Henderson, Brian
    Hoover, Robert
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Biobank Research. q International Agency for Research on Cancer, Lyon, France.
    Le Marchand, Loic
    Ma, Jing
    Navarro, Carmen
    Overvad, Kim
    Schumacher, Fredrick R.
    Severi, Gianluca
    Siddiq, Afshan
    Stampfer, Meir
    Stevens, Victoria L.
    Travis, Ruth C.
    Trichopoulos, Dimitrios
    Vineis, Paolo
    Mucci, Lorelei A.
    Yeager, Meredith
    Giovannucci, Edward
    Kraft, Peter
    Prostate Cancer (PCa) Risk Variants and Risk of Fatal PCa in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium2014In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 65, no 6, p. 1069-1075Article in journal (Refereed)
    Abstract [en]

    Background: Screening and diagnosis of prostate cancer (PCa) is hampered by an inability to predict who has the potential to develop fatal disease and who has indolent cancer. Studies have identified multiple genetic risk loci for PCa incidence, but it is unknown whether they could be used as biomarkers for PCa-specific mortality (PCSM). Objective: To examine the association of 47 established PCa risk single-nucleotide polymorphisms (SNPs) with PCSM. Design, setting, and participants: We included 10 487 men who had PCa and 11 024 controls, with a median follow-up of 8.3 yr, during which 1053 PCa deaths occurred. Outcome measurements and statistical analysis: The main outcome was PCSM. The risk allele was defined as the allele associated with an increased risk for PCa in the literature. We used Cox proportional hazards regression to calculate the hazard ratios of each SNP with time to progression to PCSM after diagnosis. We also used logistic regression to calculate odds ratios for each risk SNP, comparing fatal PCa cases to controls. Results and limitations: Among the cases, we found that 8 of the 47 SNPs were significantly associated (p < 0.05) with time to PCSM. The risk allele of rs11672691 (intergenic) was associated with an increased risk for PCSM, while 7 SNPs had risk alleles inversely associated (rs13385191 [C2orf43], rs17021918 [PDLIM5], rs10486567 [JAZF1], rs6465657 [LMTK2], rs7127900 (intergenic), rs2735839 [KLK3], rs10993994 [MSMB], rs13385191 [C2orf43]). In the case-control analysis, 22 SNPs were associated (p < 0.05) with the risk of fatal PCa, but most did not differentiate between fatal and nonfatal PCa. Rs11672691 and rs10993994 were associated with both fatal and nonfatal PCa, while rs6465657, rs7127900, rs2735839, and rs13385191 were associated with nonfatal PCa only. Conclusions: Eight established risk loci were associated with progression to PCSM after diagnosis. Twenty-two SNPs were associated with fatal PCa incidence, but most did not differentiate between fatal and nonfatal PCa. The relatively small magnitudes of the associations do not translate well into risk prediction, but these findings merit further follow-up, because they may yield important clues about the complex biology of fatal PCa. Patient summary: In this report, we assessed whether established PCa risk variants could predict PCSM. We found eight risk variants associated with PCSM: One predicted an increased risk of PCSM, while seven were associated with decreased risk. Larger studies that focus on fatal PCa are needed to identify more markers that could aid prediction. (C) 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.

  • 217.
    Shungin, Dmitry
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Skåne University Hospital, Lund University.
    Cornelis, Marilyn C.
    Divaris, Kimon
    Holtfreter, Birte
    Shaffer, John R.
    Yu, Yau-Hua
    Barros, Silvana P.
    Beck, James D.
    Biffar, Reiner
    Boerwinkle, Eric A.
    Crout, Richard J.
    Ganna, Andrea
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Hindy, George
    Hu, Frank B.
    Kraft, Peter
    McNeil, Daniel W.
    Melander, Olle
    Moss, Kevin L.
    North, Kari E.
    Orho-Melander, Marju
    Pedersen, Nancy L.
    Ridker, Paul M.
    Rimm, Eric B.
    Rose, Lynda M.
    Rukh, Gull
    Teumer, Alexander
    Weyant, Robert J.
    Chasman, Daniel I.
    Joshipura, Kaumudi
    Kocher, Thomas
    Magnusson, Patrik K. E.
    Marazita, Mary L.
    Nilsson, Peter
    Offenbacher, Steve
    Smith, George Davey
    Lundberg, Pernilla
    Umeå University, Faculty of Medicine, Department of Odontology.
    Palmer, Tom M.
    Timpson, Nicholas J.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Skåne University Hospital, Lund University; Department of Nutrition, Harvard School of Public Health, Boston, MA, USA.
    Using genetics to test the causal relationship of total adiposity and periodontitis: Mendelian randomization analyses in the Gene-Lifestyle Interactions and Dental Endpoints (GLIDE) Consortium2015In: International Journal of Epidemiology, ISSN 0300-5771, E-ISSN 1464-3685, Vol. 44, no 2, p. 638-650Article in journal (Refereed)
    Abstract [en]

    Background: The observational relationship between obesity and periodontitis is widely known, yet causal evidence is lacking. Our objective was to investigate causal associations between periodontitis and body mass index (BMI). Methods: We performed Mendelian randomization analyses with BMI-associated loci combined in a genetic risk score (GRS) as the instrument for BMI. All analyses were conducted within the Gene-Lifestyle Interactions and Dental Endpoints (GLIDE) Consortium in 13 studies from Europe and the USA, including 49 066 participants with clinically assessed (seven studies, 42.1% of participants) and self-reported (six studies, 57.9% of participants) periodontitis and genotype data (17 672/31 394 with/without periodontitis); 68 761 participants with BMI and genotype data; and 57 871 participants (18 881/38 990 with/without periodontitis) with data on BMI and periodontitis. Results: In the observational meta-analysis of all participants, the pooled crude observational odds ratio (OR) for periodontitis was 1.13 [95% confidence interval (CI): 1.03, 1.24] per standard deviation increase of BMI. Controlling for potential confounders attenuated this estimate (OR = 1.08; 95% CI: 1.03, 1.12). For clinically assessed periodontitis, corresponding ORs were 1.25 (95% CI: 1.10, 1.42) and 1.13 (95% CI: 1.10, 1.17), respectively. In the genetic association meta-analysis, the OR for periodontitis was 1.01 (95% CI: 0.99, 1.03) per GRS unit (per one effect allele) in all participants and 1.00 (95% CI: 0.97, 1.03) in participants with clinically assessed periodontitis. The instrumental variable meta-analysis of all participants yielded an OR of 1.05 (95% CI: 0.80, 1.38) per BMI standard deviation, and 0.90 (95% CI: 0.56, 1.46) in participants with clinical data. Conclusions: Our study does not support total adiposity as a causal risk factor for periodontitis, as the point estimate is very close to the null in the causal inference analysis, with wide confidence intervals.

  • 218.
    Shungin, Dmitry
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Clinical Sciences, Genetic & Molecular Epidemiology Unit, Lund University Diabetes Centre, Skåne University Hospital, Malmö, Sweden; Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA, United States of America.
    Deng, Wei Q.
    Varga, Tibor V.
    Luan, Jian'an
    Mihailov, Evelin
    Metspalu, Andres
    Morris, Andrew P.
    Forouhi, Nita G.
    Lindgren, Cecilia
    Magnusson, Patrik K. E.
    Pedersen, Nancy L.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Chu, Audrey Y.
    Justice, Anne E.
    Graff, Mariaelisa
    Winkler, Thomas W.
    Rose, Lynda M.
    Langenberg, Claudia
    Cupples, L. Adrienne
    Ridker, Paul M.
    Wareham, Nicholas J.
    Ong, Ken K.
    Loos, Ruth J. F.
    Chasman, Daniel I.
    Ingelsson, Erik
    Kilpeläinen, Tuomas O.
    Scott, Robert A.
    Mägi, Reedik
    Paré, Guillaume
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Clinical Sciences, Genetic & Molecular Epidemiology Unit, Lund University Diabetes Centre, Skåne University Hospital, Malmö, Sweden.
    Ranking and characterization of established BMI and lipid associated loci as candidates for gene-environment interactions2017In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 6, article id e1006812Article in journal (Refereed)
    Abstract [en]

    Phenotypic variance heterogeneity across genotypes at a single nucleotide polymorphism (SNP) may reflect underlying gene-environment (GxE) or gene-gene interactions. We modeled variance heterogeneity for blood lipids and BMI in up to 44,211 participants and investigated relationships between variance effects (P-v), GxE interaction effects (with smoking and physical activity), and marginal genetic effects (P-m). Correlations between P-v and P-m were stronger for SNPs with established marginal effects (Spearman's rho = 0.401 for triglycerides, and rho = 0.236 for BMI) compared to all SNPs. When P-v and P-m were compared for all pruned SNPs, only BMI was statistically significant (Spearman's rho = 0.010). Overall, SNPs with established marginal effects were overrepresented in the nominally significant part of the P-v distribution (P-binomial < 0.05). SNPs from the top 1% of the P-m distribution for BMI had more significant P-v values (Pmann-Whitney = 1.46x10(-5)), and the odds ratio of SNPs with nominally significant (< 0.05) P-m and P-v was 1.33 (95% CI: 1.12, 1.57) for BMI. Moreover, BMI SNPs with nominally significant GxE interaction P-values (Pint < 0.05) were enriched with nominally significant P-v values (P-binomial = 8.63x10(-9) and 8.52x10(-7) for SNP x smoking and SNP x physical activity, respectively). We conclude that some loci with strong marginal effects may be good candidates for GxE, and variance-based prioritization can be used to identify them.

  • 219.
    Shungin, Dmitry
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Umeå University, Faculty of Medicine, Department of Odontology.
    Winkler, Thomas W.
    Croteau-Chonka, Damien C.
    Ferreira, Teresa
    Lockes, Adam E.
    Maegi, Reedik
    Strawbridge, Rona J.
    Pers, Tune H.
    Fischer, Krista
    Justice, Anne E.
    Workalemahu, Tsegaselassie
    Wu, Joseph M. W.
    Buchkovich, Martin L.
    Heard-Costa, Nancy L.
    Roman, Tamara S.
    Drong, Alexander W.
    Song, Ci
    Gustafsson, Stefan
    Day, Felix R.
    Esko, Tonu
    Fall, Tove
    Kutalik, Zoltan
    Luan, Jian'an
    Randall, Joshua C.
    Scherag, Andre
    Vedantam, Sailaja
    Wood, Andrew R.
    Chen, Jin
    Fehrmann, Rudolf
    Karjalainen, Juha
    Kahali, Bratati
    Liu, Ching-Ti
    Schmidt, Ellen M.
    Absher, Devin
    Amin, Najaf
    Anderson, Denise
    Beekman, Marian
    Bragg-Gresham, Jennifer L.
    Buyske, Steven
    Demirkan, Ayse
    Ehret, Georg B.
    Feitosa, Mary F.
    Goel, Anuj
    Jackson, Anne U.
    Johnson, Toby
    Kleber, Marcus E.
    Kristiansson, Kati
    Mangino, Massimo
    Leach, Irene Mateo
    Medina-Gomez, Carolina
    Palmer, Cameron D.
    Pasko, Dorota
    Pechlivaniss, Sonali
    Peters, Marjolein J.
    Prokopenko, Inga
    Stancakova, Alena
    Sung, Yun Ju
    Tanakam, Toshiko
    Teumer, Alexander
    Van Vliet-Ostaptchouk, Jana V.
    Yengo, Loic
    Zhang, Weihua
    Albrecht, Eva
    Arnlov, Johan
    Arscott, Gillian M.
    Bandinelli, Stefania
    Barrett, Amy
    Bellis, Claire
    Bennett, Amanda J.
    Berne, Christian
    Blueher, Matthias
    Buhringer, Stefan
    Bonnet, Fabrice
    Boettcher, Yvonne
    Bruinenberg, Marcel
    Carba, Delia B.
    Caspersen, Ida H.
    Clarke, Robert
    Daw, E. Warwick
    Deelen, Joris
    Deelman, Ewa
    Delgado, Graciela
    Doney, Alex S. F.
    Eklund, Niina
    Erdos, Michael R.
    Estrada, Karol
    Eury, Elodie
    Friedrichs, Nele
    Garcia, Melissa E.
    Giedraitis, Vilmantas
    Gigante, Bruna
    Go, Alan S.
    Golay, Alain
    Grallert, Harald
    Grammer, Tanja B.
    Graessler, Juergen
    Grewal, Jagvir
    Groves, Christopher J.
    Haller, Toomas
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Hartman, Catharina A.
    Hassinen, Maija
    Hayward, Caroline
    Heikkila, Kauko
    Herzig, Karl-Heinz
    Helmer, Quinta
    Hillege, Hans L.
    Holmen, Oddgeir
    Hunt, Steven C.
    Isaacs, Aaron
    Ittermann, Till
    James, Alan L.
    Johansson, Ingegerd
    Juliusdottir, Thorhildur
    Kalafati, Ioanna-Panagiota
    Kinnunen, Leena
    Koenig, Wolfgang
    Kooner, Ishminder K.
    Kratzer, Wolfgang
    Lamina, Claudia
    Leander, Karin
    Lee, Nanette R.
    Lichtner, Peter
    Lind, Lars
    Lindstrom, Jaana
    Lobbens, Stephane
    Lorentzon, Mattias
    Mach, Francois
    Magnusson, Patrik K. E.
    Mahajan, Anubha
    McArdle, Wendy L.
    Menni, Cristina
    Merger, Sigrun
    Mihailov, Evelin
    Milani, Lili
    Mills, Rebecca
    Moayyeri, Alireza
    Monda, Ken L.
    Mooijaart, Simon P.
    Muehleisen, Thomas W.
    Mulas, Antonella
    Mueller, Gabriele
    Mueller-Nurasyid, Martina
    Nagaraja, Ramaiah
    Nalls, Michael A.
    Narisu, Narisu
    Glorioso, Nicola
    Nolte, Ilja M.
    Olden, Matthias
    Rayner, Nigel W.
    Renstrom, Frida
    Ried, Janina S.
    Robertson, Neil R.
    Rose, Lynda M.
    Sanna, Serena
    Scharnagl, Hubert
    Scholtens, Salome
    Sennblad, Bengt
    Seufferlein, Thomas
    Sitlani, Colleen M.
    Smith, Albert Vernon
    Stirrups, Kathleen
    Stringham, Heather M.
    Sundstrom, Johan
    Swertz, Morris A.
    Swift, Amy J.
    Syvanen, Ann-Christine
    Tayo, Bamidele O.
    Thorand, Barbara
    Thorleifsson, Gudmar
    Tomaschitz, Andreas
    Troffa, Chiara
    van Oort, Floor V. A.
    Verweij, Niek
    Vonk, Judith M.
    Waite, Lindsay L.
    Wennauer, Roman
    Wilsgaard, Tom
    Wojczynski, Mary K.
    Wong, Andrew
    Zhang, Qunyuan
    Zhao, Jing Hua
    Brennan, Eoin P.
    Choi, Murim
    Eriksson, Per
    Folkersen, Lasse
    Franco-Cereceda, Anders
    Gharavi, Ali G.
    Hedman, Asa K.
    Hivert, Marie-France
    Huang, Jinyan
    Kanoni, Stavroula
    Karpe, Fredrik
    Keildson, Sarah
    Kiryluk, Krzysztof
    Liang, Liming
    Lifton, Richard P.
    Ma, Baoshan
    McKnight, Amy J.
    McPherson, Ruth
    Metspalu, Andres
    Min, Josine L.
    Moffatt, Miriam F.
    Montgomery, Grant W.
    Murabito, Joanne M.
    Nicholson, George
    Nyholt, Dale R.
    Olsson, Christian
    Perry, John R. B.
    Reinmaa, Eva
    Salem, Rany M.
    Sandholm, Niina
    Schadt, Eric E.
    Scott, Robert A.
    Stolk, Lisette
    Vallejo, Edgar E.
    Westra, Harm-Jan
    Zondervan, Krina T.
    Amouyel, Philippe
    Arveiler, Dominique
    Bakker, Stephan J. L.
    Beilby, John
    Bergman, Richard N.
    Blangero, John
    Brown, Morris J.
    Burnier, Michel
    Campbell, Harry
    Chakravarti, Aravinda
    Chiness, Peter S.
    Claudi-Boehmi, Simone
    Collins, Francis S.
    Crawford, Dana C.
    Danesh, John
    de Faire, Ulf
    de Geusl, Eco J. C.
    Doerr, Marcus
    Erbel, Raimund
    Eriksson, Johan G.
    Farrall, Martin
    Ferrannini, Ele
    Ferrieres, Jean
    Forouhi, Nita G.
    Forrester, Terrence
    Franco, Oscar H.
    Gansevoort, Ron T.
    Gieger, Christian
    Gudnason, Vilmundur
    Haiman, Christopher A.
    Harris, Tamara B.
    Hattersley, Andrew T.
    Heliovaara, Markku
    Hicks, Andrew A.
    Hingorani, Aroon D.
    Hoffmann, Wolfgang
    Hofman, Albert
    Homuth, Georg
    Humphries, Steve E.
    Hyppoenen, Elina
    Illig, Thomas
    Jarvelin, Marjo-Riitta
    Johansen, Berit
    Jousilahti, Pekka
    Jula, Antti M.
    Kaprio, Jaakko
    Kee, Frank
    Keinanen-Kiukaanniemi, Sirkka M.
    Kooner, Jaspal S.
    Kooperberg, Charles
    Kovacs, Peter
    Kraja, Aldi T.
    Kumari, Meena
    Kuulasmaa, Kari
    Kuusisto, Johanna
    Lakka, Timo A.
    Langenberg, Claudia
    Le Marchand, Loic
    Lehtimaki, Terho
    Lyssenko, Valeriya
    Mannisto, Satu
    Marette, Andre
    Matise, Tara C.
    McKenzie, Colin A.
    McKnight, Barbara
    Musk, Arthur W.
    Mohlenkamp, Stefan
    Morris, Andrew D.
    Nelis, Mari
    Ohlsson, Claes
    Oldehinkel, Albertine J.
    Ong, Ken K.
    Palmer, Lyle J.
    Penninx, Brenda W.
    Peters, Annette
    Pramstaller, Peter P.
    Raitakari, Olli T.
    Rankinen, Tuomo
    Rao, D. C.
    Rice, Treva K.
    Ridker, Paul M.
    Ritchie, Marylyn D.
    Rudan, Igor
    Salomaa, Veikko
    Samani, Nilesh J.
    Saramies, Jouko
    Sarzynski, Mark A.
    Schwarz, Peter E. H.
    Shuldiner, Alan R.
    Staessen, Jan A.
    Steinthorsdottir, Valgerdur
    Stolk, Ronald P.
    Strauch, Konstantin
    Toenjes, Anke
    Tremblay, Angelo
    Tremoli, Elena
    Vohl, Marie-Claude
    Voelker, Uwe
    Vollenweider, Peter
    Wilson, James F.
    Witteman, Jacqueline C.
    Adair, Linda S.
    Bochud, Murielle
    Boehm, Bernhard O.
    Bornstein, Stefan R.
    Bouchard, Claude
    Cauchi, Stephane
    Caulfield, Mark J.
    Chambers, John C.
    Chasman, Daniel I.
    Cooper, Richard S.
    Dedoussis, George
    Ferrucci, Luigi
    Froguel, Philippe
    Grabe, Hans-Joergen
    Hamsten, Anders
    Hui, Jennie
    Hveem, Kristian
    Joeckel, Karl-Heinz
    Kivimaki, Mika
    Kuh, Diana
    Laakso, Markku
    Liu, Yongmei
    Maerz, Winfried
    Munroe, Patricia B.
    Njolstad, Inger
    Oostra, Ben A.
    Palmer, Colin N. A.
    Pedersen, Nancy L.
    Perola, Markus
    Perusse, Louis
    Peters, Ulrike
    Power, Chris
    Quertermous, Thomas
    Rauramaa, Rainer
    Rivadeneira, Fernando
    Saaristo, Timo E.
    Saleheen, Danish
    Sinisalo, Juha
    Slagboom, P. Eline
    Snieder, Harold
    Spector, Tim D.
    Thorsteinsdottir, Unnur R.
    Stumvoll, Michael
    Tuomilehto, Jaakko
    Uitterlinden, Andre G.
    Uusitupa, Math
    van der Harst, Pim
    Veronesi, Giovanni
    Walker, Mark
    Wareham, Nicholas J.
    Watkins, Hugh
    Wichmann, H-Erich
    Abecasis, Goncalo R.
    Assimes, Themistocles L.
    Berndt, Sonja I.
    Boehnkes, Michael
    Borecki, Ingrid B.
    Deloukas, Panos
    Franke, Lude
    Frayling, Timothy M.
    Groop, Leif C.
    Hunter, David J.
    Kaplan, Robert C.
    O'Connell, Jeffrey R.
    Qi, Lu
    Schlessinger, David
    Strachan, David P.
    Stefansson, Kari
    van Dujin, Cornelia M.
    Willer, Cristen J.
    Visscher, Peter M.
    Yang, Jian
    Hirschhorn, Joel N.
    Zillikens, M. Carola
    McCarthy, Mark I.
    Speliotes, Elizabeth K.
    North, Kari E.
    Fox, Caroline S.
    Barroso, Ines
    Franks, Paul W.
    Ingelsson, Erik
    Heid, Iris M.
    Loos, Ruth J. F.
    Cupples, L. Adrienne
    Morris, Andrew P.
    Lindgren, Cecilia M.
    Mohlke, Karen L.
    New genetic loci link adipose and insulin biology to body fat distribution2015In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 518, no 7538, p. 187-U378Article in journal (Refereed)
    Abstract [en]

    Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 x 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

  • 220. Song, Huan
    et al.
    Held, Maria
    Sandin, Sven
    Rautelin, Hilpi
    Eliasson, Mats
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Söderberg, Stefan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Engstrand, Lars
    Nyrén, Olof
    Ye, Weimin
    Increase in the Prevalence of Atrophic Gastritis Among Adults Age 35 to 44 Years Old in Northern Sweden Between 1990 and 20092015In: Clinical Gastroenterology and Hepatology, ISSN 1542-3565, E-ISSN 1542-7714, Vol. 13, no 9, p. 1592-1600Article in journal (Refereed)
    Abstract [en]

    BACKGROUND & AIMS: Atrophic corpus gastritis (ACG) is believed to be an early precursor of gastric adenocarcinoma. We aimed to investigate trends of ACG in Northern Sweden, from 1990 through 2009, and to identify possible risk factors.

    METHODS: We randomly selected serum samples collected from 5284 participants in 1990, 1994, 1999, 2004, and 2009, as part of the population-based, cross-sectional Northern Sweden Multinational Monitoring of Trends and Determinants in Cardiovascular Disease study (ages 35-64 y). Information was collected on sociodemographic, anthropometric, lifestyle, and medical factors using questionnaires. Serum samples were analyzed for levels of pepsinogen I, to identify participants with functional ACG; data from participants with ACG were compared with those from frequency-matched individuals without ACG (controls). Blood samples were analyzed for antibodies against H pylori and CagA. Associations were estimated with unconditional logistic regression models.

    RESULTS: Overall, 305 subjects tested positive for functional ACG, based on level of pepsinogen I. The prevalence of ACG in participants 55-64 y old decreased, from 124/1000 to 49/1000 individuals, between 1990 and 2009. However, the prevalence of ACG increased, from 22/1000 to 64/1000 individuals among participants 35-44 y old during this time period. CagA seropositivity was associated with risk for ACG (odds ratio, 2.29; 95% confidence interval, 1.69-3.12). Other risk factors included diabetes, low level of education, and high body mass index. The association between body mass index and ACG was confined to individuals 35-44 y old; in this group, overweight and obesity were associated with a 2.8-fold and 4.7-fold increased risk of ACG, respectively.

    CONCLUSIONS: Among residents of Northern Sweden, the prevalence of ACG increased from 1990 through 2009 specifically among adults 35-44 y old. The stabilizing seroprevalence of H pylori and increasing prevalence of overweight and obesity might contribute to this unexpected trend; studies are needed to determine whether these changes have affected the incidence of gastric cancer.

  • 221.
    Späth, Florentin
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Wibom, Carl
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Krop, Esmeralda
    Utrecht University.
    Izarra Santamaria, Antonio
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Johansson, Ann Sofie
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bergdahl, Ingvar
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Vermeulen, Roel
    Utrecht University.
    Melin, Beatrice S.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Immune marker changes and risk of multiple myeloma: a nested case-control study using repeated prediagnostic blood samples2019In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 104, no 12, p. 2456-2464Article in journal (Refereed)
    Abstract [en]

    Biomarkers reliably predicting progression to multiple myeloma (MM) are lacking. Myeloma risk has been associated with low blood levels of monocyte chemotactic protein-3 (MCP-3), macrophage inflammatory protein-1 alpha (MIP-1 alpha), vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2), fractalkine, and transforming growth factor-alpha (TGF-alpha). In this study, we aimed to replicate these findings and study the individual dynamics of each marker in a prospective longitudinal cohort, thereby examining their potential as markers of myeloma progression. For this purpose, we identified 65 myeloma cases and 65 matched cancer-free controls each with two donated blood samples within the Northern Sweden Health and Disease Study. The first and repeated samples from myeloma cases were donated at a median 13 and 4 years, respectively, before the myeloma was diagnosed. Known risk factors for progression were determined by protein-, and immunofixation electrophoresis, and free light chain assays. We observed lower levels of MCP-3, VEGF, FGF-2, and TGF-alpha in myeloma patients than in controls, consistent with previous data. We also observed that these markers decreased among future myeloma patients while remaining stable in controls. Decreasing trajectories were noted for TGF-alpha (P=2.5 x 10(-4)) indicating progression to MM. Investigating this, we found that low levels of TGF-alpha assessed at the time of the repeated sample were independently associated with risk of progression in a multivariable model (hazard ratio = 3.5; P=0.003). TGF-alpha can potentially improve early detection of MM.

  • 222.
    Späth, Florentin
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Wibom, Carl
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Krop, Esmeralda J. M.
    Johansson, Ann-Sofie
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bergdahl, Ingvar A.
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Vermeulen, Roel
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Biomarker Dynamics in B-cell Lymphoma: A Longitudinal Prospective Study of Plasma Samples Up to 25 Years before Diagnosis2017In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 77, no 6, p. 1408-1415Article in journal (Refereed)
    Abstract [en]

    The B-cell activation markers CXCL13, sCD23, (S)CD27, and sCD30 are associated with future lymphoma risk. However, a lack of information about the individual dynamics of markerdisease association hampers interpretation. In this study, we identified 170 individuals who had donated two prediagnostic blood samples before B-cell lymphoma diagnosis, along with 170 matched cancer-free controls from the Northern Sweden Health and Disease Study. Lymphoma risk associations were investigated by subtype and marker levels measured at baseline, at the time of the repeated sample, and with the rate of change in the marker level. Notably, we observed strong associations between CXCL13, sCD23, sCD27, and sCD30 and lymphoma risk in blood samples collected 15 to 25 years before diagnosis. B-cell activation marker levels increased among future lympho-ma cases over time, while remaining stable among controls. Associations between slope and risk were strongest for indolent lymphoma subtypes. We noted a marked association of sCD23 with chronic lymphocytic leukemia (ORSlope - 28, Ptrend(-)7.279 x 10 (-10)). Among aggressive lymphomas, the association between diffuse large B-cell lymphoma risk and slope was restricted to CXCL13. B-cell activation seemed to play a role in B-cell lymphoma development at early stages across different subtypes. Furthermore, B-cell activation presented differential trajectories in future lymphoma patients, mainly driven by indolent subtypes. Our results suggest a utility of these markers in predicting the presence of early occult disease and/or the screening and monitoring of indolent lymphoma in individual patients. 

  • 223.
    Stattin, Eva-Lena
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Henning, Petra
    Klar, Joakim
    McDermott, Emma
    Stecksen-Blicks, Christina
    Umeå University, Faculty of Medicine, Department of Odontology.
    Sandström, Per-Erik
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Kellgren, Therese G
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Rydén, Patrik
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Lönnerholm, Torsten
    Ameur, Adam
    Helfrich, Miep H
    Coxon, Fraser P
    Dahl, Niklas
    Wikström, Johan
    Lerner, Ulf H
    Umeå University, Faculty of Medicine, Department of Odontology. Centre for Bone and Arthritis Research, Department of internal medicine and clinical nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    SNX10 gene mutation leading to osteopetrosis with dysfunctional osteoclasts2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 3012Article in journal (Refereed)
    Abstract [en]

    Autosomal recessive osteopetrosis (ARO) is a heterogeneous disorder, characterized by defective osteoclastic resorption of bone that results in increased bone density. We have studied nine individuals with an intermediate form of ARO, from the county of Västerbotten in Northern Sweden. All afflicted individuals had an onset in early infancy with optic atrophy, and in four patients anemia was present at diagnosis. Tonsillar herniation, foramen magnum stenosis, and severe osteomyelitis of the jaw were common clinical features. Whole exome sequencing, verified by Sanger sequencing, identified a splice site mutation c.212 + 1 G > T in the SNX10 gene encoding sorting nexin 10. Sequence analysis of the SNX10 transcript in patients revealed activation of a cryptic splice site in intron 4 resulting in a frame shift and a premature stop (p.S66Nfs * 15). Haplotype analysis showed that all cases originated from a single mutational event, and the age of the mutation was estimated to be approximately 950 years. Functional analysis of osteoclast progenitors isolated from peripheral blood of patients revealed that stimulation with receptor activator of nuclear factor kappa-B ligand (RANKL) resulted in a robust formation of large, multinucleated osteoclasts which generated sealing zones; however these osteoclasts exhibited defective ruffled borders and were unable to resorb bone in vitro.

  • 224.
    Stattin, Pär
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Vickers, Andrew J.
    New York, NY, USA.
    Sjoberg, Daniel D.
    New York, NY, USA.
    Johansson, Robert
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Granfors, Torvald
    Stockholm, Sweden.
    Johansson, Mattias
    Section of Genetics, The International Agency for Research on Cancer, Lyon, France.
    Pettersson, Kim
    Turku, Finland.
    Scardino, Peter T.
    New York, NY, USA.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Lilja, Hans
    New York, NY, USA; Headington, Oxford, UK; Malmö, Sweden.
    Improving the Specificity of Screening for Lethal Prostate Cancer Using Prostate-specific Antigen and a Panel of Kallikrein Markers: a Nested Case-Control Study2015In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 68, no 2, p. 207-213Article in journal (Refereed)
    Abstract [en]

    Background: A disadvantage of prostate-specific antigen (PSA) for the early detection of prostate cancer (PCa) is that many men must be screened, biopsied, and diagnosed to prevent one death. Objective: To increase the specificity of screening for lethal PCa at an early stage. Design, setting, and participants: We conducted a case-control study nested within a population-based cohort. PSA and three additional kallikreins were measured in cryopreserved blood from a population-based cohort in Vasterbotten, Sweden. Of 40 379 men providing blood at ages 40, 50, and 60 yr from 1986 to 2009, 12 542 men were followed for > 15 yr. From this cohort, the Swedish Cancer Registry identified 1423 incident PCa cases, 235 with distant metastasis. Outcome measurements and statistical analysis: Risk of distant metastasis for different PSA levels and a prespecified statistical model based on the four kallikrein markers. Results and limitations: Mostmetastatic cases occurred in men with PSA in the top quartile at age 50 yr (69%) or 60 yr (74%), whereas 20-yr risk of metastasis for men with PSA below median was low (<= 0.6%). Among men with PSA > 2 ng/ml, a prespecified model based on four kallikrein markers significantly enhanced the prediction of metastasis compared with PSA alone. About half of all men with PSA > 2 ng/ml were defined as low risk by this model and had a <= 1% 15-yr risk of metastasis. Conclusions: Screening at ages 50-60 yr should focus on men with PSA in the top quartile. A marker panel can aid biopsy decision making. Patient summary: For men in their fifties, screening should focus on those in the top 10% to 25% of PSA values because the majority of subsequent cases of distant metastasis are found among these men. Testing of four kallikrein markers in men with an elevated PSA could aid biopsy decision making.

  • 225. Steffen, Annika
    et al.
    Huerta, José-Maria
    Weiderpass, Elisabete
    Bueno-de-Mesquita, H B As
    May, Anne M
    Siersema, Peter D
    Kaaks, Rudolf
    Neamat-Allah, Jasmine
    Pala, Valeria
    Panico, Salvatore
    Saieva, Calogero
    Tumino, Rosario
    Naccarati, Alessio
    Dorronsoro, Miren
    Sánchez-Cantalejo, Emilio
    Ardanaz, Eva
    Quirós, J Ramón
    Ohlsson, Bodil
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Biobank Research. International Agency for Research on Cancer (IARC-WHO), Lyon, France.
    Wallner, Bengt
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Overvad, Kim
    Halkjaer, Jytte
    Tjønneland, Anne
    Fagherazzi, Guy
    Racine, Antoine
    Clavel-Chapelon, Françoise
    Key, Tim J
    Khaw, Kay-Tee
    Wareham, Nick
    Lagiou, Pagona
    Bamia, Christina
    Trichopoulou, Antonia
    Ferrari, Pietro
    Freisling, Heinz
    Lu, Yunxia
    Riboli, Elio
    Cross, Amanda J
    Gonzalez, Carlos A
    Boeing, Heiner
    General and abdominal obesity and risk of esophageal and gastric adenocarcinoma in the European Prospective Investigation into Cancer and Nutrition2015In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 137, no 3, p. 646-657Article in journal (Refereed)
    Abstract [en]

    General obesity, as reflected by BMI, is an established risk factor for esophageal adenocarcinoma (EAC), a suspected risk factor for gastric cardia adenocarcinoma (GCC) and appears unrelated to gastric non-cardia adenocarcinoma (GNCC). How abdominal obesity, as commonly measured by waist circumference (WC), relates to these cancers remains largely unexplored. Using measured anthropometric data from 391,456 individuals from the European Prospective Investigation into Cancer and Nutrition (EPIC) study and 11 years of follow-up, we comprehensively assessed the association of anthropometric measures with risk of EAC, GCC and GNCC using multivariable proportional hazards regression. One hundred twenty-four incident EAC, 193 GCC and 224 GNCC were accrued. After mutual adjustment, BMI was unrelated to EAC, while WC showed a strong positive association (highest vs. lowest quintile HR = 1.19; 95% CI, 0.63-2.22 and HR = 3.76; 1.72-8.22, respectively). Hip circumference (HC) was inversely related to EAC after controlling for WC, while WC remained positively associated (HR = 0.35; 0.18-0.68, and HR=4.10; 1.94-8.63, respectively). BMI was not associated with GCC or GNCC. WC was related to higher risks of GCC after adjustment for BMI and more strongly after adjustment for HC (highest vs. lowest quintile HR = 1.91; 1.09-3.37, and HR = 2.23; 1.28-3.90, respectively). Our study demonstrates that abdominal, rather than general, obesity is an indisputable risk factor for EAC and also provides evidence for a protective effect of gluteofemoral (subcutaneous) adipose tissue in EAC. Our study further shows that general obesity is not a risk factor for GCC and GNCC, while the role of abdominal obesity in GCC needs further investigation.

  • 226.
    Stocks, Tanja
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Clinical Sciences in Malmö, Diabetes and Cardiovascular Diseases, Genetic Epidemiology, Lund University, Lund, Sweden.
    Björge, Tone
    Bergen, Norway; Oslo, Norway.
    Ulmer, Hanno
    Innsbruck, Austria.
    Manjer, Jonas
    Lund University, Malmö, Sweden.
    Häggström, Christel
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Nagel, Gabriele
    Ulm, Germany; Oslo, Norway.
    Engeland, Anders
    Oslo, Norway; Bergen, Norway.
    Johansen, Dorthe
    Lund University, Malmö, Sweden.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Selmer, Randi
    Oslo, Norway.
    Concin, Hans
    Bregenz, Austria.
    Tretli, Steinar
    Oslo, Norway.
    Jonsson, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Metabolic risk score and cancer risk: pooled analysis of seven cohorts2015In: International Journal of Epidemiology, ISSN 0300-5771, E-ISSN 1464-3685, Vol. 44, no 4, p. 1353-1387Article in journal (Refereed)
    Abstract [en]

    Background: There are few data on the joint influence of metabolic factors on risk of separate cancers. Methods: We analysed data on body mass index, blood pressure and plasma levels of glucose, total cholesterol and triglycerides from seven European cohorts comprising 564 596 men and women with a mean age of 44 years. We weighted those factors equally into a standardized metabolic risk score [MRS, mean = 0, standard deviation (SD) = 1], with an individual's level indicated as SDs from the sex-and cohort-specific means. Cancer hazard ratios were calculated by Cox regression with age as timescale and with relevant adjustments including smoking status. All statistical tests were two-sided. Results: During a mean follow-up of 12 years, 21 593 men and 14 348 women were diagnosed with cancer. MRS was linearly and positively associated with incident cancer in total and at sites (P<0.05). In men, risk per SD MRS was increased by 43% (95% confidence interval: 27-61) for renal cell cancer, 43% (16-76) for liver cancer, 29% (20-38) for colon cancer, 27% (5-54) for oesophageal cancer, 20% (9-31) for rectal cancer, 19% (4-37) for leukaemias, 15% (1-30) for oral cancer and 10% (2-19) for bladder cancer. In women, risk increases per SD MRS were 56% (42-70) for endometrial cancer, 53% (29-81) for pancreatic cancer, 40% (16-67) for renal cell cancer, 27% (9-47) for cervical cancer and 17% (3-32) for rectal cancer. Conclusion: This largest study to date on the joint influence of metabolic factors on risk of separate cancers showed increased risks for several cancers, in particular renal cell and liver cancer in men and endometrial and pancreatic cancer in women.

  • 227.
    Stocks, Tanja
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Van Hemelrijck, Mieke
    Manjer, Jonas
    Bjørge, Tone
    Ulmer, Hanno
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Lindkvist, Björn
    Selmer, Randi
    Nagel, Gabriele
    Tretli, Steinar
    Concin, Hans
    Engeland, Anders
    Jonsson, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Blood pressure and risk of cancer incidence and mortality in the metabolic syndrome and cancer project2012In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 59, no 4, p. 802-810Article in journal (Refereed)
    Abstract [en]

    Observational studies have shown inconsistent results for the association between blood pressure and cancer risk. We investigated the association in 7 cohorts from Norway, Austria, and Sweden. In total, 577799 adults with a mean age of 44 years were followed for, on average, 12 years. Incident cancers were 22184 in men and 14744 in women, and cancer deaths were 8724 and 4525, respectively. Cox regression was used to calculate hazard ratios of cancer per 10-mmHg increments of midblood pressure, which corresponded with 0.7 SDs and, for example, an increment of systolic/diastolic blood pressure of 130/80 to 142/88 mmHg. All of the models used age as the time scale and were adjusted for possible confounders, including body mass index and smoking status. In men, midblood pressure was positively related to total incident cancer (hazard ratio per 10 mmHg increment: 1.07 [95% CI: 1.04-1.09]) and to cancer of the oropharynx, colon, rectum, lung, bladder, kidney, malignant melanoma, and nonmelanoma skin cancer. In women, midblood pressure was not related to total incident cancer but was positively related to cancer of the liver, pancreas, cervix, uterine corpus, and malignant melanoma. A positive association was also found for cancer mortality, with HRs per 10-mmHg increment of 1.12 (95% CI: 1.08-1.15) for men and 1.06 (95% CI: 1.02-1.11) for women. These results suggest a small increased cancer risk overall in men with elevated blood pressure level and a higher risk for cancer death in men and women.

  • 228. Strohmaier, Susanne
    et al.
    Edlinger, Michael
    Manjer, Jonas
    Stocks, Tanja
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Bjorge, Tone
    Borena, Wegene
    Häggström, Christel
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Engeland, Anders
    Nagel, Gabriele
    Almquist, Martin
    Selmer, Randi
    Tretli, Steinar
    Concin, Hans
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Jonsson, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Ulmer, Hanno
    Total Serum Cholesterol and Cancer Incidence in the Metabolic Syndrome and Cancer Project (Me-Can)2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 1, p. e54242-Article in journal (Refereed)
    Abstract [en]

    Objective: To investigate the association between total serum cholesterol (TSC) and cancer incidence in the Metabolic syndrome and Cancer project (Me-Can).

    Methods: Me-Can consists of seven cohorts from Norway, Austria, and Sweden including 289,273 male and 288,057 female participants prospectively followed up for cancer incidence (n = 38,978) with a mean follow-up of 11.7 years. Cox regression models with age as the underlying time metric were used to estimate hazard ratios (HR) and their 95% confidence intervals (CI) for quintiles of cholesterol levels and per 1 mmol/l, adjusting for age at first measurement, body mass index (BMI), and smoking status. Estimates were corrected for regression dilution bias. Furthermore, we performed lag time analyses, excluding different times of follow-up, in order to check for reverse causation.

    Results: In men, compared with the 1st quintile, TSC concentrations in the 5th quintile were borderline significantly associated with decreasing risk of total cancer (HR = 0.94; 95% CI: 0.88, 1.00). Significant inverse associations were observed for cancers of the liver/intrahepatic bile duct (HR = 0.14; 95% CI: 0.07, 0.29), pancreas cancer (HR = 0.52, 95% CI: 0.33, 0.81), non-melanoma of skin (HR = 0.67; 95% CI: 0.46, 0.95), and cancers of the lymph-/hematopoietic tissue (HR = 0.68, 95% CI: 0.54, 0.87). In women, hazard ratios for the 5th quintile were associated with decreasing risk of total cancer (HR = 0.86, 95% CI: 0.79, 0.93) and for cancers of the gallbladder (HR = 0.23, 95% CI: 0.08, 0.62), breast (HR = 0.70, 95% CI: 0.61, 0.81), melanoma of skin (HR = 0.61, 95% CI: 0.42, 0.88), and cancers of the lymph-/hematopoietic tissue (HR = 0.61, 95% CI: 0.44, 0.83).

    Conclusion: TSC was negatively associated with risk of cancer overall in females and risk of cancer at several sites in both males and females. In lag time analyses some associations persisted, suggesting that for these cancer sites reverse causation did not apply.

  • 229. Sung, Yun J.
    et al.
    Winkler, Thomas W.
    de las Fuentes, Lisa
    Bentley, Amy R.
    Brown, Michael R.
    Kraja, Aldi T.
    Schwander, Karen
    Ntalla, Ioanna
    Guo, Xiuqing
    Franceschini, Nora
    Lu, Yingchang
    Cheng, Ching-Yu
    Sim, Xueling
    Vojinovic, Dina
    Marten, Jonathan
    Musani, Solomon K.
    Li, Changwei
    Feitosa, Mary F.
    Kilpelainen, Tuomas O.
    Richard, Melissa A.
    Noordam, Raymond
    Aslibekyan, Stella
    Aschard, Hugues
    Bartz, Traci M.
    Dorajoo, Rajkumar
    Liu, Yongmei
    Manning, Alisa K.
    Rankinen, Tuomo
    Smith, Albert Vernon
    Tajuddin, Salman M.
    Tayo, Bamidele O.
    Warren, Helen R.
    Zhao, Wei
    Zhou, Yanhua
    Matoba, Nana
    Sofer, Tamar
    Alver, Maris
    Amini, Marzyeh
    Boissel, Mathilde
    Chai, Jin Fang
    Chen, Xu
    Divers, Jasmin
    Gandin, Ilaria
    Gao, Chuan
    Giulianini, Franco
    Goel, Anuj
    Harris, Sarah E.
    Hartwig, Fernando Pires
    Horimoto, Andrea R. V. R.
    Hsu, Fang-Chi
    Jackson, Anne U.
    Kahonen, Mika
    Kasturiratne, Anuradhani
    Kuhnel, Brigitte
    Leander, Karin
    Lee, Wen-Jane
    Lin, Keng-Hung
    Luan, Jian' an
    McKenzie, Colin A.
    Meian, He
    Nelson, Christopher P.
    Rauramaa, Rainer
    Schupf, Nicole
    Scott, Robert A.
    Sheu, Wayne H. H.
    Stancakova, Alena
    Takeuchi, Fumihiko
    van der Most, Peter J.
    Varga, Tibor V.
    Wang, Heming
    Wang, Yajuan
    Ware, Erin B.
    Weiss, Stefan
    Wen, Wanqing
    Yanek, Lisa R.
    Zhang, Weihua
    Zhao, Jing Hua
    Afaq, Saima
    Alfred, Tamuno
    Amin, Najaf
    Arking, Dan
    Aung, Tin
    Barr, R. Graham
    Bielak, Lawrence F.
    Boerwinkle, Eric
    Bottinger, Erwin P.
    Braund, Peter S.
    Brody, Jennifer A.
    Broeckel, Ulrich
    Cabrera, Claudia P.
    Cade, Brian
    Caizheng, Yu
    Campbell, Archie
    Canouil, Mickael
    Chakravarti, Aravinda
    Chauhan, Ganesh
    Christensen, Kaare
    Cocca, Massimiliano
    Collins, Francis S.
    Connell, John M.
    de Mutsert, Renee
    de Silva, H. Janaka
    Debette, Stephanie
    Dorr, Marcus
    Duan, Qing
    Eaton, Charles B.
    Ehret, Georg
    Evangelou, Evangelos
    Faul, Jessica D.
    Fisher, Virginia A.
    Forouhi, Nita G.
    Franco, Oscar H.
    Friedlander, Yechiel
    Gao, He
    Gigante, Bruna
    Graff, Misa
    Gu, C. Charles
    Gu, Dongfeng
    Gupta, Preeti
    Hagenaars, Saskia P.
    Harris, Tamara B.
    He, Jiang
    Heikkinen, Sami
    Heng, Chew-Kiat
    Hirata, Makoto
    Hofman, Albert
    Howard, Barbara V.
    Hunt, Steven
    Irvin, Marguerite R.
    Jia, Yucheng
    Joehanes, Roby
    Justice, Anne E.
    Katsuya, Tomohiro
    Kaufman, Joel
    Kerrison, Nicola D.
    Khor, Chiea Chuen
    Koh, Woon-Puay
    Koistinen, Heikki A.
    Komulainen, Pirjo
    Kooperberg, Charles
    Krieger, Jose E.
    Kubo, Michiaki
    Kuusisto, Johanna
    Langefeld, Carl D.
    Langenberg, Claudia
    Launer, Lenore J.
    Lehne, Benjamin
    Lewis, Cora E.
    Li, Yize
    Lim, Sing Hui
    Lin, Shiow
    Liu, Ching-Ti
    Liu, Jianjun
    Liu, Jingmin
    Liu, Kiang
    Liu, Yeheng
    Loh, Marie
    Lohman, Kurt K.
    Long, Jirong
    Louie, Tin
    Magi, Reedik
    Mahajan, Anubha
    Meitinger, Thomas
    Metspalu, Andres
    Milani, Lili
    Momozawa, Yukihide
    Morris, Andrew P.
    Mosley, Thomas H., Jr.
    Munson, Peter
    Murray, Alison D.
    Nalls, Mike A.
    Nasri, Ubaydah
    Norris, Jill M.
    North, Kari
    Ogunniyi, Adesola
    Padmanabhan, Sandosh
    Palmas, Walter R.
    Palmer, Nicholette D.
    Pankow, James S.
    Pedersen, Nancy L.
    Peters, Annette
    Peyser, Patricia A.
    Polasek, Ozren
    Raitakari, Olli T.
    Renström, Frida
    Umeå University, Faculty of Medicine, Department of Biobank Research. Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden.
    Rice, Treva K.
    Ridker, Paul M.
    Robino, Antonietta
    Robinson, Jennifer G.
    Rose, Lynda M.
    Rudan, Igor
    Sabanayagam, Charumathi
    Salako, Babatunde L.
    Sandow, Kevin
    Schmidt, Carsten O.
    Schreiner, Pamela J.
    Scott, William R.
    Seshadri, Sudha
    Sever, Peter
    Sitlani, Colleen M.
    Smith, Jennifer A.
    Snieder, Harold
    Starr, John M.
    Strauch, Konstantin
    Tang, Hua
    Taylor, Kent D.
    Teo, Yik Ying
    Tham, Yih Chung
    Ultterlinden, Andre G.
    Waldenberger, Melanie
    Wang, Lihua
    Wang, Ya X.
    Bin Wei, Wen
    Williams, Christine
    Wilson, Gregory
    Wojczynski, Mary K.
    Yao, Jie
    Yuan, Jian-Min
    Zonderman, Alan B.
    Becker, Diane M.
    Boehnke, Michael
    Bowden, Donald W.
    Chambers, John C.
    Chen, Yii-Der Ida
    de Faire, Ulf
    Deary, Ian J.
    Esko, Tonu
    Farrall, Martin
    Forrester, Terrence
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden; Harvard T.H. Chan School of Public Health, Department of Nutrition, Harvard University, Boston, MA, USA.
    Freedman, Barry I.
    Froguel, Philippe
    Gasparini, Paolo
    Gieger, Christian
    Horta, Bernardo Lessa
    Hung, Yi-Jen
    Jonas, Jost B.
    Kato, Norihiro
    Kooner, Jaspal S.
    Laakso, Markku
    Lehtimaki, Terho
    Liang, Kae-Woei
    Magnusson, Patrik K. E.
    Newman, Anne B.
    Oldehinkel, Albertine J.
    Pereira, Alexandre C.
    Redline, Susan
    Rettig, Rainer
    Samani, Nilesh J.
    Scott, James
    Shu, Xiao-Ou
    van der Harst, Pim
    Wagenknecht, Lynne E.
    Wareham, Nicholas J.
    Watkins, Hugh
    Weir, David R.
    Wickremasinghe, Ananda R.
    Wu, Tangchun
    Zheng, Wei
    Kamatani, Yoichiro
    Laurie, Cathy C.
    Bouchard, Claude
    Cooper, Richard S.
    Evans, Michele K.
    Gudnason, Vilmundur
    Kardia, Sharon L. R.
    Kritchevsky, Stephen B.
    Levy, Daniel
    O'Connell, Jeff R.
    Psaty, Bruce M.
    van Dam, Rob M.
    Sims, Mario
    Arnett, Donna K.
    Mook-Kanamori, Dennis O.
    Kelly, Tanika N.
    Fox, Ervin R.
    Hayward, Caroline
    Fornage, Myriam
    Rotimi, Charles N.
    Province, Michael A.
    van Duijn, Cornelia M.
    Tai, E. Shyong
    Wong, Tien Yin
    Loos, Ruth J. F.
    Reiner, Alex P.
    Rotter, Jerome I.
    Zhu, Xiaofeng
    Bierut, Laura J.
    Gauderman, W. James
    Caulfield, Mark J.
    Elliott, Paul
    Rice, Kenneth
    Munroe, Patricia B.
    Morrison, Alanna C.
    Cupples, L. Adrienne
    Rao, Dabeeru C.
    Chasman, Daniel I.
    A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure2018In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 102, no 3, p. 375-400Article in journal (Refereed)
    Abstract [en]

    Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined similar to 18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 x 10(-8)) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 x 10(-8)). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling MSRA, EBF2).

  • 230. Sung, Yun Ju
    et al.
    de Las Fuentes, Lisa
    Winkler, Thomas W.
    Chasman, Daniel, I
    Bentley, Amy R.
    Kraja, Aldi T.
    Ntalla, Ioanna
    Warren, Helen R.
    Guo, Xiuqing
    Schwander, Karen
    Manning, Alisa K.
    Brown, Michael R.
    Aschard, Hugues
    Feitosa, Mary F.
    Franceschini, Nora
    Lu, Yingchang
    Cheng, Ching-Yu
    Sim, Xueling
    Vojinovic, Dina
    Marten, Jonathan
    Musani, Solomon K.
    Kilpelainen, Tuomas O.
    Richard, Melissa A.
    Aslibekyan, Stella
    Bartz, Traci M.
    Dorajoo, Rajkumar
    Li, Changwei
    Liu, Yongmei
    Rankinen, Tuomo
    Smith, Albert Vernon
    Tajuddin, Salman M.
    Tayo, Bamidele O.
    Zhao, Wei
    Zhou, Yanhua
    Matoba, Nana
    Sofer, Tamar
    Alver, Maris
    Amini, Marzyeh
    Boissel, Mathilde
    Chai, Jin Fang
    Chen, Xu
    Divers, Jasmin
    Gandin, Ilaria
    Gao, Chuan
    Giulianini, Franco
    Goel, Anuj
    Harris, Sarah E.
    Hartwig, Fernando P.
    He, Meian
    Horimoto, Andrea R. V. R.
    Hsu, Fang-Chi
    Jackson, Anne U.
    Kammerer, Candace M.
    Kasturiratne, Anuradhani
    Komulainen, Pirjo
    Kuehnel, Brigitte
    Leander, Karin
    Lee, Wen-Jane
    Lin, Keng-Hung
    Luan, Jian'an
    Lyytikainen, Leo-Pekka
    McKenzie, Colin A.
    Nelson, Christopher P.
    Noordam, Raymond
    Scott, Robert A.
    Sheu, Wayne H. H.
    Stancakova, Alena
    Takeuchi, Fumihiko
    van Der Most, Peter J.
    Varga, Tibor V.
    Waken, Robert J.
    Wang, Heming
    Wang, Yajuan
    Ware, Erin B.
    Weiss, Stefan
    Wen, Wanqing
    Yanek, Lisa R.
    Zhang, Weihua
    Zhao, Jing Hua
    Afaq, Saima
    Alfred, Tamuno
    Amin, Najaf
    Arking, Dan E.
    Aung, Tin
    Barr, R. Graham
    Bielak, Lawrence F.
    Boerwinkle, Eric
    Bottinger, Erwin P.
    Braund, Peter S.
    Brody, Jennifer A.
    Broeckel, Ulrich
    Cade, Brian
    Campbell, Archie
    Canouil, Mickael
    Chakravarti, Aravinda
    Cocca, Massimiliano
    Collins, Francis S.
    Connell, John M.
    de Mutsert, Renee
    de Silva, H. Janaka
    Doerr, Marcus
    Duan, Qing
    Eaton, Charles B.
    Ehret, Georg
    Evangelou, Evangelos
    Faul, Jessica D.
    Forouhi, Nita G.
    Franco, Oscar H.
    Friedlander, Yechiel
    Gao, He
    Gigante, Bruna
    Gu, C. Charles
    Gupta, Preeti
    Hagenaars, Saskia P.
    Harris, Tamara B.
    He, Jiang
    Heikkinen, Sami
    Heng, Chew-Kiat
    Hofman, Albert
    Howard, Barbara, V
    Hunt, Steven C.
    Irvin, Marguerite R.
    Jia, Yucheng
    Katsuya, Tomohiro
    Kaufman, Joel
    Kerrison, Nicola D.
    Khor, Chiea Chuen
    Koh, Woon-Puay
    Koistinen, Heikki A.
    Kooperberg, Charles B.
    Krieger, Jose E.
    Kubo, Michiaki
    Kutalik, Zoltan
    Kuusisto, Johanna
    Lakka, Timo A.
    Langefeld, Carl D.
    Langenberg, Claudia
    Launer, Lenore J.
    Lee, Joseph H.
    Lehne, Benjamin
    Levy, Daniel
    Lewis, Cora E.
    Li, Yize
    Lim, Sing Hui
    Liu, Ching-Ti
    Liu, Jianjun
    Liu, Jingmin
    Liu, Yeheng
    Loh, Marie
    Lohman, Kurt K.
    Louie, Tin
    Magi, Reedik
    Matsuda, Koichi
    Meitinger, Thomas
    Metspalu, Andres
    Milani, Lili
    Momozawa, Yukihide
    Mosley, Thomas H., Jr.
    Nalls, Mike A.
    Nasri, Ubaydah
    O'Connell, Jeff R.
    Ogunniyi, Adesola
    Palmas, Walter R.
    Palmer, Nicholette D.
    Pankow, James S.
    Pedersen, Nancy L.
    Peters, Annette
    Peyser, Patricia A.
    Polasek, Ozren
    Porteous, David
    Raitakari, Olli T.
    Renström, Frida
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, Skåne University Hospital, Malmö, Sweden.
    Rice, Treva K.
    Ridker, Paul M.
    Robino, Antonietta
    Robinson, Jennifer G.
    Rose, Lynda M.
    Rudan, Igor
    Sabanayagam, Charumathi
    Salako, Babatunde L.
    Sandow, Kevin
    Schmidt, Carsten O.
    Schreiner, Pamela J.
    Scott, William R.
    Sever, Peter
    Sims, Mario
    Sitlani, Colleen M.
    Smith, Blair H.
    Smith, Jennifer A.
    Snieder, Harold
    Starr, John M.
    Strauch, Konstantin
    Tang, Hua
    Taylor, Kent D.
    Teo, Yik Ying
    Tham, Yih Chung
    Uitterlinden, Andre G.
    Waldenberger, Melanie
    Wang, Lihua
    Wang, Ya Xing
    Wei, Wen Bin
    Wilson, Gregory
    Wojczynski, Mary K.
    Xiang, Yong-Bing
    Yao, Jie
    Yu, Caizheng
    Yuan, Jian-Min
    Zonderman, Alan B.
    Becker, Diane M.
    Boehnke, Michael
    Bowden, Donald W.
    Chambers, John C.
    Chen, Yii-Der Ida
    Weir, David R.
    de Faire, Ulf
    Deary, Ian J.
    Esko, Tonu
    Farrall, Martin
    Forrester, Terrence
    Freedman, Barry, I
    Froguel, Philippe
    Gasparini, Paolo
    Gieger, Christian
    Horta, Bernardo Lessa
    Hung, Yi-Jen
    Jonas, Jost Bruno
    Kato, Norihiro
    Kooner, Jaspal S.
    Laakso, Markku
    Lehtimaki, Terho
    Liang, Kae-Woei
    Magnusson, Patrik K. E.
    Oldehinkel, Albertine J.
    Pereira, Alexandre C.
    Perls, Thomas
    Rauramaa, Rainer
    Redline, Susan
    Rettig, Rainer
    Samani, Nilesh J.
    Scott, James
    Shu, Xiao-Ou
    van Der Harst, Pim
    Wagenknecht, Lynne E.
    Wareham, Nicholas J.
    Watkins, Hugh
    Wickremasinghe, Ananda R.
    Wu, Tangchun
    Kamatani, Yoichiro
    Laurie, Cathy C.
    Bouchard, Claude
    Cooper, Richard S.
    Evans, Michele K.
    Gudnason, Vilmundur
    Hixson, James
    Kardia, Sharon L. R.
    Kritchevsky, Stephen B.
    Psaty, Bruce M.
    van Dam, Rob M.
    Arnett, Donna K.
    Mook-Kanamori, Dennis O.
    Fornage, Myriam
    Fox, Ervin R.
    Hayward, Caroline
    van Duijn, Cornelia M.
    Tai, E. Shyong
    Wong, Tien Yin
    Loos, Ruth J. F.
    Reiner, Alex P.
    Rotimi, Charles N.
    Bierut, Laura J.
    Zhu, Xiaofeng
    Cupples, L. Adrienne
    Province, Michael A.
    Rotter, Jerome, I
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, Skåne University Hospital, Malmö, Sweden; Harvard T. H. Chan School of Public Health, Department of Nutrition, Harvard University, Boston, MA, USA.
    Rice, Kenneth
    Elliott, Paul
    Caulfield, Mark J.
    Gauderman, W. James
    Munroe, Patricia B.
    Rao, Dabeeru C.
    Morrison, Alanna C.
    A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure2019In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 28, no 15, p. 2615-2633Article in journal (Refereed)
    Abstract [en]

    Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene–smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene–smoking interaction analysis and 38 were newly identified (P < 5 × 10−8, false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings.

  • 231. Surendran, Praveen
    et al.
    Drenos, Fotios
    Young, Robin
    Warren, Helen
    Cook, James P.
    Manning, Alisa K.
    Grarup, Niels
    Sim, Xueling
    Barnes, Daniel R.
    Witkowska, Kate
    Staley, James R.
    Tragante, Vinicius
    Tukiainen, Taru
    Yaghootkar, Hanieh
    Masca, Nicholas
    Freitag, Daniel F.
    Ferreira, Teresa
    Giannakopoulou, Olga
    Tinker, Andrew
    Harakalova, Magdalena
    Mihailov, Evelin
    Liu, Chunyu
    Kraja, Aldi T.
    Nielsen, Sune Fallgaard
    Rasheed, Asif
    Samue, Maria
    Zhao, Wei
    Bonnycastle, Lori L.
    Jackson, Anne U.
    Narisu, Narisu
    Swift, Amy J.
    Southam, Lorraine
    Marten, Jonathan
    Huyghe, Jeroen R.
    Stancakova, Alena
    Fava, Cristiano
    Ohlsson, Therese
    Matchan, Angela
    Stirrups, Kathleen E.
    Bork-Jensen, Jette
    Gjesing, Anette P.
    Kontto, Jukka
    Perola, Markus
    Shaw-Hawkins, Susan
    Havulinna, Aki S.
    Zhang, He
    Donnelly, Louise A.
    Groves, Christopher J.
    Rayner, N. William
    Neville, Matt J.
    Robertson, Neil R.
    Yiorkas, Andrianos M.
    Herzig, Karl-Heinz
    Kajantie, Eero
    Zhang, Weihua
    Willems, Sara M.
    Lannfelt, Lars
    Malerba, Giovanni
    Soranzo, Nicole
    Trabetti, Elisabetta
    Verweij, Niek
    Evangelou, Evangelos
    Moayyeri, Alireza
    Vergnaud, Anne-Claire
    Nelson, Christopher P.
    Poveda, Alaitz
    Varga, Tibor V.
    Caslake, Muriel
    de Craen, Anton J. M.
    Trompet, Stella
    Luan, Jian'an
    Scott, Robert A.
    Harris, Sarah E.
    Liewald, David C. M.
    Marioni, Riccardo
    Menni, Cristina
    Farmaki, Aliki-Eleni
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Renström, Frida
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden.
    Huffman, Jennifer E.
    Hassinen, Maija
    Burgess, Stephen
    Vasan, Ramachandran S.
    Felix, Janine F.
    Uria-Nickelsen, Maria
    Malarstign, Anders
    Reilly, Dermot F.
    Hoek, Maarten
    Vogt, Thomas F.
    Lin, Honghuang
    Lieb, Wolfgang
    Traylor, Matthew
    Markus, Hugh S.
    Highland, Heather M.
    Justice, Anne E.
    Marouli, Eirini
    Lindstrom, Jaana
    Uusitupa, Matti
    Komulainen, Pirjo
    Lakka, Timo A.
    Rauramaa, Rainer
    Polasek, Ozren
    Rudan, Igor
    Rolandsson, Olov
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden; Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.
    Dedoussis, George
    Spector, Timothy D.
    Jousilahti, Pekka
    Mannisto, Satu
    Deary, Ian J.
    Starr, John M.
    Langenberg, Claudia
    Wareham, Nick J.
    Brown, Morris J.
    Dominiczak, Anna F.
    Connell, John M.
    Jukema, J. Wouter
    Sattar, Naveed
    Ford, Ian
    Packard, Chris J.
    Esko, Tonu
    Magi, Reedik
    Metspalu, Andres
    de Boer, Rudolf A.
    van der Meer, Peter
    van der Harst, Pim
    Gambaro, Giovanni
    Ingelsson, Erik
    Lind, Lars
    de Bakker, Paul I. W.
    Numans, Mattijs E.
    Brandslund, Ivan
    Christensen, Cramer
    Petersen, Eva R. B.
    Korpi-Hyovalti, Eeva
    Oksa, Heikki
    Chambers, John C.
    Kooner, Jaspal S.
    Blakemore, Alexandra I. F.
    Franks, Steve
    Jarvelin, Marjo-Riitta
    Husemoen, Lise L.
    Linneberg, Allan
    Skaaby, Tea
    Thuesen, Betina
    Karpe, Fredrik
    Tuomilehto, Jaakko
    Doney, Alex S. F.
    Morris, Andrew D.
    Palmer, Colin N. A.
    Holmen, Oddgeir Lingaas
    Hveem, Kristian
    Willer, Cristen J.
    Tuomi, Tiinamaija
    Groop, Leif
    Karajamaki, AnneMari
    Palotie, Aarno
    Ripatti, Samuli
    Salomaa, Veikko
    Alam, Dewan S.
    Majmnder, Abdulla Al Shafi
    Di Angelantonio, Emanuele
    Chowdhury, Rajiv
    McCarthy, Mark I.
    Poulter, Neil
    Stanton, Alice V.
    Sever, Peter
    Amouyel, Philippe
    Arveiler, Dominique
    Blankenberg, Stefan
    Ferrieres, Jean
    Kee, Frank
    Kuulasmaa, Kari
    Muller-Nurasyid, Martina
    Veronesi, Giovanni
    Virtamo, Jarmo
    Deloukas, Panos
    Elliott, Paul
    Zeggini, Eleftheria
    Kathiresan, Sekar
    Melander, Olle
    Kuusisto, Johanna
    Laakso, Markku
    Padmanabhan, Sandosh
    Porteous, David J.
    Hayward, Caroline
    Scotland, Generation
    Collins, Francis S.
    Mohlke, Karen L.
    Hansen, Torben
    Pedersen, Oluf
    Boehnke, Michael
    Stringham, Heather M.
    Frossard, Philippe
    Newton-Cheh, Christopher
    Tobin, Martin D.
    Nordestgaard, Borge Gronne
    Caulfield, Mark J.
    Mahajan, Anubha
    Morris, Andrew P.
    Tomaszewski, Maciej
    Samani, Nilesh J.
    Saleheen, Danish
    Asselbergs, Folkert W.
    Lindgren, Cecilia M.
    Danesh, John
    Wain, Louise V.
    Butterworth, Adam S.
    Howson, Joanna M. M.
    Munroe, Patricia B.
    Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension2016In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 48, no 10, p. 1151-1161Article in journal (Refereed)
    Abstract [en]

    High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low frequency and common genetic variants in up to 192,763 individuals and used similar to 155,063 samples for independent replication. We identified 30 new blood pressure- or hypertension-associated genetic regions in the general population, including 3 rare missense variants in RBM47, COL21A1 and RRAS with larger effects (>1.5 mm Hg/allele) than common variants. Multiple rare nonsense and missense variant associations were found in A2ML1, and a low-frequency nonsense variant in ENPEP was identified. Our data extend the spectrum of allelic variation underlying blood pressure traits and hypertension, provide new insights into the pathophysiology of hypertension and indicate new targets for clinical intervention.

  • 232.
    Söderberg, Stefan
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Eriksson, M.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Wennberg, Patrik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Weinehall, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Olsson, Tommy
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Jansson, Jan-Håkan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Leptin predicts independently a first-ever STEMI in men, data from a large prospective nested case-referent study2013Conference paper (Other academic)
    Abstract [en]

    Purpose: The adipocyte derived hormone leptin could be a mediator between obesity and increased risk for cardiovascular disease (CVD), asleptin has been linked to the atherosclerotic process. We hypothesised that leptin predicted independently a myocardial infarction (MI).

    Methods: A prospective nested case-referent study was set up within the framework of the Northern Sweden MONitoring of Trends and Determinants in CArdiovascular Diseases (MONICA) project, the Västerbotten Intervention Program (VIP), and the Mammary Screening Program (MSP). Subjects (n=564, 40% women) with a first-ever acute MI that had participated in one of these surveys prior to the MI were selected. Age, sex, survey and location matched referents (n=1082, 40% women) were selected within the surveys. Leptin was measured instored plasma. Conditional logistic regression was used to determine the risk for MI. Type of MI (STEMI and NSTEMI) was classified according to Minnesota codes.

    Results: The time period between survey and event was 3.9 years (interquartile range 3.6), and 51% of the cases had STEMI, 29% had NSTEMI, and 21% were unclassified. Male and female cases had higher levels of leptin (5.0 vs. 4.1 ng/mL, p<0.001 and 15.4 vs. 14.0 ng/mL, p=0.03), compared to referents. High leptin levels predicted MIindependently in men (OR 2.17 [1.32-3.54], ptrend<0.001), but not inwomen (OR 1.10 [0.55-2.18], ptrend=0.05). The risk related to leptin inmen was seen for STEMI in particular.

    Conclusions: High leptin predicts first–ever fatal and non–fatal MI, notably with a gender and MI-type difference. Leptin may affect theatherosclerotic process differentially in men and women and may promote plaque rupture and thrombus formation in larger coronary vessels.

  • 233.
    Söderström, Elisabet
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Eliasson, Mats
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Johnson, Owe
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Weinehall, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Jansson, Jan-Håkan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Plasma folate, but not homocysteine, is associated with Apolipoprotein A1 levels in a non-fortified population2013In: Lipids in Health and Disease, ISSN 1476-511X, E-ISSN 1476-511X, Vol. 12, p. 74-Article in journal (Refereed)
    Abstract [en]

    Background: Elevated total plasma homocysteine (tHcy) in humans is associated with cardiovascular disease but prevention trials have failed to confirm causality. Reported reasons for this association have been that homocysteine and its major genetic determinant methylenetetrahydrofolate reductase (MTHFR) may have an effect on HDL and Apolipoprotein (Apo) A1 levels. We wanted to study if tHcy and its major determinants were correlated with Apo A1 levels in a large population without folate fortification. Methods: This study was a prospective incident nested case-referent study within the Northern Sweden Health and Disease Study Cohort (NSHDSC), including 545 cases with first myocardial infarction and 1054 matched referents, median age at inclusion was 59 years. Univariate and multiple regression analyzes was used to study the associations between apolipoproteins Apo A1 and B, tHcy, folate and vitamin B12 in plasma as well as MTHFR polymorphisms 677C>T and 1298A>C. Results: Apo A1 and Apo B were strongly associated with the risk of a first myocardial infarction. tHcy was not associated with Apo A1 levels. Instead, folate had an independent positive association with Apo A1 levels in univariate and multiple regression models. The associations were seen in all men and women, among referents but not among cases. MTHFR polymorphisms had no clear effect on Apo A1 levels. Conclusions: Analyzing over 1500 subjects we found an independent positive association between plasma folate (major dietary determinant of tHcy) and Apo A1 levels among those who later did not develop a first myocardial infarction. No association was seen between tHcy and Apo A1.

  • 234. Tanaka, Toshiko
    et al.
    Ngwa, Julius S.
    van Rooij, Frank J. A.
    Zillikens, M. Carola
    Wojczynski, Mary K.
    Frazier-Wood, Alexis C.
    Houston, Denise K.
    Kanoni, Stavroula
    Lemaitre, Rozenn N.
    Luan, Jian'an
    Mikkila, Vera
    Renstrom, Frida
    Sonestedt, Emily
    Zhao, Jing Hua
    Chu, Audrey Y.
    Qi, Lu
    Chasman, Daniel I.
    Otto, Marcia C. de Oliveira
    Dhurandhar, Emily J.
    Feitosa, Mary F.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Khaw, Kay-Tee
    Lohman, Kurt K.
    Manichaikul, Ani
    McKeown, Nicola M.
    Mozaffarian, Dariush
    Singleton, Andrew
    Stirrups, Kathleen
    Viikari, Jorma
    Ye, Zheng
    Bandinelli, Stefania
    Barroso, Ines
    Deloukas, Panos
    Forouhi, Nita G.
    Hofman, Albert
    Liu, Yongmei
    Lyytikainen, Leo-Pekka
    North, Kari E.
    Dimitriou, Maria
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Kahonen, Mika
    Langenberg, Claudia
    Ordovas, Jose M.
    Uitterlinden, Andre G.
    Hu, Frank B.
    Kalafati, Ioanna-Panagiota
    Raitakari, Olli
    Franco, Oscar H.
    Johnson, Andrew
    Emilsson, Valur
    Schrack, Jennifer A.
    Semba, Richard D.
    Siscovick, David S.
    Arnett, Donna K.
    Borecki, Ingrid B.
    Franks, Paul
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Kritchevsky, Stephen B.
    Lehtimaki, Terho
    Loos, Ruth J. F.
    Orho-Melander, Marju
    Rotter, Jerome I.
    Wareham, Nicholas J.
    Witteman, Jacqueline C. M.
    Ferrucci, Luigi
    Dedoussis, George
    Cupples, L. Adrienne
    Nettleton, Jennifer A.
    Genome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake2013In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 97, no 6, p. 1395-1402Article in journal (Refereed)
    Abstract [en]

    Background: Macronutrient intake varies substantially between individuals, and there is evidence that this variation is partly accounted for by genetic variants.

    Objective: The objective of the study was to identify common genetic variants that are associated with macronutrient intake.

    Design: We performed 2-stage genome-wide association (GWA) meta-analysis of macronutrient intake in populations of European descent. Macronutrients were assessed by using food-frequency questionnaires and analyzed as percentages of total energy consumption from total fat, protein, and carbohydrate. From the discovery GWA (n = 38,360), 35 independent loci associated with macronutrient intake at P < 5 x 10(-6) were identified and taken forward to replication in 3 additional cohorts (n = 33,533) from the DietGen Consortium. For one locus, fat mass obesity-associated protein (FTO), cohorts with Illumina MetaboChip genotype data (n 7724) provided additional replication data.

    Results: A variant in the chromosome 19 locus (rs838145) was associated with higher carbohydrate (beta +/- SE: 0.25 +/- 0.04%; P = 1.68 x 10(-8)) and lower fat (beta = SE: -0.21 +/- 0.04%; P = 1.57 x 10(-9)) consumption. A candidate gene in this region, fibroblast growth factor 21 (FGF21), encodes a fibroblast growth factor involved in glucose and lipid metabolism. The variants in this locus were associated with circulating FGF21 protein concentrations (P < 0.05) but not mRNA concentrations in blood or brain. The body mass index (BMI) increasing allele of the FTO variant (rs1421085) was associated with higher protein intake (beta +/- SE: 0.10 +/- 0.02%; P = 9.96 x 10(-10)), independent of BMI (after adjustment for BMI, beta +/- SE: 0.08 +/- 0.02%; P = 3.15 x 10(-7)).

    Conclusion: Our results indicate that variants in genes involved in nutrient metabolism and obesity are associated with macronutrient consumption in humans. Trials related to this study were registered at clinicaltrials.gov as NCT00005131 (Atherosclerosis Risk in Communities), NCT00005133 (Cardiovascular Health Study), NCT00005136 (Family Heart Study), NCT00005121 (Framingham Heart Study), NCT00083369 (Genetic and Environmental Determinants of Triglycerides), NCT01331512 (InCHIANTI Study), and NCT00005487 (Multi-Ethnic Study of Atherosclerosis).

  • 235. Teleka, Stanley
    et al.
    Häggström, Christel
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden; .
    Nagel, Gabriele
    Bjorge, Tone
    Manjer, Jonas
    Ulmer, Hanno
    Liedberg, Fredrik
    Ghaderi, Sara
    Lang, Alois
    Jonsson, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Jahnson, Staffan
    Orho-Melander, Marju
    Tretli, Steinar
    Stattin, Pär
    Stocks, Tanja
    Risk of bladder cancer by disease severity in relation to metabolic factors and smoking: a prospective pooled cohort study of 800,000 men and women2018In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 143, no 12, p. 3071-3082Article in journal (Refereed)
    Abstract [en]

    Previous studies on metabolic factors and bladder cancer (BC) risk have shown inconsistent results and have commonly not investigated associations separately by sex, smoking, and tumor invasiveness. Among 811,633 participants in six European cohorts, we investigated sex‐specific associations between body mass index (BMI), mid‐blood pressure (BP, [systolic + diastolic]/2), plasma glucose, triglycerides, total cholesterol and risk of BC overall, non‐muscle invasive BC (NMIBC) and muscle invasive BC (MIBC). Among men, we additionally assessed additive interactions between metabolic factors and smoking on BC risk. During follow‐up, 2,983 men and 754 women were diagnosed with BC. Among men, triglycerides and BP were positively associated with BC risk overall (hazard ratio [HR] per standard deviation [SD]: 1.17 [95% confidence interval (CI) 1.06–1.27] and 1.09 [1.02–1.17], respectively), and among women, BMI was inversely associated with risk (HR: 0.90 [0.82–0.99]). The associations for BMI and BP differed between men and women (pinteraction ≤ 0.005). Among men, BMI, cholesterol and triglycerides were positively associated with risk for NMIBC (HRs: 1.09 [95% CI 1.01–1.18], 1.14 [1.02–1.25], and 1.30 [1.12–1.48] respectively), and BP was positively associated with MIBC (HR: 1.23 [1.02–1.49]). Among women, glucose was positively associated with MIBC (HR: 1.99 [1.04–3.81]). Apart from cholesterol, HRs for metabolic factors did not significantly differ between MIBC and NMIBC, and there were no interactions between smoking and metabolic factors on BC. Our study supports an involvement of metabolic aberrations in BC risk. Whilst some associations were significant only in certain sub‐groups, there were generally no significant differences in associations by smoking or tumor invasiveness.

  • 236. Thomas, Hanna S.
    et al.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Andersson, Linda
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Gunnarsson, Ulf
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Blanco, R.
    Pooled analysis of WHO Surgical Safety Checklist use and mortality after emergency laparotomy2019In: British Journal of Surgery, ISSN 0007-1323, E-ISSN 1365-2168, Vol. 106, no 2, p. E103-E112Article in journal (Refereed)
    Abstract [en]

    Background: The World Health Organization (WHO) Surgical Safety Checklist has fostered safe practice for 10 years, yet its place in emergency surgery has not been assessed on a global scale. The aim of this study was to evaluate reported checklist use in emergency settings and examine the relationship with perioperative mortality in patients who had emergency laparotomy.

    Methods: In two multinational cohort studies, adults undergoing emergency laparotomy were compared with those having elective gastrointestinal surgery. Relationships between reported checklist use and mortality were determined using multivariable logistic regression and bootstrapped simulation.

    Results: Of 12 296 patients included from 76 countries, 4843 underwent emergency laparotomy. After adjusting for patient and disease factors, checklist use before emergency laparotomy was more common in countries with a high Human Development Index (HDI) (2455 of 2741, 89⋅6 per cent) compared with that in countries with a middle (753 of 1242, 60⋅6 per cent; odds ratio (OR) 0⋅17, 95 per cent c.i. 0⋅14 to 0⋅21, P < 0⋅001) or low (363 of 860, 42⋅2 per cent; OR 0⋅08, 0⋅07 to 0⋅10, P < 0⋅001) HDI. Checklist use was less common in elective surgery than for emergency laparotomy in high-HDI countries (risk difference −9⋅4 (95 per cent c.i. −11⋅9 to −6⋅9) per cent; P < 0⋅001), but the relationship was reversed in low-HDI countries (+12⋅1 (+7⋅0 to +17⋅3) per cent; P < 0⋅001). In multivariable models, checklist use was associated with a lower 30-day perioperative mortality (OR 0⋅60, 0⋅50 to 0⋅73; P < 0⋅001). The greatest absolute benefit was seen for emergency surgery in low- and middle-HDI countries.

    Conclusion: Checklist use in emergency laparotomy was associated with a significantly lower perioperative mortality rate. Checklist use in low-HDI countries was half that in high-HDI countries.

  • 237. Tognon, Gianluca
    et al.
    Nilsson, Lena Maria
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Lissner, Lauren
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology, Cariology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Lindahl, Bernt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Winkvist, Anna
    The Mediterranean Diet Score and Mortality Are Inversely Associated in Adults Living in the Subarctic Region2012In: Journal of Nutrition, ISSN 0022-3166, E-ISSN 1541-6100, Vol. 142, no 8, p. 1547-1553Article in journal (Refereed)
    Abstract [en]

    The Mediterranean diet has been widely promoted and may be associated with chronic disease prevention and a better overall health status. The aim of this study was to evaluate whether the Mediterranean diet score inversely predicted total or cause-specific mortality in a prospective population study in Northern Sweden (Vasterbotten Intervention Program). The analyses were performed in 77,151 participants (whose diet was measured by means of a validated FFQ) by Cox proportional hazard models adjusted for several potential confounders. The Mediterranean diet score was inversely associated with all-cause mortality in men [HR = 0.96(95% Cl = 0.93, 0.99)] and women [HR = 0.95 (95% Cl = 0.91, 0.99)], although not in obese men. In men, but not in women, the score was inversely associated with total cancer mortality [HR = 0.92 (95% Cl = 0.87, 0.98)], particularly for pancreas cancer [HR = 0.82 (95% Cl = 0.68, 0.99)]. Cardiovascular mortality was inversely associated with diet only in women [HR = 0.90(95% Cl = 0.82, 0.99)]. Except for alcohol [HR = 0.83(95% Cl = 0.76, 0.90)] and fruit intake [HR = 0.90 (95% Cl = 0.83, 0.98)], no food item of the Mediterranean diet score independently predicted mortality. Higher scores were associated with increasing age, education, and physical activity. Moreover, healthful dietary and lifestyle-related factors additively decreased the mortality likelihood. Even in a subarctic region, increasing Mediterranean diet scores were associated with a longer life, although the protective effect of diet was of small magnitude compared with other healthful dietary and lifestyle-related factors examined.

  • 238. Tolstrup, Janne S
    et al.
    Hvidtfeldt, Ulla A
    Flachs, Esben Meulengracht
    Spiegelman, Donna
    Heitmann, Berit L
    Bälter, Katarina
    Goldbourt, Uri
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Knekt, Paul
    Liu, Simin
    Pereira, Mark
    Stevens, June
    Virtamo, Jarmo
    Feskanich, Diane
    Smoking and risk of coronary heart disease in younger, middle-aged, and older adults2014In: American Journal of Public Health, ISSN 0090-0036, E-ISSN 1541-0048, Vol. 104, no 1, p. 96-102Article in journal (Refereed)
    Abstract [en]

    Objectives. We investigated associations of smoking and coronary heart disease (CHD) by age. Methods. Data came from the Pooling Project on Diet and Coronary Heart Disease (8 prospective studies, 1974-1996; n = 192 067 women and 74 720 men, aged 40-89 years). Results. During follow-up, 4326 cases of CHD were reported. Relative to never smokers, CHD risk among current smokers was highest in the youngest and lowest in the oldest participants. For example, among women aged 40 to 49 years the hazard ratio was 8.5 (95% confidence interval [CI] = 5.0, 14) and 3.1 (95% CI = 2.0, 4.9) among those aged 70 years or older. The largest absolute risk differences between current smokers and never smokers were observed among the oldest participants. Finally, the majority of CHD cases among smokers were attributable to smoking. For example, attributable proportions of CHD by age group were 88% (40-49 years), 81% (50-59 years), 71% for (60-69 years), and 68% (70+ years) among women who smoked. Conclusions. Among smokers, the majority of CHD cases are attributable to smoking in all age groups. Smoking prevention is important, irrespective of age.

  • 239.
    Tomic, Katarina
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Ventimiglia, Eugenio
    Division of Experimental Oncology/Unit of Urology, URI; IRCCS Ospedale San Raffaele, Milan, Italy.
    Robinson, David
    Department of Urology, Ryhov Hospital, Jönköping, Sweden .
    Häggström, Christel
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Surgical Sciences, Uppsala University Hospital, Uppsala, Sweden.
    Lambe, Mats
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Regional Cancer Centre Uppsala Örebro, Uppsala University Hospital, Uppsala, Sweden.
    Stattin, Pär
    Department of Surgical Sciences, Uppsala University Hospital, Uppsala, Sweden.
    Socioeconomic status and diagnosis, treatment, and mortality in men with prostate cancer. Nationwide population-based study2018In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 142, no 12, p. 2478-2484Article in journal (Refereed)
    Abstract [en]

    Patients with high socioeconomic status (SES) have better cancer outcomes than patients with low SES. This has also been shown in Sweden, a country with tax-financed health care aiming to provide care on equal terms to all residents. The association between income and educational level and diagnostics and treatment as outlined in national guidelines and prostate cancer (Pca) and all-cause mortality was assessed in 74,643 men by use of data in the National Prostate Cancer Register of Sweden and a number of other health care registers and demographic databases. In multivariable logistic regression analysis, men with high income had higher probability of Pca detected in a health-check-up, top versus bottom income quartile, odds ratio (OR) 1.60 (95% CI 1.45-1.77) and lower probability of waiting more than 3 months for prostatectomy, OR 0.77 (0.69-0.86). Men with the highest incomes also had higher probability of curative treatment for intermediate and high-risk cancer, OR 1.77 (1.61-1.95) and lower risk of positive margins, (incomplete resection) at prostatectomy, OR 0.80 (0.71-0.90). Similar, but weaker associations were observed for educational level. At 6 years of follow-up, Pca mortality was modestly lower for men with high income, which was statistically significant for localized high-risk and metastatic Pca in men with no comorbidities. All-cause mortality was less than half in top versus bottom quartile of income (12% vs. 30%, p < 0.001) among men above age 65. Our findings underscore the importance of adherence to guidelines to ensure optimal and equal care for all patients diagnosed with cancer.

  • 240. Tsilidis, Konstantinos K.
    et al.
    Allen, Naomi E.
    Appleby, Paul N.
    Rohrmann, Sabine
    Nöthlings, Ute
    Arriola, Larraitz
    Gunter, Marc J.
    Chajes, Veronique
    Rinaldi, Sabina
    Romieu, Isabelle
    Murphy, Neil
    Riboli, Elio
    Tzoulaki, Ioanna
    Kaaks, Rudolf
    Lukanova, Annekatrin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Department of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.
    Boeing, Heiner
    Pischon, Tobias
    Dahm, Christina C.
    Overvad, Kim
    Quirós, J. Ramón
    Fonseca-Nunes, Ana
    Molina-Montes, Esther
    Gavrila Chervase, Diana
    Ardanaz, Eva
    Khaw, Kay T.
    Wareham, Nick J.
    Roswall, Nina
    Tjønneland, Anne
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Trichopoulou, Antonia
    Palli, Domenico
    Pala, Valeria
    Tumino, Rosario
    Vineis, Paolo
    Bueno-de-Mesquita, H. B(as)
    Malm, Johan
    Orho-Melander, Marju
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Biobank Research. International Agency for Research on Cancer, Lyon, France.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Travis, Ruth C.
    Key, Timothy J.
    Diabetes mellitus and risk of prostate cancer in the European Prospective Investigation into Cancer and Nutrition2015In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 136, no 2, p. 372-381Article in journal (Refereed)
    Abstract [en]

    The current epidemiologic evidence suggests that men with type 2 diabetes mellitus may be at lower risk of developing prostate cancer, but little is known about its association with stage and grade of the disease. The association between self-reported diabetes mellitus at recruitment and risk of prostate cancer was examined in the European Prospective Investigation into Cancer and Nutrition (EPIC). Among 139,131 eligible men, 4,531 were diagnosed with prostate cancer over an average follow-up of 12 years. Multivariable hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards models stratified by EPIC-participating center and age at recruitment, and adjusted for education, smoking status, body mass index, waist circumference, and physical activity. In a subset of men without prostate cancer, the cross-sectional association between circulating concentrations of androgens and insulin-like growth factor proteins with diabetes status was also investigated using linear regression models. Compared to men with no diabetes, men with diabetes had a 26% lower risk of prostate cancer (HR, 0.74; 95% CI, 0.63-0.86). There was no evidence that the association differed by stage (p-heterogeneity, 0.19) or grade (p-heterogeneity, 0.48) of the disease, although the numbers were small in some disease subgroups. In a subset of 626 men with hormone measurements, circulating concentrations of androstenedione, total testosterone and insulin-like growth factor binding protein-three were lower in men with diabetes compared to men without diabetes. This large European study has confirmed an inverse association between self-reported diabetes mellitus and subsequent risk of prostate cancer.

    What's new? Emerging evidence suggests that men with type 2 diabetes are at lower risk to develop prostate cancer. Using data obtained within the European Prospective Investigation into Cancer and Nutrition (EPIC), the authors show that the prostate cancer risk was, indeed, reduced by 26% in men with type 2 diabetes but no association with cancer stage or grade was observed. In a subset of men for whom data on circulating hormones were available, levels of androstenedione, total testosterone and insulin-like growth factor binding protein-three were lower in those with diabetes as compared to those without diabetes, giving clues to how having diabetes could affect prostate cancer development.

  • 241. Tsilidis, Konstantinos K
    et al.
    Papadimitriou, Nikos
    Capothanassi, Despoina
    Bamia, Christina
    Benetou, Vassiliki
    Jenab, Mazda
    Freisling, Heinz
    Kee, Frank
    Nelen, Annemarie
    O'Doherty, Mark G
    Scott, Angela
    Soerjomataram, Isabelle
    Tjønneland, Anne
    May, Anne M
    Ramón Quirós, J
    Pettersson-Kymmer, Ulrika
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Brenner, Hermann
    Schöttker, Ben
    Ordóñez-Mena, José M
    Karina Dieffenbach, Aida
    Eriksson, Sture
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Bøgeberg Mathiesen, Ellisiv
    Njølstad, Inger
    Siganos, Galatios
    Wilsgaard, Tom
    Boffetta, Paolo
    Trichopoulos, Dimitrios
    Trichopoulou, Antonia
    Burden of Cancer in a Large Consortium of Prospective Cohorts in Europe2016In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 108, no 10, article id djw127Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Disability-adjusted life-years (DALYs) are an indicator of mortality, morbidity, and disability. We calculated DALYs for cancer in middle-aged and older adults participating in the Consortium on Health and Ageing Network of Cohorts in Europe and the United States (CHANCES) consortium.

    METHODS: A total of 90 199 participants from five European cohorts with 10 455 incident cancers and 4399 deaths were included in this study. DALYs were calculated as the sum of the years of life lost because of premature mortality (YLLs) and the years lost because of disability (YLDs). Population-attributable fractions (PAFs) were also estimated for five cancer risk factors, ie, smoking, adiposity, physical inactivity, alcohol intake, and type II diabetes.

    RESULTS: After a median follow-up of 12 years, the total number of DALYs lost from cancer was 34 474 (382 per 1000 individuals) with a similar distribution by sex. Lung cancer was responsible for the largest number of lost DALYs (22.9%), followed by colorectal (15.3%), prostate (10.2%), and breast cancer (8.7%). Mortality (81.6% of DALYs) predominated over disability. Ever cigarette smoking was the risk factor responsible for the greatest total cancer burden (24.0%, 95% confidence interval [CI] = 22.2% to 26.0%), followed by physical inactivity (4.9%, 95% CI = 0.8% to 8.1%) and adiposity (1.8%, 95% CI = 0.2% to 2.8%).

    CONCLUSIONS: DALYs lost from cancer were substantial in this large European sample of middle-aged and older adults. Even if the burden of disease because of cancer is predominantly caused by mortality, some cancers have sizeable consequences for disability. Smoking remained the predominant risk factor for total cancer burden.

  • 242. Turcot, Valerie
    et al.
    Lu, Yingchang
    Highland, Heather M.
    Schurmann, Claudia
    Justice, Anne E.
    Fine, Rebecca S.
    Bradfield, Jonathan P.
    Esko, Tonu
    Giri, Ayush
    Graff, Mariaelisa
    Guo, Xiuqing
    Hendricks, Audrey E.
    Karaderi, Tugce
    Lempradl, Adelheid
    Locke, Adam E.
    Mahajan, Anubha
    Marouli, Eirini
    Sivapalaratnam, Suthesh
    Young, Kristin L.
    Alfred, Tamuno
    Feitosa, Mary F.
    Masca, Nicholas G. D.
    Manning, Alisa K.
    Medina-Gomez, Carolina
    Mudgal, Poorva
    Ng, Maggie C. Y.
    Reiner, Alex P.
    Vedantam, Sailaja
    Willems, Sara M.
    Winkler, Thomas W.
    Abecasis, Goncalo
    Aben, Katja K.
    Alam, Dewan S.
    Alharthi, Sameer E.
    Allison, Matthew
    Amouyel, Philippe
    Asselbergs, Folkert W.
    Auer, Paul L.
    Balkau, Beverley
    Bang, Lia E.
    Barroso, Ines
    Bastarache, Lisa
    Benn, Marianne
    Bergmann, Sven
    Bielak, Lawrence F.
    Blueher, Matthias
    Boehnke, Michael
    Boeing, Heiner
    Boerwinkle, Eric
    Boeger, Carsten A.
    Bork-Jensen, Jette
    Bots, Michiel L.
    Bottinger, Erwin P.
    Bowden, Donald W.
    Brandslund, Ivan
    Breen, Gerome
    Brilliant, Murray H.
    Broer, Linda
    Brumat, Marco
    Burt, Amber A.
    Butterworth, Adam S.
    Campbell, Peter T.
    Cappellani, Stefania
    Carey, David J.
    Catamo, Eulalia
    Caulfield, Mark J.
    Chambers, John C.
    Chasman, Daniel I.
    Chen, Yii-Der I.
    Chowdhury, Rajiv
    Christensen, Cramer
    Chu, Audrey Y.
    Cocca, Massimiliano
    Collins, Francis S.
    Cook, James P.
    Corley, Janie
    Galbany, Jordi Corominas
    Cox, Amanda J.
    Crosslin, David S.
    Cuellar-Partida, Gabriel
    D'Eustacchio, Angela
    Danesh, John
    Davies, Gail
    Bakker, Paul I. W.
    Groot, Mark C. H.
    Mutsert, Renee
    Deary, Ian J.
    Dedoussis, George
    Demerath, Ellen W.
    Heijer, Martin
    Hollander, Anneke I.
    Ruijter, Hester M.
    Dennis, Joe G.
    Denny, Josh C.
    Angelantonio, Emanuele
    Drenos, Fotios
    Du, Mengmeng
    Dube, Marie-Pierre
    Dunning, Alison M.
    Easton, Douglas F.
    Edwards, Todd L.
    Ellinghaus, David
    Ellinor, Patrick T.
    Elliott, Paul
    Evangelou, Evangelos
    Farmaki, Aliki-Eleni
    Farooqi, I. Sadaf
    Faul, Jessica D.
    Fauser, Sascha
    Feng, Shuang
    Ferrannini, Ele
    Ferrieres, Jean
    Florez, Jose C.
    Ford, Ian
    Fornage, Myriam
    Franco, Oscar H.
    Franke, Andre
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden; Department of Nutrition, Harvard School of Public Health, Boston, MA, USA.
    Friedrich, Nele
    Frikke-Schmidt, Ruth
    Galesloot, Tessel E.
    Gan, Wei
    Gandin, Ilaria
    Gasparini, Paolo
    Gibson, Jane
    Giedraitis, Vilmantas
    Gjesing, Anette P.
    Gordon-Larsen, Penny
    Gorski, Mathias
    Grabe, Hans-Joergen
    Grant, Struan F. A.
    Grarup, Niels
    Griffiths, Helen L.
    Grove, Megan L.
    Gudnason, Vilmundur
    Gustafsson, Stefan
    Haessler, Jeff
    Hakonarson, Hakon
    Hammerschlag, Anke R.
    Hansen, Torben
    Harris, Kathleen Mullan
    Harris, Tamara B.
    Hattersley, Andrew T.
    Have, Christian T.
    Hayward, Caroline
    He, Liang
    Heard-Costa, Nancy L.
    Heath, Andrew C.
    Heid, Iris M.
    Helgeland, Oyvind
    Hernesniemi, Jussi
    Hewitt, Alex W.
    Holmen, Oddgeir L.
    Hovingh, G. Kees
    Howson, Joanna M. M.
    Hu, Yao
    Huang, Paul L.
    Huffman, Jennifer E.
    Ikram, M. Arfan
    Ingelsson, Erik
    Jackson, Anne U.
    Jansson, Jan-Håkan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine. Research Unit Skellefteå, Skellefteå, Sweden.
    Jarvik, Gail P.
    Jensen, Gorm B.
    Jia, Yucheng
    Johansson, Stefan
    Jorgensen, Marit E.
    Jorgensen, Torben
    Jukema, J. Wouter
    Kahali, Bratati
    Kahn, Rene S.
    Kahonen, Mika
    Kamstrup, Pia R.
    Kanoni, Stavroula
    Kaprio, Jaakko
    Karaleftheri, Maria
    Kardia, Sharon L. R.
    Karpe, Fredrik
    Kathiresan, Sekar
    Kee, Frank
    Kiemeney, Lambertus A.
    Kim, Eric
    Kitajima, Hidetoshi
    Komulainen, Pirjo
    Kooner, Jaspal S.
    Kooperberg, Charles
    Korhonen, Tellervo
    Kovacs, Peter
    Kuivaniemi, Helena
    Kutalik, Zoltan
    Kuulasmaa, Kari
    Kuusisto, Johanna
    Laakso, Markku
    Lakka, Timo A.
    Lamparter, David
    Lange, Ethan M.
    Lange, Leslie A.
    Langenberg, Claudia
    Larson, Eric B.
    Lee, Nanette R.
    Lehtimaki, Terho
    Lewis, Cora E.
    Li, Huaixing
    Li, Jin
    Li-Gao, Ruifang
    Lin, Honghuang
    Lin, Keng-Hung
    Lin, Li-An
    Lin, Xu
    Lind, Lars
    Lindstrom, Jaana
    Linneberg, Allan
    Liu, Ching-Ti
    Liu, Dajiang J.
    Liu, Yongmei
    Lo, Ken S.
    Lophatananon, Artitaya
    Lotery, Andrew J.
    Loukola, Anu
    Luan, Jian'an
    Lubitz, Steven A.
    Lyytikainen, Leo-Pekka
    Mannisto, Satu
    Marenne, Gaelle
    Mazul, Angela L.
    McCarthy, Mark I.
    McKean-Cowdin, Roberta
    Medland, Sarah E.
    Meidtner, Karina
    Milani, Lili
    Mistry, Vanisha
    Mitchell, Paul
    Mohlke, Karen L.
    Moilanen, Leena
    Moitry, Marie
    Montgomery, Grant W.
    Mook-Kanamori, Dennis O.
    Moore, Carmel
    Mori, Trevor A.
    Morris, Andrew D.
    Morris, Andrew P.
    Mueller-Nurasyid, Martina
    Munroe, Patricia B.
    Nalls, Mike A.
    Narisu, Narisu
    Nelson, Christopher P.
    Neville, Matt
    Nielsen, Sune F.
    Nikus, Kjell
    Njolstad, Pal R.
    Nordestgaard, Borge G.
    Nyholt, Dale R.
    O'Connel, Jeffrey R.
    O'Donoghue, Michelle L.
    Loohuis, Loes M. Olde
    Ophoff, Roel A.
    Owen, Katharine R.
    Packard, Chris J.
    Padmanabhan, Sandosh
    Palmer, Colin N. A.
    Palmer, Nicholette D.
    Pasterkamp, Gerard
    Patel, Aniruddh P.
    Pattie, Alison
    Pedersen, Oluf
    Peissig, Peggy L.
    Peloso, Gina M.
    Pennell, Craig E.
    Perola, Markus
    Perry, James A.
    Perry, John R. B.
    Pers, Tune H.
    Person, Thomas N.
    Peters, Annette
    Petersen, Eva R. B.
    Peyser, Patricia A.
    Pirie, Ailith
    Polasek, Ozren
    Polderman, Tinca J.
    Puolijoki, Hannu
    Raitakari, Olli T.
    Rasheed, Asif
    Rauramaa, Rainer
    Reilly, Dermot F.
    Renström, Frida
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden.
    Rheinberger, Myriam
    Ridker, Paul M.
    Rioux, John D.
    Rivas, Manuel A.
    Roberts, David J.
    Robertson, Neil R.
    Robino, Antonietta
    Rolandsson, Olov
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Rudan, Igor
    Ruth, Katherine S.
    Saleheen, Danish
    Salomaa, Veikko
    Samani, Nilesh J.
    Sapkota, Yadav
    Sattar, Naveed
    Schoen, Robert E.
    Schreiner, Pamela J.
    Schulze, Matthias B.
    Scott, Robert A.
    Segura-Lepe, Marcelo P.
    Shah, Svati H.
    Sheu, Wayne H. -H.
    Sim, Xueling
    Slater, Andrew J.
    Small, Kerrin S.
    Smith, Albert V.
    Southam, Lorraine
    Spector, Timothy D.
    Speliotes, Elizabeth K.
    Starr, John M.
    Stefansson, Kari
    Steinthorsdottir, Valgerdur
    Stirrups, Kathleen E.
    Strauch, Konstantin
    Stringham, Heather M.
    Stumvoll, Michael
    Sun, Liang
    Surendran, Praveen
    Swift, Amy J.
    Tada, Hayato
    Tansey, Katherine E.
    Tardif, Jean-Claude
    Taylor, Kent D.
    Teumer, Alexander
    Thompson, Deborah J.
    Thorleifsson, Gudmar
    Thorsteinsdottir, Unnur
    Thuesen, Betina H.
    Toenjes, Anke
    Tromp, Gerard
    Trompet, Stella
    Tsafantakis, Emmanouil
    Tuomilehto, Jaakko
    Tybjaerg-Hansen, Anne
    Tyrer, Jonathan P.
    Uher, Rudolf
    Uitterlinden, Andre G.
    Uusitupa, Matti
    Laan, Sander W.
    Duijn, Cornelia M.
    Leeuwen, Nienke
    van Setten, Jessica
    Vanhala, Mauno
    Varbo, Anette
    Varga, Tibor V.
    Varma, Rohit
    Edwards, Digna R. Velez
    Vermeulen, Sita H.
    Veronesi, Giovanni
    Vestergaard, Henrik
    Vitart, Veronique
    Vogt, Thomas F.
    Voelker, Uwe
    Vuckovic, Dragana
    Wagenknecht, Lynne E.
    Walker, Mark
    Wallentin, Lars
    Wang, Feijie
    Wang, Carol A.
    Wang, Shuai
    Wang, Yiqin
    Ware, Erin B.
    Wareham, Nicholas J.
    Warren, Helen R.
    Waterworth, Dawn M.
    Wessel, Jennifer
    White, Harvey D.
    Willer, Cristen J.
    Wilson, James G.
    Witte, Daniel R.
    Wood, Andrew R.
    Wu, Ying
    Yaghootkar, Hanieh
    Yao, Jie
    Yao, Pang
    Yerges-Armstrong, Laura M.
    Young, Robin
    Zeggini, Eleftheria
    Zhan, Xiaowei
    Zhang, Weihua
    Zhao, Jing Hua
    Zhao, Wei
    Zhou, Wei
    Zondervan, Krina T.
    Rotter, Jerome I.
    Pospisilik, John A.
    Rivadeneira, Fernando
    Borecki, Ingrid B.
    Deloukas, Panos
    Frayling, Timothy M.
    Lettre, Guillaume
    North, Kari E.
    Lindgren, Cecilia M.
    Hirschhorn, Joel N.
    Loos, Ruth J. F.
    Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity2018In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 50, no 1, p. 26-41Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are similar to 10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed similar to 7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.

  • 243. van Duijnhoven, Fraenzel J. B.
    et al.
    Jenab, Mazda
    Hveem, Kristian
    Siersema, Peter D.
    Fedirko, Veronika
    Duell, Eric J.
    Kampman, Ellen
    Halfweeg, Anouk
    van Kranen, Henk J.
    van den Ouweland, Jody M. W.
    Weiderpass, Elisabete
    Murphy, Neil
    Langhammer, Arnulf
    Ness-Jensen, Eivind
    Olsen, Anja
    Tjonneland, Anne
    Overvad, Kim
    Cadeau, Claire
    Kvaskoff, Marina
    Boutron-Ruault, Marie-Christine
    Katzke, Verena A.
    Kuehn, Tilman
    Boeing, Heiner
    Trichopoulou, Antonia
    Kotanidou, Anastasia
    Kritikou, Maria
    Palli, Domenico
    Agnoli, Claudia
    Tumino, Rosario
    Panico, Salvatore
    Matullo, Giuseppe
    Peeters, Petra
    Brustad, Magritt
    Olsen, Karina Standahl
    Lasheras, Cristina
    Obon-Santacana, Mireia
    Sanchez, Maria-Jose
    Dorronsoro, Miren
    Chirlaque, Maria-Dolores
    Barricarte, Aurelio
    Manjer, Jonas
    Almquist, Martin
    Renström, Frida
    Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden.
    Ye, Weimin
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Swede.
    Wareham, Nick
    Khaw, Kay-Tee
    Bradbury, Kathryn E.
    Freisling, Heinz
    Aune, Dagfinn
    Norat, Teresa
    Riboli, Elio
    Bueno-de-Mesquita, H. B(as)
    Circulating concentrations of vitamin D in relation to pancreatic cancer risk in European populations2018In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 142, no 6, p. 1189-1201Article in journal (Refereed)
    Abstract [en]

    Evidence from in vivo, in vitro and ecological studies are suggestive of a protective effect of vitamin D against pancreatic cancer (PC). However, this has not been confirmed by analytical epidemiological studies. We aimed to examine the association between pre-diagnostic circulating vitamin D concentrations and PC incidence in European populations. We conducted a pooled nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) and the Nord-TrOndelag Health Study's second survey (HUNT2) cohorts. In total, 738 primary incident PC cases (EPIC n=626; HUNT2 n=112; median follow-up=6.9 years) were matched to 738 controls. Vitamin D [25(OH)D-2 and 25(OH)D-3 combined] concentrations were determined using isotope-dilution liquid chromatography-tandem mass spectrometry. Conditional logistic regression models with adjustments for body mass index and smoking habits were used to estimate incidence rate ratios (IRRs) and 95% confidence intervals (95%CI). Compared with a reference category of >50 to 75 nmol/L vitamin D, the IRRs (95% CIs) were 0.71 (0.42-1.20); 0.94 (0.72-1.22); 1.12 (0.82-1.53) and 1.26 (0.79-2.01) for clinically pre-defined categories of 25; >25 to 50; >75 to 100; and >100 nmol/L vitamin D, respectively (p for trend=0.09). Corresponding analyses by quintiles of season-standardized vitamin D concentrations also did not reveal associations with PC risk (p for trend=0.23). Although these findings among participants from the largest combination of European cohort studies to date show increasing effect estimates of PC risk with increasing pre-diagnostic concentrations of vitamin D, they are not statistically significant.

  • 244. Van Hemelrijck, Mieke
    et al.
    Ulmer, Hanno
    Nagel, Gabriele
    Peter, Raphael Simon
    Fritz, Josef
    Myte, Robin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Föger, Bernhard
    Concin, Hans
    Häggström, Christel
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Uppsala University, Department of Surgical Sciences, Uppsala, Sweden.
    Stattin, Pär
    Uppsala University, Department of Surgical Sciences, Uppsala, Sweden.
    Stocks, Tanja
    Longitudinal study of body mass index, dyslipidemia, hyperglycemia, and hypertension in 60,000 men and women in Sweden and Austria2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 6, article id e0197830Article in journal (Refereed)
    Abstract [en]

    Background: Obesity is suggested to underlie development of other metabolic aberrations, but longitudinal relationships between metabolic factors at various ages has not been studied in detail. Methods: Data from 27,379 men and 32,275 women with in total 122,940 health examinations in the Västerbotten Intervention Project, Sweden and the Vorarlberg Health Monitoring and Prevention Programme, Austria were used to investigate body mass index (BMI), mid-blood pressure, and fasting levels of glucose, triglycerides, and total cholesterol at baseline in relation to 10-year changes of these factors and weight. We included paired examinations performed 10 +/- 2 years apart and used them for longitudinal analysis with linear regression of changes between the ages 30 and 40, 40 and 50, or 50 and 60 years. Results: Higher levels of BMI were associated with increases in glucose and mid-blood pressure as well as triglycerides levels, and, to a lesser extent, decreases in cholesterol levels. For instance, per 5 kg/m(2) higher BMI at age 40, glucose at age 50 increased by 0.24 mmol/l (95%Cl:0.22-0.26) and mid-blood pressure increased by 1.54 mm Hg (95%Cl: 1.35-1.74). The strongest association observed was between BMI at age 30 and mid-blood pressure, which was 2.12 mm Hg (95% CI: 1.79-2.45) increase over ten years per 5 kg/m(2) higher BMI level. This association was observed at an age when blood pressure levels on average remained stable. Other associations than those with BMI at baseline were much weaker. However, triglyceride levels were associated with future glucose changes among individuals with elevated BMI, particularly in the two older age groups. Conclusion: BMI was most indicative of long-term changes in metabolic factors, and the strongest impact was observed for increases in blood pressure between 30 and 40 years of age. Our study supports that lifestyle interventions preventing metabolic aberrations should focus on avoiding weight increases.

  • 245. Varga, Tibor V
    et al.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Hu, Frank B
    Renström, Frida
    Franks, Paul W
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Smoking status, snus use, and variation at the CHRNA5-CHRNA3-CHRNB4 locus in relation to obesity: the GLACIER study2013In: American Journal of Epidemiology, ISSN 0002-9262, E-ISSN 1476-6256, Vol. 178, no 1, p. 31-37Article in journal (Refereed)
    Abstract [en]

    A genetic variant within the CHRNA5-CHRNA3-CHRNB4 region (rs1051730), previously associated with smoking quantity, was recently shown to interact with smoking on obesity predisposition. We attempted to replicate this finding in the Gene-Lifestyle Interactions and Complex Traits Involved in Elevated Disease Risk (GLACIER) Study, a prospective cohort study of adults from northern Sweden (n = 16,426). We also investigated whether a similar interaction is apparent between rs1051730 and snus, a type of moist oral tobacco, to determine whether this interaction is driven by factors that cigarettes and snus have in common, such as nicotine. Main effects of smoking, snus, and the rs1051730 variant and pairwise interaction terms (smoking x rs1051730 and snus x rs1051730) were tested in relation to body mass index (BMI; calculated as weight (kg)/height (m)(2)) through the use of multivariate linear models adjusted for age and sex. Smoking status and BMI were inversely related (beta = -0.46 kg/m(2), standard error (SE) = 0.08; P < 0.0001). Snus use and BMI were positively related (beta = 0.35 kg/m(2), SE = 0.12; P = 0.003). The rs1051730 variant was not significantly associated with smoking status or snus use (P > 0.05); the T allele was associated with lower BMI in the overall cohort (beta = -0.10 kg/m(2), SE = 0.05; P = 0.03) and with smoking quantity in those in whom this was measured (n = 5,304) (beta = 0.08, SE = 0.01; P < 0.0001). Neither smoking status (P-interaction = 0.29) nor snus use (P-interaction = 0.89) modified the association between the rs1051730 variant and BMI.

  • 246. Varga, Tibor V.
    et al.
    Kurbasic, Azra
    Aine, Mattias
    Eriksson, Pontus
    Ali, Ashfaq
    Hindy, George
    Gustafsson, Stefan
    Luan, Jian'an
    Shungin, Dmitry
    Umeå University, Faculty of Medicine, Department of Odontology. Lund Univ, Skane Univ Hosp, Malmo, Sweden.
    Chen, Yan
    Schulz, Christina-Alexandra
    Nilsson, Peter M.
    Hallmans, Goran
    Barroso, Ines
    Deloukas, Panos
    Langenberg, Claudia
    Scott, Robert A.
    Wareham, Nicholas J.
    Lind, Lars
    Ingelsson, Erik
    Melander, Olle
    Orho-Melander, Marju
    Renström, Frida
    Umeå University, Faculty of Medicine, Department of Biobank Research. Lund Univ, Skane Univ Hosp, Malmo, Sweden.
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Lund Univ, Skane Univ Hosp, Malmo, Sweden ; Harvard, Boston, MA USA.
    Novel genetic loci associated with long-term deterioration in blood lipid concentrations and coronary artery disease in European adults2017In: International Journal of Epidemiology, ISSN 0300-5771, E-ISSN 1464-3685, Vol. 46, no 4, p. 1211-1222Article in journal (Refereed)
    Abstract [en]

    Background: Cross-sectional genome-wide association studies have identified hundreds of loci associated with blood lipids and related cardiovascular traits, but few genetic association studies have focused on long-term changes in blood lipids. Methods: Participants from the GLACIER Study (N-max = 3492) were genotyped with the MetaboChip array, from which 29 387 SNPs (single nucleotide polymorphisms;replication, fine-mapping regions and wildcard SNPs for lipid traits) were extracted for association tests with 10-year change in total cholesterol (Delta TC) and triglycerides (Delta TG). Four additional prospective cohort studies (MDC, PIVUS, ULSAM, MRC Ely; N-max = 8263 participants) were used for replication. We conducted an in silico look-up for association with coronary artery disease (CAD) in the Coronary ARtery DIsease Genome-wide Replication and Meta-analysis (CARDIoGRAMplusC4D) Consortium (N similar to 190 000) and functional annotation for the top ranking variants. Results: In total, 956 variants were associated (P < 0.01) with either Delta TC or Delta TG in GLACIER. In GLACIER, chr19:50121999 at APOE was associated with Delta TG and multiple SNPs in the APOA1/A4/C3/A5 region at genome-wide significance (P < 5 x 10(-8)), whereas variants in four loci, DOCK7, BRE, SYNE1 and KCNIP1, reached study-wide significance (P < 1.7 x 10(-6)). The rs7412 variant at APOE was associated with DTC in GLACIER (P < 1.7 x 10(-6)). In pooled analyses of all cohorts, 139 SNPs at six and five loci were associated with Delta TC and for Delta TG, respectively (P < 10(-3)). Of these, a variant at CAPN3 (P = 1.2 x 10(-4)), multiple variants at HPR (P-min = 1.5 x 10(-6)) and a variant at SIX5 (P = 1.9 x 10(-4)) showed evidence for association with CAD. Conclusions: We identified seven novel genomic regions associated with long-term changes in blood lipids, of which three also raise CAD risk.

  • 247. Varga, Tibor V.
    et al.
    Sonestedt, Emily
    Shungin, Dmitry
    Umeå University, Faculty of Medicine, Department of Odontology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Skåne University Hospital Malmö, Malmö, Sweden.
    Koivula, Robert W.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Andersson Escher, Stefan
    Barroso, Ines
    Nilsson, Peter
    Melander, Olle
    Orho-Melander, Marju
    Renström, Frida
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Skåne University Hospital Malmö, Malmö, Sweden.
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Skåne University Hospital Malmö, Malmö, Sweden ; Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.
    Genetic determinants of long-term changes in blood lipid concentrations: 10-year follow-up of the GLACIER study2014In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, no 6, p. e1004388-Article in journal (Refereed)
    Abstract [en]

    Recent genome-wide meta-analyses identified 157 loci associated with cross-sectional lipid traits. Here we tested whether these loci associate (singly and in trait-specific genetic risk scores [GRS]) with longitudinal changes in total cholesterol (TC) and triglyceride (TG) levels in a population-based prospective cohort from Northern Sweden (the GLACIER Study). We sought replication in a southern Swedish cohort (the MDC Study; N = 2,943). GLACIER Study participants (N = 6,064) were genotyped with the MetaboChip array. Up to 3,495 participants had 10-yr follow-up data available in the GLACIER Study. The TC- and TG-specific GRSs were strongly associated with change in lipid levels (beta = 0.02 mmol/l per effect allele per decade follow-up, P = 2.0x10(-11) for TC; beta = 0.02 mmol/l per effect allele per decade follow-up, P = 5.0x10(-5) for TG). In individual SNP analysis, one TC locus, apolipoprotein E (APOE) rs4420638 (beta = 0.12 mmol/l per effect allele per decade follow-up, P = 2.0x10(-5)), and two TG loci, tribbles pseudokinase 1 (TRIB1) rs2954029 (beta = 0.09 mmol/l per effect allele per decade follow-up, P = 5.1x10(-4)) and apolipoprotein A-I (APOA1) rs6589564 (beta = 0.31 mmol/l per effect allele per decade follow-up, P = 1.4x10(-8)), remained significantly associated with longitudinal changes for the respective traits after correction for multiple testing. An additional 12 loci were nominally associated with TC or TG changes. In replication analyses, the APOE rs4420638, TRIB1 rs2954029, and APOA1 rs6589564 associations were confirmed (P <= 0.001). In summary, trait-specific GRSs are robustly associated with 10-yr changes in lipid levels and three individual SNPs were strongly associated with 10-yr changes in lipid levels.

  • 248. Varga, Tibor V.
    et al.
    Winters, Alexandra H.
    Jablonski, Kathleen A.
    Horton, Edward S.
    Khare-Ranade, Prajakta
    Knowler, William C.
    Marcovina, Santica M.
    Renström, Frida
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden.
    Watson, Karol E.
    Goldberg, Ronald
    Florez, José C.
    Pollin, Toni I.
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA.
    Comprehensive Analysis of Established Dyslipidemia-Associated Loci in the Diabetes Prevention Program2016In: Circulation: Cardiovascular Genetics, ISSN 1942-325X, E-ISSN 1942-3268, Vol. 9, no 6, p. 495-503Article in journal (Refereed)
    Abstract [en]

    Background: We assessed whether 234 established dyslipidemia-associated loci modify the effects of metformin treatment and lifestyle intervention (versus placebo control) on lipid and lipid subfraction levels in the Diabetes Prevention Program randomized controlled trial. Methods and Results: We tested gene treatment interactions in relation to baseline-adjusted follow-up blood lipid concentrations (high-density lipoprotein [HDL] and low-density lipoprotein-cholesterol, total cholesterol, and triglycerides) and lipoprotein subfraction particle concentrations and size in 2993 participants with pre-diabetes. Of the previously reported single-nucleotide polymorphism associations, 32.5% replicated at P<0.05 with baseline lipid traits. Trait-specific genetic risk scores were robustly associated (3x10(-4)>P>1.1x10(-16)) with their respective baseline traits for all but 2 traits. Lifestyle modified the effect of the genetic risk score for large HDL particle numbers, such that each risk allele of the genetic risk scores was associated with lower concentrations of large HDL particles at follow-up in the lifestyle arm (beta=-0.11 mu mol/L per genetic risk scores risk allele; 95% confidence interval, -0.188 to -0.033; P=5x10(-3); P-interaction=1x10(-3) for lifestyle versus placebo), but not in the metformin or placebo arms (P>0.05). In the lifestyle arm, participants with high genetic risk had more favorable or similar trait levels at 1-year compared with participants at lower genetic risk at baseline for 17 of the 20 traits. Conclusions: Improvements in large HDL particle concentrations conferred by lifestyle may be diminished by genetic factors. Lifestyle intervention, however, was successful in offsetting unfavorable genetic loading for most lipid traits.

  • 249. Vedtofte, Mia Sadowa
    et al.
    Jakobsen, Marianne U.
    Lauritzen, Lotte
    O'Reilly, Eilis J.
    Virtamo, Jarmo
    Knekt, Paul
    Colditz, Graham
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Buring, Julie
    Steffen, Lyn M.
    Robien, Kimberly
    Rimm, Eric B.
    Heitmann, Berit L.
    Association between the intake of alpha-linolenic acid and the risk of CHD2014In: British Journal of Nutrition, ISSN 0007-1145, E-ISSN 1475-2662, Vol. 112, no 5, p. 735-743Article in journal (Refereed)
    Abstract [en]

    The intake of the mainly plant-derived n-3 PUFA alpha-linolenic acid (ALA) has been reported to be associated with a lower risk of CHD. However, the results have been inconsistent. Therefore, the objective of the present study was to examine the association between the intake of ALA and the risk of CHD. Potential effect modification by the intake of long-chain n-3 PUFA (n-3 LCPUFA) was also investigated. Data from eight American and European prospective cohort studies including 148 675 women and 80 368 men were used. The outcome measure was incident CHD (CHD event and death). During 4-10 years of follow-up, 4493 CHD events and 1751 CHD deaths occurred. Among men, an inverse association (not significant) between the intake of ALA and the risk of CHD events and deaths was observed. For each additional gram of ALA consumed, a 15% lower risk of CHD events (hazard ratios (HR) 0.85, 95% CI 0.72, 1.01) and a 23% lower risk of CHD deaths (HR 0.77, 95% CI 0.58, 1.01) were observed. No consistent association was observed among women. No effect modification by the intake of n-3 LCPUFA was observed.

  • 250. Vergnaud, Anne-Claire
    et al.
    Norat, Teresa
    Mouw, Traci
    Romaguera, Dora
    May, Anne M.
    Bueno-de-Mesquita, H. Bas
    van der Daphne, A.
    Agudo, Antonio
    Wareham, Nicholas
    Khaw, Kay-Tee
    Romieu, Isabelle
    Freisling, Heinz
    Slimani, Nadia
    Perquier, Florence
    Boutron-Ruault, Marie-Christine
    Clavel-Chapelon, Francoise
    Palli, Domenico
    Berrino, Franco
    Mattiello, Amalia
    Tumino, Rosario
    Ricceri, Fulvio
    Rodriguez, Laudina
    Molina-Montes, Esther
    Amiano, Pilar
    Barricarte, Aurelio
    Chirlaque, Maria-Dolores
    Crowe, Francesca L.
    Orfanos, Philippos
    Naska, Androniki
    Trichopoulou, Antonia
    Teucher, Birgit
    Kaaks, Rudolf
    Boeing, Heiner
    Buijsse, Brian
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Drake, Isabel
    Sonestedt, Emily
    Jakobsen, Marianne Uhre
    Overvad, Kim
    Tjonneland, Anne
    Halkjaer, Jytte
    Skeie, Guri
    Braaten, Tonje
    Lund, Eiliv
    Riboli, Elio
    Peeters, Petra H. M.
    Macronutrient Composition of the Diet and Prospective Weight Change in Participants of the EPIC-PANACEA Study2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 3, p. e57300-Article in journal (Refereed)
    Abstract [en]

    Background: The effect of the macronutrient composition of the usual diet on long term weight maintenance remains controversial.

    Methods: 373,803 subjects aged 25-70 years were recruited in 10 European countries (1992-2000) in the PANACEA project of the EPIC cohort. Diet was assessed at baseline using country-specific validated questionnaires and weight and height were measured at baseline and self-reported at follow-up in most centers. The association between weight change after 5 years of follow-up and the iso-energetic replacement of 5% of energy from one macronutrient by 5% of energy from another macronutrient was assessed using multivariate linear mixed-models. The risk of becoming overweight or obese after 5 years was investigated using multivariate Poisson regressions stratified according to initial Body Mass Index.

    Results: A higher proportion of energy from fat at the expense of carbohydrates was not significantly associated with weight change after 5 years. However, a higher proportion of energy from protein at the expense of fat was positively associated with weight gain. A higher proportion of energy from protein at the expense of carbohydrates was also positively associated with weight gain, especially when carbohydrates were rich in fibre. The association between percentage of energy from protein and weight change was slightly stronger in overweight participants, former smokers, participants >= 60 years old, participants underreporting their energy intake and participants with a prudent dietary pattern. Compared to diets with no more than 14% of energy from protein, diets with more than 22% of energy from protein were associated with a 23-24% higher risk of becoming overweight or obese in normal weight and overweight subjects at baseline.

    Conclusion: Our results show that participants consuming an amount of protein above the protein intake recommended by the American Diabetes Association may experience a higher risk of becoming overweight or obese during adult life.

23456 201 - 250 of 271
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