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  • 101.
    Häggström, Christel
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
    Stocks, Tanja
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Clinical Sciences, Diabetes and Cardiovascular Diseases, Genetic Epidemiology, Lund University, Lund, Sweden.
    Garmo, Hans
    Holmberg, Lars
    Van Hemelrijck, Mieke
    Interpretation of conventional survival analysis and competing-risk analysis: an example of hypertension and prostate cancer2016In: BJU International, ISSN 1464-4096, E-ISSN 1464-410X, Vol. 118, no 6, p. 850-852Article in journal (Refereed)
  • 102.
    Häggström, Christel
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Stocks, Tanja
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Nagel, Gabriele
    Manjer, Jonas
    Bjørge, Tone
    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.
    Engeland, Anders
    Ulmer, Hanno
    Lindkvist, Bjorn
    Selmer, Randi
    Concin, Hans
    Tretli, Steinar
    Jonsson, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Prostate Cancer, Prostate Cancer Death, and Death from Other Causes, Among Men with Metabolic Aberrations2014In: Epidemiology, ISSN 1044-3983, E-ISSN 1531-5487, Vol. 25, no 6, p. 823-828Article in journal (Refereed)
    Abstract [en]

    Background: Few previous studies of metabolic aberrations and prostate cancer risk have taken into account the fact that men with metabolic aberrations have an increased risk of death from causes other than prostate cancer. The aim of this study was to calculate, in a real-life scenario, the risk of prostate cancer diagnosis, prostate cancer death, and death from other causes.

    Methods: In the Metabolic Syndrome and Cancer Project, prospective data on body mass index, blood pressure, glucose, cholesterol, and triglycerides were collected from 285,040 men. Risks of prostate cancer diagnosis, prostate cancer death, and death from other causes were calculated by use of competing risk analysis for men with normal (bottom 84%) and high (top 16%) levels of each factor, and a composite score.

    Results: During a mean follow-up period of 12 years, 5,893 men were diagnosed with prostate cancer, 1,013 died of prostate cancer, and 26,328 died of other causes. After 1996, when prostate-specific antigen testing was introduced, men up to age 80 years with normal metabolic levels had 13% risk of prostate cancer, 2% risk of prostate cancer death, and 30% risk of death from other causes, whereas men with metabolic aberrations had corresponding risks of 11%, 2%, and 44%.

    Conclusions: In contrast to recent studies using conventional survival analysis, in a real-world scenario taking risk of competing events into account, men with metabolic aberrations had lower risk of prostate cancer diagnosis, similar risk of prostate cancer death, and substantially higher risk of death from other causes compared with men who had normal metabolic levels.

  • 103.
    Häggström, Christel
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Stocks, Tanja
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Nagel, Gabriele
    Institute of Epidemiology and Medical Biometry, Ulm University, Ulm, Germany.
    Manjer, Jonas
    Department of Surgery, Skåne University Hospital, Lund University, Malmö, Sweden.
    Bjørge, Tone
    Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Engeland, Anders
    Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway.
    Ulmer, Hanno
    Department of Medical Statistics, Informatics and Health Economics, Innsbruck Medical University, Innsbruck, Austria.
    Lindkvist, Björn
    Department of Surgery, Skåne University Hospital, Lund University, Malmö, Sweden.
    Selmer, Randi
    Norwegian Institute of Public Health, Oslo, Norway.
    Concin, Hans
    Agency for Preventive and Social Medicine, Bregenz, Austria.
    Tretli, Steinar
    Institute of Population-based Cancer Research, The Cancer Registry of Norway, 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.
    Competing risk analysis of metabolic factors and prostate cancerManuscript (preprint) (Other academic)
    Abstract [en]

    Background: Men at risk of prostate cancer are also at risk of competing events but this has been ignored in most studies of metabolic aberrations and prostate cancer. The aim of this study was to assess probabilities of prostate cancer and prostate cancer death by use of competing risk analysis.

    Methods: In the Metabolic syndrome and Cancer project (Me-Can), data on body mass index, blood pressure, glucose, total cholesterol, and triglycerides were collected from 285 040 men. Probabilities of prostate cancer, prostate cancer death and competing events, i.e. all-cause death or death from other causes, respectively, were calculated for men with normal (bottom 84%) and high (top 16%) levels of each metabolic factor and a composite score based on all metabolic factors

    Results: During follow up, 5893 men were diagnosed with prostate cancer, 1013 men died of prostate cancer, and 26 328 men died of other causes. Men with high levels of metabolic factors had decreased probability of prostate cancer, similar probability of prostate cancer death, and increased probability of other causes of death compared to men with normal levels. After 1996, when prostate specific antigen was used for detection of prostate cancer, men up to 80 years with normal levels of metabolic factors had 13% probability of prostate cancer and 37% probability of death from all causes. For men with high levels of metabolic factors, corresponding probabilities were 12% and 47%.

    Conclusions: Men with metabolic aberrations had a decreased probability of prostate cancer but a substantially higher probability of death from all causes.

  • 104.
    Häggström, Christel
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Stocks, Tanja
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. null.
    Rapp, Kilian
    Univ Ulm, Inst Epidemiol, Ulm, Germany.
    Bjørge, Tone
    Univ Bergen, Dept Publ Hlth & Primary Hlth Care, Bergen, Norway.
    Lindkvist, Björn
    Univ Gothenburg, Sahlgrenska Acad, Dept Med, Gothenburg, Sweden.
    Concin, Hans
    Agcy Prevent & Social Med, Bregenz, Austria.
    Engeland, Anders
    Univ Bergen, Dept Publ Hlth & Primary Hlth Care, Bergen, Norway.
    Manjer, Jonas
    Malmö Univ Hosp, Dept Surg, Malmö, Sweden.
    Ulmer, Hanno
    Innsbruck Med Univ, Dept Med Stat Informat & Hlth Econ, Innsbruck, Austria.
    Selmer, Randi
    Norwegian Inst Publ Hlth, Oslo, Norway.
    Tretli, Steinar
    Canc Registry Norway, Inst Populat Based Canc Res, Oslo, Norway.
    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. null.
    Jonsson, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. null.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. null.
    Metabolic syndrome and risk of bladder cancer: prospective cohort study in the metabolic syndrome and cancer project (Me-Can)2011In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 128, no 8, p. 1890-1898Article in journal (Refereed)
    Abstract [en]

    There are little data on the putative association between factors in the metabolic syndrome (MetS) and risk of bladder cancer. In the Metabolic Syndrome and Cancer project (Me-Can), measurements of height, weight, blood pressure and circulating levels of glucose, cholesterol, and triglycerides had been collected from 578,700 subjects in cohorts in Norway, Austria, and Sweden. We used Cox proportional hazard models to calculate relative risks (RRs) of bladder cancer by exposures divided into quintiles, in categories according to the World Health Organisation (WHO) and as a continuous standardized variable (z-score with mean = 0 and standard deviation = 1) for each separate component and its standardized sum, a composite MetS score. RRs were corrected for random error in measurements. During a mean follow-up of 11.7 years (SD = 7.6), 1,587 men and 327 women were diagnosed with bladder cancer. Significant associations with risk were found among men per one unit increment of z-score for blood pressure, RR = 1.13 (95% CI 1.03-1.25), and the composite MetS score, RR = 1.10 (95% CI 1.01-1.18). Among women, glucose was nonsignificantly associated with risk, RR = 1.41 (95% CI 0.97-2.06). No statistically significant interactions were found between the components in the MetS in relation to bladder cancer risk. Hypertension and a composite MetS score were significantly but modestly associated with an increased risk of bladder cancer among men and elevated glucose was associated with a nonsignificant increase in risk among women.

  • 105.
    Häggström, Christel
    et al.
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden; King’s College London, School of Cancer and Pharmaceutical Sciences, Translational Oncology & Urology Research (TOUR), London, United Kingdom.
    Van Hemelrijck, Mieke
    Garmo, Hans
    Robinson, David
    Stattin, Pär
    Rowley, Mark
    Coolen, Anthony C. C.
    Holmberg, Lars
    Heterogeneity in risk of prostate cancer: a Swedish population-based cohort study of competing risks and Type 2 diabetes mellitus2018In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 143, no 8, p. 1868-1875Article in journal (Refereed)
    Abstract [en]

    Most previous studies of prostate cancer have not taken into account that men in the studied populations are also at risk of competing event, and that these men may have different susceptibility to prostate cancer risk. The aim of our study was to investigate heterogeneity in risk of prostate cancer, using a recently developed latent class regression method for competing risks. We further aimed to elucidate the association between Type 2 diabetes mellitus (T2DM) and prostate cancer risk, and to compare the results with conventional methods for survival analysis. We analysed the risk of prostate cancer in 126,482 men from the comparison cohort of the Prostate Cancer Data base Sweden (PCBaSe) 3.0. During a mean follow-up of 6years 6,036 men were diagnosed with prostate cancer and 22,393 men died. We detected heterogeneity in risk of prostate cancer with two distinct latent classes in the study population. The smaller class included 9% of the study population in which men had a higher risk of prostate cancer and the risk was stronger associated with class membership than any of the covariates included in the study. Moreover, we found no association between T2DM and risk of prostate cancer after removal of the effect of informative censoring due to competing risks. The recently developed latent class for competing risks method could be used to provide new insights in precision medicine with the target to classify individuals regarding different susceptibility to a particular disease, reaction to a risk factor or response to treatment.

  • 106.
    Häggström, Christel
    et al.
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
    Van Hemelrijck, Mieke
    Zethelius, Björn
    Robinson, David
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Grundmark, Birgitta
    Holmberg, Lars
    Gudbjörnsdottir, Soffia
    Garmo, Hans
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
    Prospective study of Type 2 diabetes mellitus, anti-diabetic drugs and risk of prostate cancer2017In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 140, no 3, p. 611-617Article in journal (Refereed)
    Abstract [en]

    Type 2 diabetes mellitus (T2DM) has consistently been associated with decreased risk of prostate cancer; however, if this decrease is related to the use of anti-diabetic drugs is unknown. We prospectively studied men in the comparison cohort in the Prostate Cancer data Base Sweden 3.0, with data on T2DM, use of metformin, sulfonylurea and insulin retrieved from national health care registers and demographic databases. Cox proportional hazards regression models were used to compute hazard ratios (HR) and 95% confidence intervals (CI) of prostate cancer, adjusted for confounders. The study consisted of 612,846 men, mean age 72 years (standard deviation; SD = 9 years), out of whom 25,882 men were diagnosed with prostate cancer during follow up, mean time of 5 years (SD = 3 years). Men with more than 1 year's duration of T2DM had a decreased risk of prostate cancer compared to men without T2DM (HR = 0.85, 95% CI = 0.82-0.88) but among men with T2DM, those on metformin had no decrease (HR = 0.96, 95% CI = 0.77-1.19), whereas men on insulin (89%) or sulfonylurea (11%) had a decreased risk (HR = 0.73, 95% CI = 0.55-0.98), compared to men with T2DM not on anti-diabetic drugs. Men with less than 1 year's duration of T2DM had no decrease in prostate cancer risk (HR = 1.11, 95% CI = 0.95-1.31). Our results gave no support to the hypothesis that metformin protects against prostate cancer as recently proposed. However, our data gave some support to an inverse association between T2DM severity and prostate cancer risk.

  • 107. Isaksson, Hanna
    et al.
    Landberg, Rikard
    Sundberg, Birgitta
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    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.
    Zhang, Jie-Xian
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Tidehag, Per
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Knudsen, Knud Erik Bach
    Moazzami, Ali A.
    Åman, Per
    High-fiber rye diet increases ileal excretion of energy and macronutrients compared with low-fiber wheat diet independent of meal frequency in ileostomy subjects2013In: Food & Nutrition Research, ISSN 1654-6628, E-ISSN 1654-661X, Vol. 57, p. 18519-Article in journal (Refereed)
    Abstract [en]

    Background: Whole-grain foods and cereal dietary fiber intake is associated with lower body weight. This may partly result from lower energy utilization of high-fiber diets. Objective: In the present study, the impact on ileal excretion of energy and macronutrients in response to a rye bread high-fiber diet compared to a refined wheat low-fiber diet was investigated. Furthermore, the effect of meal frequency on apparent absorption of nutrients was studied for the first time. Design: Ten participants that had undergone ileostomy consumed standardized iso-caloric diets, including low-fiber wheat bread (20 g dietary fiber per day) for 2 weeks followed by high-fiber rye bread (52 g dietary fiber per day) for 2 weeks. The diets were consumed in an ordinary (three meals per day) and a nibbling (seven meals per day) meal frequency in a cross-over design. Ileal effluents were collected during 24 h at the third day of each of the four dietary periods and analyzed for gross energy and nutrient contents. Results: The results showed that intake of rye bread high-fiber diet compared to the refined wheat low-fiber diet caused an increase in ileal excretion of energy and macronutrients. The effect was independent of meal frequency. This suggests that a high intake of rye may result in lower availability of macronutrients for small intestinal digestion and absorption. A regular intake of rye may therefore have implications for weight management.

  • 108.
    Jacobson, Sofie
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
    Larsson, Peter
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Idrottsmedicin.
    Johansson, Göran
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
    Norberg, Margareta
    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.
    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.
    Winsö, Ola
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
    Söderberg, Stefan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Leptin independently predicts development of future sepsis and determines survival in the acute phaseManuscript (preprint) (Other academic)
    Abstract [en]

    Objective: To determine if levels of the adipocyte-derived hormones leptin and adiponectin (adipokines) predict sepsis development and if intra-individual changes in circulating levels from baseline to the acute phase affect outcome.

    Method: A nested case-referent study within the framework of the Northern Sweden Health and Disease Study (NSHDS) and the Northern Sweden Maternity Cohort (NSMC). Patients aged 18 years or more with documented sepsis within 24 hours after admission to the intensive care unit (ICU) were included if they had participated in a health survey and donated blood samples prior to the sepsis event, and if possible also had stored plasma from the acute phase. Two matched referents free of known sepsis were selected for each case. Baseline and acute phase plasma leptin and adiponectin levels were determined. The associations between adipokines and sepsis and its severity and outcome were determined.

    Results: We identified 57 men and 97 women with a first-time sepsis event 6.5 years (median with IQR 7.7) after participation in the health survey, and 83% of them had also samples from the acute septic phase. Hyperleptinemia associated with a future sepsis event (OR 1.77, 95% CI 1.04-3.00, P=0.03), with stronger associations with severe sepsis and septic shock than with sepsis. High leptin levels were also associated with hospital death in the fully adjusted model. Leptin remained associated with sepsis in men (P=0.02), but not in women (P=0.36), after stratification and adjustment for BMI. In the acute phase, leptin increased more in men than in women (P=0.001), and high leptin levels were associated with increased risk for in-hospital death in women (OR 4.18, 95%CI 1.17-15.00, P=0.03), while being protective in men (OR 0.05, 95% CI 0.01-0.48, P=0.01). Adiponectin did not associate with sepsis or outcome.

    Conclusions: Hyperleptinemia independently predicted the development of sepsis, and an unfavourable outcome in men. Adiponectin was not associated with sepsis development.

  • 109.
    Jacobson, Sofie
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
    Åberg, Anna-Maja
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
    Johansson, Göran
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
    Norberg, Margareta
    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.
    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.
    Winsö, Ola
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
    Söderberg, Stefan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Levels of mannose-binding lectin (MBL) predicts sepsis and associates with sepsis-related in-hospital mortality differentially in men and womenManuscript (preprint) (Other academic)
    Abstract [en]

    Objective: To determine if levels of mannose-binding lectin (MBL) predict sepsis development and if intra-individual changes in circulating levels from baseline to the acute septic phase associate with in-hospital mortality.

    Method: A nested case-referent study within the framework of the Northern Sweden Health and Disease Study (NSHDS) and the Northern Sweden Maternity Cohort (NSMC). Patients aged 18 years or more with documented sepsis within 24 hours after admission to the intensive care unit were included if they had participated in a health survey and donated blood samples prior to the sepsis event. A subset of these patients had stored plasma also from the acute phase. Two matched referents free of known sepsis were selected for each case. Baseline and acute phase plasma MBL levels were determined. The association between MBL and sepsis, sepsis severity and in-hospital mortality were determined.

    Results: We identified 57 men and 95 women with a first-time sepsis event 6.5 years (median with IQR 7.7) after participation in a health survey, of which 127 also had samples from the acute septic phase. High baseline levels predicted future sepsis (OR 1.81, 95% CI 1.01-3.26), but were not associated with severity of sepsis or in-hospital fatality. Both high MBL levels in the acute phase (OR 4.94, 95% CI 1.44-16.89), and an increase from base line to the acute phase (OR 3.67, 95% CI 1.19-11.28) were associated with increased risk for in-hospital death in women, but not in men (OR 0.71, 95% CI 0.18-2.88). Low levels at baseline were not associated with future sepsis. Neither low levels at baseline, nor in the acute phase were associated with sepsis severity or in-hospital mortality.

    Conclusions: High pre-sepsis levels predicted a future sepsis event, and an increase from baseline to the acute phase as well as high levels in the acute phase associated with an unfavourable outcome in women.

  • 110. Jahnson, Staffan
    et al.
    Gårdmark, Truls
    Hosseini, Abolfazl
    Jerlström, Tomas
    Liedberg, Fredrik
    Malmström, Per-Uno
    Rosell, Johan
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Ströck, Viveka
    Häggström, Christel
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
    Holmberg, Lars
    Aljabery, Firas
    Management and outcome of TaG3 tumours of the urinary bladder in the nationwide, population-based bladder cancer database Sweden (BladderBaSe)2019In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 53, no 4, p. 200-205Article in journal (Refereed)
    Abstract [en]

    Purpose: To investigate the management of TaG3 tumours of the urinary bladder using nationwide population-based data in relation to the prevailing guidelines, patients' characteristics, and outcome.

    Materials and methods: The Bladder Cancer Data Base Sweden (BladderBaSe), including data from the Swedish National Register for Urinary Bladder Cancer (SNRUBC), was used to study all patients with TaG3 bladder cancer diagnosed from 2008 to 2014. Patients were divided into the following management groups: (1) transurethral resection (TUR) only, (2) TUR and intravesical instillation therapy (IVIT), (3) TUR and second-look resection (SLR), and (4) TUR with both SLR and IVIT. Patient and tumour characteristics and outcome were studied.

    Results: There were 831 patients (83% males) with a median age of 74 years. SLR was performed more often on younger patients, on men, and less often in the Western and Uppsala/Örebro Healthcare regions. IVIT was performed more often with younger patients, with men, in the Western Healthcare region, and less often in the Uppsala/Örebro Healthcare region. Death from bladder cancer occurred in 6% of cases within a median of 29 months (0-84 months) and was lower in the TUR/IVIT and TUR/SLR/IVIT groups compared to the other two groups.

    Conclusion: In the present study, there was, according to the prevailing treatment guidelines, an under-treatment with SLR for older patients, women, and in some healthcare regions and, similarly, there was an under-treatment with IVIT for older patients. Cancer-specific survival and relative survival were lower in the TUR only group compared to the TUR/IVIT and TUR/SLR/IVIT groups.

  • 111. Jakobsdottir, Johanna
    et al.
    van der Lee, Sven J.
    Bis, Joshua C.
    Chouraki, Vincent
    Li-Kroeger, David
    Yamamoto, Shinya
    Grove, Megan L.
    Naj, Adam
    Vronskaya, Maria
    Salazar, Jose L.
    DeStefano, Anita L.
    Brody, Jennifer A.
    Smith, Albert V.
    Amin, Najaf
    Sims, Rebecca
    Ibrahim-Verbaas, Carla A.
    Choi, Seung-Hoan
    Satizabal, Claudia L.
    Lopez, Oscar L.
    Beiser, Alexa
    Ikram, M. Arfan
    Garcia, Melissa E.
    Hayward, Caroline
    Varga, Tibor V.
    Ripatti, Samuli
    Franks, Paul W.
    Department of Public Health & Clinical Medicine, Umeå University Hospital, Umeå, Sweden; .
    Hallmans, Göran
    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.
    Jansson, Jan-Hakon
    Porteous, David J.
    Salomaa, Veikko
    Eiriksdottir, Gudny
    Rice, Kenneth M.
    Bellen, Hugo J.
    Levy, Daniel
    Uitterlinden, Andre G.
    Emilsson, Valur
    Rotter, Jerome I.
    Aspelund, Thor
    O'Donnell, Christopher J.
    Fitzpatrick, Annette L.
    Launer, Lenore J.
    Hofman, Albert
    Wang, Li-San
    Williams, Julie
    Schellenberg, Gerard D.
    Boerwinkle, Eric
    Psaty, Bruce M.
    Seshadri, Sudha
    Shulman, Joshua M.
    Gudnason, Vilmundur
    Van Duijn, Cornelia M.
    Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease2016In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 12, no 10, article id e1006327Article in journal (Refereed)
    Abstract [en]

    We performed an exome-wide association analysis in 1393 late-onset Alzheimer's disease (LOAD) cases and 8141 controls from the CHARGE consortium. We found that a rare variant (P155L) in TM2D3 was enriched in Icelanders (similar to 0.5% versus < 0.05% in other European populations). In 433 LOAD cases and 3903 controls from the Icelandic AGES substudy, P155L was associated with increased risk and earlier onset of LOAD [odds ratio (95% CI) = 7.5 (3.5-15.9), p = 6.6x10(-9)]. Mutation in the Drosophila TM2D3 homolog, almondex, causes a phenotype similar to loss of Notch/Presenilin signaling. Human TM2D3 is capable of rescuing these phenotypes, but this activity is abolished by P155L, establishing it as a functionally damaging allele. Our results establish a rare TM2D3 variant in association with LOAD susceptibility, and together with prior work suggests possible links to the beta-amyloid cascade.

  • 112. Jakobsen, Marianne U.
    et al.
    Dethlefsen, Claus
    Due, Karen M.
    May, Anne M.
    Romaguera, Dora
    Vergnaud, Anne-Claire
    Norat, Teresa
    Sorensen, Thorkild I. A.
    Halkjaer, Jytte
    Tjonneland, Anne
    Boutron-Ruault, Marie-Christine
    Clavel-Chapelon, Francoise
    Fagherazzi, Guy
    Teucher, Birgit
    Kuehn, Tilman
    Bergmann, Manuela M.
    Boeing, Heiner
    Naska, Androniki
    Orfanos, Philippos
    Trichopoulou, Antonia
    Palli, Domenico
    De Magistris, Maria Santucci
    Sieri, Sabina
    Bueno-de-Mesquita, H. B.
    van der A, Daphne L.
    Engeset, Dagrun
    Hjartaker, Anette
    Rodriguez, Laudina
    Agudo, Antonio
    Molina-Montes, Esther
    Huerta, Jose M.
    Barricarte, Aurelio
    Amiano, Pilar
    Manjer, Jonas
    Wirfalt, Elisabet
    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.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Khaw, Kay-Tee
    Wareham, Nicholas J.
    Key, Timothy J.
    Chajes, Veronique
    Slimani, Nadia
    Riboli, Elio
    Peeters, Petra H. M.
    Overvad, Kim
    Fish consumption and subsequent change in body weight in European women and men2013In: British Journal of Nutrition, ISSN 0007-1145, E-ISSN 1475-2662, Vol. 109, no 2, p. 353-362Article in journal (Refereed)
    Abstract [en]

    Fish consumption is the major dietary source of EPA and DHA, which according to rodent experiments may reduce body fat mass and prevent obesity. Only a few human studies have investigated the association between fish consumption and body-weight gain. We investigated the association between fish consumption and subsequent change in body weight. Women and men (n 344 757) participating in the European Prospective Investigation into Cancer and Nutrition were followed for a median of 5.0 years. Linear and logistic regression were used to investigate the associations between fish consumption and subsequent change in body weight. Among women, the annual weight change was 5.70 (95% CI 4.35, 7.06), 2.23 (95% CI 0.16, 4.31) and 11.12 (95% CI 8.17, 14.08) g/10 g higher total, lean and fatty fish consumption per d, respectively. The OR of becoming overweight in 5 years among women who were normal weight at enrolment was 1.02 (95% CI 1.01, 1.02), 1.01 (95% CI 1.00, 1.02) and 1.02 (95% CI 1.01, 1.04) g/10 g higher total, lean and fatty consumption per d, respectively. Among men, fish consumption was not statistically significantly associated with weight change. Adjustment for potential over-or underestimation of fish consumption did not systematically change the observed associations, but the 95% CI became wider. The results in subgroups from analyses stratified by age or BMI at enrolment were not systematically different. In conclusion, the present study suggests that fish consumption has no appreciable association with body-weight gain.

  • 113. Jakszyn, Paula
    et al.
    Lujan-Barroso, Leila
    Agudo, Antonio
    Bueno-de-Mesquita, H Bas
    Molina, Esther
    Sanchez, Ma Jose
    Fonseca-Nunes, Ana
    Siersema, Peter D
    Matiello, Amalia
    Tumino, Rosario
    Saieva, Calogero
    Pala, Valeria
    Vineis, Paolo
    Boutron-Ruault, Marie-Christine
    Racine, Antoine
    Bastide, Nadie
    Travis, Ruth C
    Khaw, Kay-Tee
    Riboli, Elio
    Murphy, Neil
    Vergnaud, Anne-Claire
    Trichopoulou, Antonia
    Valanou, Elissavet
    Oikonomidou, EDespina
    Weiderpass, Elisabete
    Skeie, Guri
    Johansen, Dorthe
    Lindkvist, Bjorn
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Biobank Research. International Agency for Research on Cancer (IARC/WHO), Lyon, France.
    Duarte-Salles, Talita
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Freisling, Heinz
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Barricarte, Aurelio
    Huerta, Jose Ma
    Amiano, Pilar
    Tjonneland, Anne
    Overvad, Kim
    Kuehn, Tilman
    Grote, Verena
    Boeing, Heiner
    Peeters, Petra HM
    Gonzalez, Carlos A
    Meat and heme iron intake and esophageal adenocarcinoma in the European Prospective Investigation into Cancer and Nutrition study2013In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 133, no 11, p. 2744-2750Article in journal (Refereed)
    Abstract [en]

    Although recent studies suggest that high intakes of meat and heme iron are risk factors for several types of cancer, studies in relation to esophageal adenocarcinoma (EAC) are scarce. Previous results in the European Prospective Investigation into Cancer and Nutrition (EPIC) based on a relatively small number of cases suggested a positive association between processed meat and EAC. In this study, we investigate the association between intake of different types of meats and heme iron intake and EAC risk in a larger number of cases from EPIC. The study included 481,419 individuals and 137 incident cases of EAC that occurred during an average of 11 years of follow-up. Dietary intake of meat (unprocessed/processed red and white meat) was assessed by validated center-specific questionnaires. Heme iron was calculated as a type-specific percentage of the total iron content in meat. After adjusting for relevant confounders, we observed a statistically significant positive association of EAC risk with heme iron and processed meat intake, with HR: 1.67, 95% CI: 1.05-2.68 and HR: 2.27, 95% CI:1.33-3.89, respectively, for comparison of the highest vs. lowest tertile of intake. Our results suggest a potential association between higher intakes of processed meat and heme iron and risk of EAC.

  • 114. Jankovic, Nicole
    et al.
    Geelen, Anouk
    Streppel, Martinette T
    de Groot, Lisette C P G M
    Orfanos, Philippos
    van den Hooven, Edith H
    Pikhart, Hynek
    Boffetta, Paolo
    Trichopoulou, Antonia
    Bobak, Martin
    Bueno-de-Mesquita, H B
    Kee, Frank
    Franco, Oscar H
    Park, Yikyung
    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.
    Tjønneland, Anne
    May, Anne M
    Pajak, Andrzej
    Malyutina, Sofia
    Kubinova, Růžena
    Amiano, Pilar
    Kampman, Ellen
    Feskens, Edith J
    Adherence to a healthy diet according to the world health organization guidelines and all-cause mortality in elderly adults from Europe and the United States2014In: American Journal of Epidemiology, ISSN 0002-9262, E-ISSN 1476-6256, Vol. 180, no 10, p. 978-988Article in journal (Refereed)
    Abstract [en]

    The World Health Organization (WHO) has formulated guidelines for a healthy diet to prevent chronic diseases and postpone death worldwide. Our objective was to investigate the association between the WHO guidelines, measured using the Healthy Diet Indicator (HDI), and all-cause mortality in elderly men and women from Europe and the United States. We analyzed data from 396,391 participants (42% women) in 11 prospective cohort studies who were 60 years of age or older at enrollment (in 1988-2005). HDI scores were based on 6 nutrients and 1 food group and ranged from 0 (least healthy diet) to 70 (healthiest diet). Adjusted cohort-specific hazard ratios were derived by using Cox proportional hazards regression and subsequently pooled using random-effects meta-analysis. During 4,497,957 person-years of follow-up, 84,978 deaths occurred. Median HDI scores ranged from 40 to 54 points across cohorts. For a 10-point increase in HDI score (representing adherence to an additional WHO guideline), the pooled adjusted hazard ratios were 0.90 (95% confidence interval (CI): 0.87, 0.93) for men and women combined, 0.89 (95% CI: 0.85, 0.92) for men, and 0.90 (95% CI: 0.85, 0.95) for women. These estimates translate to an increased life expectancy of 2 years at the age of 60 years. Greater adherence to the WHO guidelines is associated with greater longevity in elderly men and women in Europe and the United States.

  • 115. Johansson, Mattias
    et al.
    Carreras-Torres, Robert
    Scelo, Ghislaine
    Purdue, Mark P.
    Mariosa, Daniela
    Muller, David C.
    Timpson, Nicolas J.
    Haycock, Philip C.
    Brown, Kevin M.
    Wang, Zhaoming
    Ye, Yuanqing
    Hofmann, Jonathan N.
    Foll, Matthieu
    Gaborieau, Valerie
    Machiela, Mitchell J.
    Colli, Leandro M.
    Li, Peng
    Garnier, Jean-Guillaume
    Blanche, Helene
    Boland, Anne
    Burdette, Laurie
    Prokhortchouk, Egor
    Skryabin, Konstantin G.
    Yeager, Meredith
    Radojevic-Skodric, Sanja
    Ognjanovic, Simona
    Foretova, Lenka
    Holcatova, Ivana
    Janout, Vladimir
    Mates, Dana
    Mukeriya, Anush
    Rascu, Stefan
    Zaridze, David
    Bencko, Vladimir
    Cybulski, Cezary
    Fabianova, Eleonora
    Jinga, Viorel
    Lissowska, Jolanta
    Lubinski, Jan
    Navratilova, Marie
    Rudnai, Peter
    Benhamou, Simone
    Cancel-Tassin, Geraldine
    Cussenot, Olivier
    Weiderpass, Elisabete
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Tumkur Sitaram, Raviprakash
    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, Sweden.
    Bruinsma, Fiona
    Jordan, Susan J
    Severi, Gianluca
    Winship, Ingrid
    Hveem, Kristian
    Vatten, Lars J
    Fletcher, Tony
    Larsson, Susanna C
    Wolk, Alicja
    Banks, Rosamonde E
    Selby, Peter J
    Easton, Douglas F
    Andreotti, Gabriella
    Beane Freeman, Laura E
    Koutros, Stella
    Männistö, Satu
    Weinstein, Stephanie
    Clark, Peter E
    Edwards, Todd L
    Lipworth, Loren
    Gapstur, Susan M
    Stevens, Victoria L
    Carol, Hallie
    Freedman, Matthew L
    Pomerantz, Mark M
    Cho, Eunyoung
    Wilson, Kathryn M
    Gaziano, J Michael
    Sesso, Howard D
    Freedman, Neal D
    Parker, Alexander S
    Eckel-Passow, Jeanette E
    Huang, Wen-Yi
    Kahnoski, Richard J
    Lane, Brian R
    Noyes, Sabrina L
    Petillo, David
    Teh, Bin Tean
    Peters, Ulrike
    White, Emily
    Anderson, Garnet L
    Johnson, Lisa
    Luo, Juhua
    Buring, Julie
    Lee, I-Min
    Chow, Wong-Ho
    Moore, Lee E
    Eisen, Timothy
    Henrion, Marc
    Larkin, James
    Barman, Poulami
    Leibovich, Bradley C
    Choueiri, Toni K
    Lathrop, G Mark
    Deleuze, Jean-Francois
    Gunter, Marc
    McKay, James D
    Wu, Xifeng
    Houlston, Richard S
    Chanock, Stephen J
    Relton, Caroline
    Richards, J Brent
    Martin, Richard M
    Davey Smith, George
    Brennan, Paul
    The influence of obesity-related factors in the etiology of renal cell carcinoma: A mendelian randomization study2019In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 16, no 1, article id e1002724Article in journal (Refereed)
    Abstract [en]

    Background: Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation.

    Methods and findings: Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval [CI] 1.44–1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40–1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44–1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30–2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11–1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84–1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose.

    Conclusions: This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk.

  • 116.
    Johansson, Mattias
    et al.
    International Agency for Research on Cancer, Lyon, France.
    Fanidi, Anouar
    Muller, David C.
    Bassett, Julie K.
    Midttun, Oivind
    Vollset, Stein Emil
    Travis, Ruth C.
    Palli, Domenico
    Mattiello, Amalia
    Sieri, Sabina
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    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.
    Weiderpass, Elisabete
    Skeie, Guri
    Gonzalez, Carlos A.
    Dorronsoro, Miren
    Peeters, Petra H.
    Bueno-de-Mesquita, H. B(as).
    Ros, Martine M.
    Ruault, Marie-Christine Boutron
    Fagherazzi, Guy
    Clavel, Francoise
    Sanchez, Maria-Jose
    Barricarte Gurrea, Aurelio
    Navarro, Carmen
    Ramon Quiros, J.
    Overvad, Kim
    Tjonneland, Anne
    Aleksandrova, Krassimira
    Vineis, Paolo
    Gunter, Marc J.
    Kaaks, Rudolf
    Giles, Graham
    Relton, Caroline
    Riboli, Elio
    Boeing, Heiner
    Ueland, Per Magne
    Severi, Gianluca
    Brennan, Paul
    Circulating Biomarkers of One-Carbon Metabolism in Relation to Renal Cell Carcinoma Incidence and Survival2014In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 106, no 12, article id dju327Article in journal (Refereed)
    Abstract [en]

    Background: The etiology of renal cell carcinoma (RCC) is only partially understood, but a metabolic component appears likely. We investigated biomarkers of one-carbon metabolism and RCC onset and survival. Methods: The European Prospective Investigation into Cancer and Nutrition (EPIC) recruited 385 747 participants with blood samples between 1992 and 2000, and this analysis included 556 RCC case-control pairs. A subsequent replication study included 144 case-control pairs nested within the Melbourne Collaborative Cohort Study (MCCS). Plasma concentrations of vitamin B2, vitamin B6, folate, vitamin B12, methionine and homocysteine were measured in prediagnostic samples and evaluated with respect to RCC risk using conditional and unconditional logistic regression models, and to all-cause mortality in RCC cases using Cox regression models. All statistical tests were two-sided. Results: EPIC participants with higher plasma concentrations of vitamin B6 had lower risk of RCC, the odds ratio comparing the 4th and 1st quartiles (OR4vs1) being 0.40 95% confidence interval [CI] = 0.28 to 0.57, P-trend < .001. We found similar results after adjusting for potential confounders (adjusted P-trend < .001). In survival analysis, the hazard ratio for all-cause mortality in RCC cases when comparing the 4th and 1st quartiles (HR4vs1) of vitamin B6 was 0.57 (95% CI = 0.37 to 0.87, P-trend < .001). Subsequent replication of these associations within the MCCS yielded very similar results for both RCC risk (OR4vs1 = 0.47, 95% CI = 0.23 to 0.99, P-trend = .07) and all-cause mortality (HR4vs1 = 0.56, 95% CI = 0.27 to 1.17, P-trend = .02). No association was evident for the other measured biomarkers. Conclusion: Study participants with higher circulating concentrations of vitamin B6 had lower risk of RCC and improved survival following diagnosis in two independent cohorts.

  • 117. Justice, Anne E
    et al.
    Winkler, Thomas W
    Feitosa, Mary F
    Graff, Misa
    Fisher, Virginia A
    Young, Kristin
    Barata, Llilda
    Deng, Xuan
    Czajkowski, Jacek
    Hadley, David
    Ngwa, Julius S
    Ahluwalia, Tarunveer S
    Chu, Audrey Y
    Heard-Costa, Nancy L
    Lim, Elise
    Perez, Jeremiah
    Eicher, John D
    Kutalik, Zoltan
    Xue, Luting
    Mahajan, Anubha
    Renström, Frida
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, SE-205 02 Malmö, Sweden.
    Wu, Joseph
    Qi, Qibin
    Ahmad, Shafqat
    Alfred, Tamuno
    Amin, Najaf
    Bielak, Lawrence F
    Bonnefond, Amelie
    Bragg, Jennifer
    Cadby, Gemma
    Chittani, Martina
    Coggeshall, Scott
    Corre, Tanguy
    Direk, Nese
    Eriksson, Joel
    Fischer, Krista
    Gorski, Mathias
    Neergaard Harder, Marie
    Horikoshi, Momoko
    Huang, Tao
    Huffman, Jennifer E
    Jackson, Anne U
    Justesen, Johanne Marie
    Kanoni, Stavroula
    Kinnunen, Leena
    Kleber, Marcus E
    Komulainen, Pirjo
    Kumari, Meena
    Lim, Unhee
    Luan, Jian'an
    Lyytikainen, Leo-Pekka
    Mangino, Massimo
    Manichaikul, Ani
    Marten, Jonathan
    Middelberg, Rita P S
    Muller-Nurasyid, Martina
    Navarro, Pau
    Perusse, Louis
    Pervjakova, Natalia
    Sarti, Cinzia
    Smith, Albert Vernon
    Smith, Jennifer A
    Stancakova, Alena
    Strawbridge, Rona J
    Stringham, Heather M
    Sung, Yun Ju
    Tanaka, Toshiko
    Teumer, Alexander
    Trompet, Stella
    van der Laan, Sander W
    van der Most, Peter J
    Van Vliet-Ostaptchouk, Jana V
    Vedantam, Sailaja L
    Verweij, Niek
    Vink, Jacqueline M
    Vitart, Veronique
    Wu, Ying
    Yengo, Loic
    Zhang, Weihua
    Hua Zhao, Jing
    Zimmermann, Martina E
    Zubair, Niha
    Abecasis, Goncalo R
    Adair, Linda S
    Afaq, Saima
    Afzal, Uzma
    Bakker, Stephan J L
    Bartz, Traci M
    Beilby, John
    Bergman, Richard N
    Bergmann, Sven
    Biffar, Reiner
    Blangero, John
    Boerwinkle, Eric
    Bonnycastle, Lori L
    Bottinger, Erwin
    Braga, Daniele
    Buckley, Brendan M
    Buyske, Steve
    Campbell, Harry
    Chambers, John C
    Collins, Francis S
    Curran, Joanne E
    de Borst, Gert J
    de Craen, Anton J M
    de Geus, Eco J C
    Dedoussis, George
    Delgado, Graciela E
    den Ruijter, Hester M
    Eiriksdottir, Gudny
    Eriksson, Anna L
    Esko, Tonu
    Faul, Jessica D
    Ford, Ian
    Forrester, Terrence
    Gertow, Karl
    Gigante, Bruna
    Glorioso, Nicola
    Gong, Jian
    Grallert, Harald
    Grammer, Tanja B
    Grarup, Niels
    Haitjema, Saskia
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Hamsten, Anders
    Hansen, Torben
    Harris, Tamara B
    Hartman, Catharina A
    Hassinen, Maija
    Hastie, Nicholas D
    Heath, Andrew C
    Hernandez, Dena
    Hindorff, Lucia
    Hocking, Lynne J
    Hollensted, Mette
    Holmen, Oddgeir L
    Homuth, Georg
    Jan Hottenga, Jouke
    Huang, Jie
    Hung, Joseph
    Hutri-Kahonen, Nina
    Ingelsson, Erik
    James, Alan L
    Jansson, John-Olov
    Jarvelin, Marjo-Riitta
    Jhun, Min A
    Jorgensen, Marit E
    Juonala, Markus
    Kahonen, Mika
    Karlsson, Magnus
    Koistinen, Heikki A
    Kolcic, Ivana
    Kolovou, Genovefa
    Kooperberg, Charles
    Kramer, Bernhard K
    Kuusisto, Johanna
    Kvaloy, Kirsti
    Lakka, Timo A
    Langenberg, Claudia
    Launer, Lenore J
    Leander, Karin
    Lee, Nanette R
    Lind, Lars
    Lindgren, Cecilia M
    Linneberg, Allan
    Lobbens, Stephane
    Loh, Marie
    Lorentzon, Mattias
    Luben, Robert
    Lubke, Gitta
    Ludolph-Donislawski, Anja
    Lupoli, Sara
    Madden, Pamela A F
    Mannikko, Reija
    Marques-Vidal, Pedro
    Martin, Nicholas G
    McKenzie, Colin A
    McKnight, Barbara
    Mellstrom, Dan
    Menni, Cristina
    Montgomery, Grant W
    Musk, Aw Bill
    Narisu, Narisu
    Nauck, Matthias
    Nolte, Ilja M
    Oldehinkel, Albertine J
    Olden, Matthias
    Ong, Ken K
    Padmanabhan, Sandosh
    Peyser, Patricia A
    Pisinger, Charlotta
    Porteous, David J
    Raitakari, Olli T
    Rankinen, Tuomo
    Rao, D C
    Rasmussen-Torvik, Laura J
    Rawal, Rajesh
    Rice, Treva
    Ridker, Paul M
    Rose, Lynda M
    Bien, Stephanie A
    Rudan, Igor
    Sanna, Serena
    Sarzynski, Mark A
    Sattar, Naveed
    Savonen, Kai
    Schlessinger, David
    Scholtens, Salome
    Schurmann, Claudia
    Scott, Robert A
    Sennblad, Bengt
    Siemelink, Marten A
    Silbernagel, Gunther
    Slagboom, P Eline
    Snieder, Harold
    Staessen, Jan A
    Stott, David J
    Swertz, Morris A
    Swift, Amy J
    Taylor, Kent D
    Tayo, Bamidele O
    Thorand, Barbara
    Thuillier, Dorothee
    Tuomilehto, Jaakko
    Uitterlinden, Andre G
    Vandenput, Liesbeth
    Vohl, Marie-Claude
    Volzke, Henry
    Vonk, Judith M
    Waeber, Gerard
    Waldenberger, Melanie
    Westendorp, R G J
    Wild, Sarah
    Willemsen, Gonneke
    Wolffenbuttel, Bruce H R
    Wong, Andrew
    Wright, Alan F
    Zhao, Wei
    Zillikens, M Carola
    Baldassarre, Damiano
    Balkau, Beverley
    Bandinelli, Stefania
    Boger, Carsten A
    Boomsma, Dorret I
    Bouchard, Claude
    Bruinenberg, Marcel
    Chasman, Daniel I
    Chen, Yii-DerIda
    Chines, Peter S
    Cooper, Richard S
    Cucca, Francesco
    Cusi, Daniele
    Faire, Ulf de
    Ferrucci, Luigi
    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, SE-205 02 Malmö, Sweden; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA.
    Froguel, Philippe
    Gordon-Larsen, Penny
    Grabe, Hans-Jorgen
    Gudnason, Vilmundur
    Haiman, Christopher A
    Hayward, Caroline
    Hveem, Kristian
    Johnson, Andrew D
    Wouter Jukema, J
    Kardia, Sharon L R
    Kivimaki, Mika
    Kooner, Jaspal S
    Kuh, Diana
    Laakso, Markku
    Lehtimaki, Terho
    Marchand, Loic Le
    Marz, Winfried
    McCarthy, Mark I
    Metspalu, Andres
    Morris, Andrew P
    Ohlsson, Claes
    Palmer, Lyle J
    Pasterkamp, Gerard
    Pedersen, Oluf
    Peters, Annette
    Peters, Ulrike
    Polasek, Ozren
    Psaty, Bruce M
    Qi, Lu
    Rauramaa, Rainer
    Smith, Blair H
    Sorensen, Thorkild I A
    Strauch, Konstantin
    Tiemeier, Henning
    Tremoli, Elena
    van der Harst, Pim
    Vestergaard, Henrik
    Vollenweider, Peter
    Wareham, Nicholas J
    Weir, David R
    Whitfield, John B
    Wilson, James F
    Tyrrell, Jessica
    Frayling, Timothy M
    Barroso, Ines
    Boehnke, Michael
    Deloukas, Panagiotis
    Fox, Caroline S
    Hirschhorn, Joel N
    Hunter, David J
    Spector, Tim D
    Strachan, David P
    van Duijn, Cornelia M
    Heid, Iris M
    Mohlke, Karen L
    Marchini, Jonathan
    Loos, Ruth J F
    Kilpelainen, Tuomas O
    Liu, Ching-Ti
    Borecki, Ingrid B
    North, Kari E
    Cupples, L Adrienne
    Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits2017In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, p. 14977-14977Article in journal (Refereed)
    Abstract [en]

    Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution.

  • 118. Kachuri, Linda
    et al.
    Amos, Christopher I.
    Mckay, James D.
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Vineis, Paolo
    Bueno-de-Mesquita, H. Bas
    Boutron-Ruault, Marie-Christine
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Quiros, J. Ramon
    Sieri, Sabina
    Travis, Ruth C.
    Weiderpass, Elisabete
    Le Marchand, Loic
    Henderson, Brian E.
    Wilkens, Lynne
    Goodman, Gary E.
    Chen, Chu
    Doherty, Jennifer A.
    Christiani, David C.
    Wei, Yongyue
    Su, Li
    Tworoger, Shelley
    Zhang, Xuehong
    Kraft, Peter
    Zaridze, David
    Field, John K.
    Marcus, Michael W.
    Davies, Michael P. A.
    Hyde, Russell
    Caporaso, Neil E.
    Landi, Maria Teresa
    Severi, Gianluca
    Giles, Graham G.
    Liu, Geoffrey
    McLaughlin, John R.
    Li, Yafang
    Xiao, Xiangjun
    Fehringer, Gord
    Zong, Xuchen
    Denroche, Robert E.
    Zuzarte, Philip C.
    McPherson, John D.
    Brennan, Paul
    Hung, Rayjean J.
    Fine mapping of chromosome 5p15.33 based on a targeted deep sequencing and high density genotyping identifies novel lung cancer susceptibility loci2016In: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 37, no 1, p. 96-105Article in journal (Refereed)
    Abstract [en]

    Chromosome 5p15.33 has been identified as a lung cancer susceptibility locus, however the underlying causal mechanisms were not fully elucidated. Previous fine-mapping studies of this locus have relied on imputation or investigated a small number of known, common variants. This study represents a significant advance over previous research by investigating a large number of novel, rare variants, as well as their underlying mechanisms through telomere length. Variants for this fine-mapping study were identified through a targeted deep sequencing (average depth of coverage greater than 4000x) of 576 individuals. Subsequently, 4652 SNPs, including 1108 novel SNPs, were genotyped in 5164 cases and 5716 controls of European ancestry. After adjusting for known risk loci, rs2736100 and rs401681, we identified a new, independent lung cancer susceptibility variant in LPCAT1: rs139852726 (OR = 0.46, P = 4.73x10(-9)), and three new adenocarcinoma risk variants in TERT: rs61748181 (OR = 0.53, P = 2.64x10(-6)), rs112290073 (OR = 1.85, P = 1.27x10(-5)), rs138895564 (OR = 2.16, P = 2.06x10(-5); among young cases, OR = 3.77, P = 8.41x10(-4)). In addition, we found that rs139852726 (P = 1.44x10(-3)) was associated with telomere length in a sample of 922 healthy individuals. The gene-based SKAT-O analysis implicated TERT as the most relevant gene in the 5p15.33 region for adenocarcinoma (P = 7.84x10(-7)) and lung cancer (P = 2.37x10(-5)) risk. In this largest fine-mapping study to investigate a large number of rare and novel variants within 5p15.33, we identified novel lung and adenocarcinoma susceptibility loci with large effects and provided support for the role of telomere length as the potential underlying mechanism.

  • 119. Kanoni, Stavroula
    et al.
    Masca, Nicholas G D
    Stirrups, Kathleen E
    Varga, Tibor V
    Warren, Helen R
    Scott, Robert A
    Southam, Lorraine
    Zhang, Weihua
    Yaghootkar, Hanieh
    Müller-Nurasyid, Martina
    Couto Alves, Alexessander
    Strawbridge, Rona J
    Lataniotis, Lazaros
    An Hashim, Nikman
    Besse, Céline
    Boland, Anne
    Braund, Peter S
    Connell, John M
    Dominiczak, Anna
    Farmaki, Aliki-Eleni
    Franks, Stephen
    Grallert, Harald
    Jansson, Jan-Håkan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Karaleftheri, Maria
    Keinänen-Kiukaanniemi, Sirkka
    Matchan, Angela
    Pasko, Dorota
    Peters, Annette
    Poulter, Neil
    Rayner, Nigel W
    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.
    Rolandsson, Olov
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Sabater-Lleal, Maria
    Sennblad, Bengt
    Sever, Peter
    Shields, Denis
    Silveira, Angela
    Stanton, Alice V
    Strauch, Konstantin
    Tomaszewski, Maciej
    Tsafantakis, Emmanouil
    Waldenberger, Melanie
    Blakemore, Alexandra I F
    Dedoussis, George
    Escher, Stefan A
    Kooner, Jaspal S
    McCarthy, Mark I
    Palmer, Colin N A
    Hamsten, Anders
    Caulfield, Mark J
    Frayling, Timothy M
    Tobin, Martin D
    Jarvelin, Marjo-Riitta
    Zeggini, Eleftheria
    Gieger, Christian
    Chambers, John C
    Wareham, Nick J
    Munroe, Patricia B
    Franks, Paul W
    Samani, Nilesh J
    Deloukas, Panos
    Analysis with the exome array identifies multiple new independent variants in lipid loci2016In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 25, no 18, p. 4094-4106Article in journal (Refereed)
    Abstract [en]

    It has been hypothesized that low frequency (1-5% minor allele frequency (MAF)) and rare (<1% MAF) variants with large effect sizes may contribute to the missing heritability in complex traits. Here, we report an association analysis of lipid traits (total cholesterol, LDL-cholesterol, HDL-cholesterol triglycerides) in up to 27 312 individuals with a comprehensive set of low frequency coding variants (ExomeChip), combined with conditional analysis in the known lipid loci. No new locus reached genome-wide significance. However, we found a new lead variant in 26 known lipid association regions of which 16 were >1000-fold more significant than the previous sentinel variant and not in close LD (six had MAF <5%). Furthermore, conditional analysis revealed multiple independent signals (ranging from 1 to 5) in a third of the 98 lipid loci tested, including rare variants. Addition of our novel associations resulted in between 1.5- and 2.5-fold increase in the proportion of heritability explained for the different lipid traits. Our findings suggest that rare coding variants contribute to the genetic architecture of lipid traits.

  • 120. Key, Timothy J.
    et al.
    Appleby, Paul N.
    Travis, Ruth C.
    Albanes, Demetrius
    Alberg, Anthony J.
    Barricarte, Aurelio
    Black, Amanda
    Boeing, Heiner
    Bueno-de-Mesquita, H. Bas
    Chan, June M.
    Chen, Chu
    Cook, Michael B.
    Donovan, Jenny L.
    Galan, Pilar
    Gilbert, Rebecca
    Giles, Graham G.
    Giovannucci, Edward
    Goodman, Gary E.
    Goodman, Phyllis J.
    Gunter, Marc J.
    Hamdy, Freddie C.
    Heliovaara, Markku
    Helzlsouer, Kathy J.
    Henderson, Brian E.
    Hercberg, Serge
    Hoffman-Bolton, Judy
    Hoover, Robert N.
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Biobank Research. International Agency for Research on Cancer, Lyon, France.
    Khaw, Kay-Tee
    King, Irena B.
    Knekt, Paul
    Kolonel, Laurence N.
    Le Marchand, Loic
    Mannisto, Satu
    Martin, Richard M.
    Meyer, Haakon E.
    Mondul, Alison M.
    Moy, Kristin A.
    Neal, David E.
    Neuhouser, Marian L.
    Palli, Domenico
    Platz, Elizabeth A.
    Pouchieu, Camille
    Rissanen, Harri
    Schenk, Jeannette M.
    Severi, Gianluca
    Stampfer, Meir J.
    Tjonneland, Anne
    Touvier, Mathilde
    Trichopoulou, Antonia
    Weinstein, Stephanie J.
    Ziegler, Regina G.
    Zhou, Cindy Ke
    Allen, Naomi E.
    Carotenoids, retinol, tocopherols, and prostate cancer risk: pooled analysis of 15 studies2015In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 102, no 5, p. 1142-1157Article in journal (Refereed)
    Abstract [en]

    Background: Individual studies have suggested that circulating carotenoids, retinol, or tocopherols may be associated with prostate cancer risk, but the studies have not been large enough to provide precise estimates of associations, particularly by stage and grade of disease. Objective: The objective of this study was to conduct a pooled analysis of the associations of the concentrations of 7 carotenoids, retinol, alpha-tocopherol, and gamma-tocopherol with risk of prostate cancer and to describe whether any associations differ by stage or grade of the disease or other factors. Design: Principal investigators of prospective studies provided individual participant data for prostate cancer cases and controls. Risk by study-specific fifths of each biomarker was estimated by using multivariable-adjusted conditional logistic regression in matched case-control sets. Results: Data were available for up to 11,239 cases (including 1654 advanced stage and 1741 aggressive) and 18,541 controls from 15 studies. Lycopene was not associated with overall risk of prostate cancer, but there was statistically significant heterogeneity by stage of disease, and the OR for aggressive disease for the highest compared with the lowest fifth of lycopene was 0.65 (95% CI: 0.46, 0.91; P-trend = 0.032). No other carotenoid was significantly associated with overall risk of prostate cancer or with risk of advanced-stage or aggressive disease. For retinol, the OR for the highest compared with the lowest fifth was 1.13 (95% CI: 1.04, 1.22; P-trend = 0.015). For alpha-tocopherol, the OR for the highest compared with the lowest fifth was 0.86 (95% CI: 0.78, 0.94; P-trend < 0.001), with significant heterogeneity by stage of disease; the OR for aggressive prostate cancer was 0.74 (95% CI: 0.59, 0.92; P-trend = 0.001). gamma-Tocopherol was not associated with risk. Conclusions: Overall prostate cancer risk was positively associated with retinol and inversely associated with alpha-tocopherol, and risk of aggressive prostate cancer was inversely associated with lycopene and alpha-tocopherol. Whether these associations reflect causal relations is unclear.

  • 121. Khan, Aneire E
    et al.
    Gallo, Valentina
    Linseisen, Jakob
    Kaaks, Rudolf
    Rohrmann, Sabine
    Raaschou-Nielsen, Ole
    Tjønneland, Anne
    Johnsen, Hans E
    Overvad, Kim
    Bergmann, Manuela M
    Boeing, Heiner
    Benetou, Vasiliki
    Psaltopoulou, Theodora
    Trichopoulou, Antonia
    Masala, Giovanna
    Mattiello, Amalia
    Grioni, Sara
    Tumino, Rosario
    Vermeulen, Roel C H
    Peeters, Petra H M
    Bueno-de-Mesquita, H Bas
    Ros, Martine M
    Lund, Eiliv
    Ardanaz, Eva
    Chirlaque, María-Dolores
    Jakszyn, Paula
    Larrañaga, Nerea
    Losada, Adamina
    Becker, Nikolaus
    Nieters, Alexandra
    Martínez-García, Carmen
    Ågren, Åsa
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Berglund, Göran
    Manjer, Jonas
    Allen, Naomi E
    Key, Timothy J
    Bingham, Sheila
    Khaw, Kay Tee
    Slimani, Nadia
    Ferrari, Pietro
    Boffetta, Paolo
    Norat, Teresa
    Vineis, Paolo
    Riboli, Elio
    Diabetes and the risk of non-Hodgkin's lymphoma and multiple myeloma in the European prospective investigation into Cancer and nutrition2008In: Haematologica (online), ISSN 0390-6078, E-ISSN 1592-8721, Vol. 93, no 6, p. 842-850Article in journal (Refereed)
  • 122. Kilpelainen, Tuomas O.
    et al.
    Carli, Jayne F. Martin
    Skowronski, Alicja A.
    Sun, Qi
    Kriebel, Jennifer
    Feitosa, Mary F.
    Hedman, Asa K.
    Drong, Alexander W.
    Hayes, James E.
    Zhao, Jinghua
    Pers, Tune H.
    Schick, Ursula
    Grarup, Niels
    Kutalik, Zoltan
    Trompet, Stella
    Mangino, Massimo
    Kristiansson, Kati
    Beekman, Marian
    Lyytikainen, Leo-Pekka
    Eriksson, Joel
    Henneman, Peter
    Lahti, Jari
    Tanaka, Toshiko
    Luan, Jian'an
    Del Greco M, Fabiola
    Pasko, Dorota
    Renström, Frida
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö 20502, Sweden.
    Willems, Sara M.
    Mahajan, Anubha
    Rose, Lynda M.
    Guo, Xiuqing
    Liu, Yongmei
    Kleber, Marcus E.
    Perusse, Louis
    Gaunt, Tom
    Ahluwalia, Tarunveer S.
    Sung, Yun Ju
    Ramos, Yolande F.
    Amin, Najaf
    Amuzu, Antoinette
    Barroso, Ines
    Bellis, Claire
    Blangero, John
    Buckley, Brendan M.
    Boehringer, Stefan
    Chen, Yii-Der I.
    de Craen, Anton J. N.
    Crosslin, David R.
    Dale, Caroline E.
    Dastani, Zari
    Day, Felix R.
    Deelen, Joris
    Delgado, Graciela E.
    Demirkan, Ayse
    Finucane, Francis M.
    Ford, Ian
    Garcia, Melissa E.
    Gieger, Christian
    Gustafsson, Stefan
    Hallmans, Goran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Hankinson, Susan E.
    Havulinna, Aki S.
    Herder, Christian
    Hernandez, Dena
    Hicks, Andrew A.
    Hunter, David J.
    Illig, Thomas
    Ingelsson, Erik
    Ioan-Facsinay, Andreea
    Jansson, John-Olov
    Jenny, Nancy S.
    Jorgensen, Marit E.
    Jorgensen, Torben
    Karlsson, Magnus
    Koenig, Wolfgang
    Kraft, Peter
    Kwekkeboom, Joanneke
    Laatikainen, Tiina
    Ladwig, Karl-Heinz
    LeDuc, Charles A.
    Lowe, Gordon
    Lu, Yingchang
    Marques-Vidal, Pedro
    Meisinger, Christa
    Menni, Cristina
    Morris, Andrew P.
    Myers, Richard H.
    Mannisto, Satu
    Nalls, Mike A.
    Paternoster, Lavinia
    Peters, Annette
    Pradhan, Aruna D.
    Rankinen, Tuomo
    Rasmussen-Torvik, Laura J.
    Rathmann, Wolfgang
    Rice, Treva K.
    Richards, J. Brent
    Ridker, Paul M.
    Sattar, Naveed
    Savage, David B.
    Söderberg, Stefan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Timpson, Nicholas J.
    Vandenput, Liesbeth
    van Heemst, Diana
    Uh, Hae-Won
    Vohl, Marie-Claude
    Walker, Mark
    Wichmann, Heinz-Erich
    Widen, Elisabeth
    Wood, Andrew R.
    Yao, Jie
    Zeller, Tanja
    Zhang, Yiying
    Meulenbelt, Ingrid
    Kloppenburg, Margreet
    Astrup, Arne
    Sorensen, Thorkild I. A.
    Sarzynski, Mark A.
    Rao, D. C.
    Jousilahti, Pekka
    Vartiainen, Erkki
    Hofman, Albert
    Rivadeneira, Fernando
    Uitterlinden, Andre G.
    Kajantie, Eero
    Osmond, Clive
    Palotie, Aarno
    Eriksson, Johan G.
    Heliovaara, Markku
    Knekt, Paul B.
    Koskinen, Seppo
    Jula, Antti
    Perola, Markus
    Huupponen, Risto K.
    Viikari, Jorma S.
    Kahonen, Mika
    Lehtimaki, Terho
    Raitakari, Olli T.
    Mellstrom, Dan
    Lorentzon, Mattias
    Casas, Juan P.
    Bandinelli, Stefanie
    Maerz, Winfried
    Isaacs, Aaron
    van Dijk, Ko W.
    van Duijn, Cornelia M.
    Harris, Tamara B.
    Bouchard, Claude
    Allison, Matthew A.
    Chasman, Daniel I.
    Ohlsson, Claes
    Lind, Lars
    Scott, Robert A.
    Langenberg, Claudia
    Wareham, Nicholas J.
    Ferrucci, Luigi
    Frayling, Timothy M.
    Pramstaller, Peter P.
    Borecki, Ingrid B.
    Waterworth, Dawn M.
    Bergmann, Sven
    Waeber, Gerard
    Vollenweider, Peter
    Vestergaard, Henrik
    Hansen, Torben
    Pedersen, Oluf
    Hu, Frank B.
    Slagboom, P. Eline
    Grallert, Harald
    Spector, Tim D.
    Jukema, J. W.
    Klein, Robert J.
    Schadt, Erik E.
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachussetts 02115, USA; Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö 20502, Sweden.
    Lindgren, Cecilia M.
    Leibel, Rudolph L.
    Loos, Ruth J. F.
    Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels2016In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, article id 10494Article in journal (Refereed)
    Abstract [en]

    Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P < 10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P < 5 x 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.

  • 123. Klein, Alison P.
    et al.
    Lindström, Sara
    Mendelsohn, Julie B.
    Steplowski, Emily
    Arslan, Alan A.
    Bueno-de-Mesquita, H. Bas
    Fuchs, Charles S.
    Gallinger, Steven
    Gross, Myron
    Helzlsouer, Kathy
    Holly, Elizabeth A.
    Jacobs, Eric J.
    Lacroix, Andrea
    Li, Donghui
    Mandelson, Margaret T.
    Olson, Sara H.
    Petersen, Gloria M.
    Risch, Harvey A.
    Stolzenberg-Solomon, Rachael Z.
    Zheng, Wei
    Amundadottir, Laufey
    Albanes, Demetrius
    Allen, Naomi E.
    Bamlet, William R.
    Boutron-Ruault, Marie-Christine
    Buring, Julie E.
    Bracci, Paige M.
    Canzian, Federico
    Clipp, Sandra
    Cotterchio, Michelle
    Duell, Eric J.
    Elena, Joanne
    Gaziano, J. Michael
    Giovannucci, Edward L.
    Goggins, Michael
    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.
    Hassan, Manal
    Hutchinson, Amy
    Hunter, David J.
    Kooperberg, Charles
    Kurtz, Robert C.
    Liu, Simin
    Overvad, Kim
    Palli, Domenico
    Patel, Alpa V.
    Rabe, Kari G.
    Shu, Xiao-Ou
    Slimani, Nadia
    Tobias, Geoffrey S.
    Trichopoulos, Dimitrios
    Van Den Eeden, Stephen K.
    Vineis, Paolo
    Virtamo, Jarmo
    Wactawski-Wende, Jean
    Wolpin, Brian M.
    Yu, Herbert
    Yu, Kai
    Zeleniuch-Jacquotte, Anne
    Chanock, Stephen J.
    Hoover, Robert N.
    Hartge, Patricia
    Kraft, Peter
    An absolute risk model to identify individuals at elevated risk for pancreatic cancer in the general population.2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 9, article id e72311Article in journal (Refereed)
    Abstract [en]

    PURPOSE: We developed an absolute risk model to identify individuals in the general population at elevated risk of pancreatic cancer.

    PATIENTS AND METHODS: Using data on 3,349 cases and 3,654 controls from the PanScan Consortium, we developed a relative risk model for men and women of European ancestry based on non-genetic and genetic risk factors for pancreatic cancer. We estimated absolute risks based on these relative risks and population incidence rates.

    RESULTS: Our risk model included current smoking (multivariable adjusted odds ratio (OR) and 95% confidence interval: 2.20 [1.84-2.62]), heavy alcohol use (>3 drinks/day) (OR: 1.45 [1.19-1.76]), obesity (body mass index >30 kg/m(2)) (OR: 1.26 [1.09-1.45]), diabetes >3 years (nested case-control OR: 1.57 [1.13-2.18], case-control OR: 1.80 [1.40-2.32]), family history of pancreatic cancer (OR: 1.60 [1.20-2.12]), non-O ABO genotype (AO vs. OO genotype) (OR: 1.23 [1.10-1.37]) to (BB vs. OO genotype) (OR 1.58 [0.97-2.59]), rs3790844(chr1q32.1) (OR: 1.29 [1.19-1.40]), rs401681(5p15.33) (OR: 1.18 [1.10-1.26]) and rs9543325(13q22.1) (OR: 1.27 [1.18-1.36]). The areas under the ROC curve for risk models including only non-genetic factors, only genetic factors, and both non-genetic and genetic factors were 58%, 57% and 61%, respectively. We estimate that fewer than 3/1,000 U.S. non-Hispanic whites have more than a 5% predicted lifetime absolute risk.

    CONCLUSION: Although absolute risk modeling using established risk factors may help to identify a group of individuals at higher than average risk of pancreatic cancer, the immediate clinical utility of our model is limited. However, a risk model can increase awareness of the various risk factors for pancreatic cancer, including modifiable behaviors.

  • 124.
    Klingberg, Sofia
    et al.
    Department of Internal Medicine and Clinical Nutrition, Sahlgrenska Academy, University of Gothenburg, Gothenburg.
    Ellegård, Lars
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Jansson, Jan-Håkan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    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.
    Winkvist, Anna
    Department of Internal Medicine and Clinical Nutrition, Sahlgrenska Academy, University of Gothenburg, Gothenburg.
    Dietary intake of naturally occurring plant sterols is related to a lower risk of a first myocardial infarction in men but not in women in northern sweden2013In: Journal of Nutrition, ISSN 0022-3166, E-ISSN 1541-6100, Vol. 143, no 10, p. 1630-1635Article in journal (Refereed)
    Abstract [en]

    Dietary intake of naturally occurring plant sterols is inversely related to serum cholesterol concentrations. Elevated serum cholesterol increases the risk of myocardial infarction (MI), but it is unknown if this can be reduced by dietary intake of naturally occurring plant sterols. Our aim was to investigate if a high intake of naturally occurring plant sterols is related to a lower risk of contracting a first MI. The analysis included 1005 prospective cases (219 women, 786 men) and 3148 matched referents (723 women, 2425 men), aged 29-73 y at baseline, from the population-based Northern Sweden Health and Disease Study. A food frequency questionnaire (FFQ) was completed at baseline. Absolute plant sterol intake was inversely related to the risk of a first MI in men (OR highest vs. lowest quartile = 0.70; 95% CI: 0.53, 0.85; P-trend = 0.006) but not in women. After adjustment for confounders, the estimated risk was somewhat attenuated (OR highest vs. lowest quartile = 0.71; 95% CI: 0.55, 0.92; P-trend = 0.067), suggesting that increasing sterol intake from 150 to 340 mg/d reduces the risk of a first MI by 29%. Energy-adjusted plant sterol intake was not related to the risk of a first MI in either men or women. In conclusion, the findings of this observational study show that a high absolute intake of naturally occurring plant sterols is significantly related to a lower risk of a first MI in men in northern Sweden, whereas no significant relation was seen for energy-adjusted plant sterol intake. In women, no significant associations were found. The results from this study show that intake of plant sterols may be important in prevention of MI.

  • 125. Klingberg, Sofia
    et al.
    Winkvist, Anna
    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.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Evaluation of plant sterol intake estimated with the Northern Sweden FFQ2013In: Public Health Nutrition, ISSN 1368-9800, E-ISSN 1475-2727, Vol. 16, no 3, p. 460-467Article in journal (Refereed)
    Abstract [en]

    Objective: To evaluate plant sterol intake estimated with the eighty-four-item Northern Sweden FFQ against repeated 24 h dietary recalls (24-HDR) as the reference method. Design: Randomly recruited participants from the Vasterbotten Intervention Programme (VIP) responded to an FFQ (FFQ1). Over the subsequent 12 months, ten repeated 24-HDR were carried out. After this, a second FFQ (FFQ2) was completed. Setting: Vasterbotten county, northern Sweden. Subjects: Ninety-six men and ninety-nine women. Results: The Pearson correlation coefficient for absolute total plant sterol intake estimated with FFQ1 and 24-HDR was 0.58 and 0.55 for the men and women, respectively. Cross-classification of participants into quartiles of absolute plant sterol intake estimated with FFQ1 and 24-HDR showed that 90% of the men and 83% of the women were classified into the same or an adjacent quartile. For energy-adjusted plant sterol intake, 71% of the men and 74% of the women were classified into the same or an adjacent quartile. The agreement for cross-classification of participants into quartiles between FFQ1 and FFQ2 was good for both absolute and energy-adjusted plant sterol intake. Conclusions: The FFQ is able to capture absolute plant sterol intake to the same extent as other nutrients, and to rank individuals according to both their absolute and energy-adjusted plant sterol intake. The reproducibility of the FFQ was good, suggesting that the method is reliable. This makes it possible to use plant sterol data from the FFQ in large-scale studies of the association between plant sterol intake and disease.

  • 126. Koivula, R. W.
    et al.
    Grontved, A.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Wennberg, Patrik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Ostergaard, L.
    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.
    Renstrom, Frida
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Clinical Sciences, Lund University, Malmö, Sweden.
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Bicycling to work and primordial prevention of cardiovascular and type 2 diabetes risk: a cohort study from Northern Sweden2016In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 59, p. S150-S150, article id 298Article in journal (Refereed)
  • 127. Kraja, Aldi T.
    et al.
    Cook, James P.
    Warren, Helen R.
    Surendran, Praveen
    Liu, Chunyu
    Evangelou, Evangelos
    Manning, Alisa K.
    Grarup, Niels
    Drenos, Fotios
    Sim, Xueling
    Smith, Albert Vernon
    Amin, Najaf
    Blakemore, Alexandra I. F.
    Bork-Jensen, Jette
    Brandslund, Ivan
    Farmaki, Aliki-Eleni
    Fava, Cristiano
    Ferreira, Teresa
    Herzig, Karl-Heinz
    Giri, Ayush
    Giulianini, Franco
    Grove, Megan L.
    Guo, Xiuqing
    Harris, Sarah E.
    Have, Christian T.
    Havulinna, Aki S.
    Zhang, He
    Jorgensen, Marit E.
    Karajamaki, AnneMari
    Kooperberg, Charles
    Linneberg, Allan
    Little, Louis
    Liu, Yongmei
    Bonnycastle, Lori L.
    Lu, Yingchang
    Magi, Reedik
    Mahajan, Anubha
    Malerba, Giovanni
    Marioni, Riccardo E.
    Mei, Hao
    Menni, Cristina
    Morrison, Alanna C.
    Padmanabhan, Sandosh
    Palmas, Walter
    Poveda, Alaitz
    Rauramaa, Rainer
    Rayner, Nigel William
    Riaz, Muhammad
    Rice, Ken
    Richard, Melissa A.
    Smith, Jennifer A.
    Southam, Lorraine
    Stancakova, Alena
    Stirrups, Kathleen E.
    Tragante, Vinicius
    Tuomi, Tiinamaija
    Umeå University, Faculty of Medicine, Department of Biobank Research. Folkhälsan Research Centre, Finland; Department of Endocrinology, Helsinki University Central Hospital, Finland; Finnish Institute for Molecular Medicine (FIMM), Helsinki University, Finland.
    Tzoulald, Ioanna
    Varga, Tibor V.
    Weiss, Stefan
    Yiorkas, Andrianos M.
    Young, Robin
    Zhang, Weihua
    Barnes, Michael R.
    Cabrera, Claudia P.
    Gao, He
    Boehnke, Michael
    Boerwinkle, Eric
    Chambers, John C.
    Connell, John M.
    Christensen, Cramer K.
    de Boer, Rudolf A.
    Deary, Ian J.
    Dedoussis, George
    Deloukas, Panos
    Dominiczak, Anna F.
    Dorr, Marcus
    Joehanes, Roby
    Edwards, Todd L.
    Esko, Tonu
    Fornage, Myriam
    Franceschini, Nora
    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, United States.
    Gambaro, Giovanni
    Groop, Leif
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Hansen, Torben
    Hayward, Caroline
    Heikki, Oksa
    Ingelsson, Erik
    Tuomilehto, Jaakko
    Jarvelin, Marjo-Riitta
    Kardia, Sharon L. R.
    Karpe, Fredrik
    Kooner, Jaspal S.
    Lakka, Timo A.
    Langenberg, Claudia
    Lind, Lars
    Loos, Ruth J. F.
    Laakso, Markku
    McCarthy, Mark I.
    Melander, Olle
    Mohlke, Karen L.
    Moris, Andrwe P.
    Palmer, Colin N. A.
    Pedersen, Oluf
    Polasek, Ozren
    Poulter, Neil R.
    Province, Michael A.
    Psaty, Bruce M.
    Ridker, Paul M.
    Rotter, Jerome I.
    Rudan, Igor
    Salomaa, Veikko
    Samani, Nilesh J.
    Sever, Peter J.
    Skaaby, Tea
    Stafford, Jeanette M.
    Starr, John M.
    van der Harst, Pim
    van der Meer, Peter
    van Duijn, Cornelia M.
    Vergnaud, Anne-Claire
    Gudnason, Vilmundur
    Wareham, Nicholas J.
    Wilson, James G.
    Willer, Cristen J.
    Witte, Daniel R.
    Zeggini, Eleftheria
    Saleheen, Danish
    Butterworth, Adam S.
    Danesh, John
    Asselbergs, Folkert W.
    Wain, Louise V.
    Ehret, Georg B.
    Chasman, Daniel I.
    Caulfield, Mark J.
    Elliott, Paul
    Lindgren, Cecilia M.
    Levy, Daniel
    Newton-Cheh, Christopher
    Munroe, Patricia B.
    Howson, Joanna M. M.
    New Blood Pressure-Associated Loci Identified in Meta-Analyses of 475000 Individuals2017In: Circulation: Cardiovascular Genetics, ISSN 1942-325X, E-ISSN 1942-3268, Vol. 10, no 5, article id e001778Article in journal (Refereed)
    Abstract [en]

    Background-Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association. & para;& para;Methods and Results-Here, we augment the sample with 140886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, approximate to 475000), and the other in the subset of individuals of European descent (approximate to 423000). Twenty-one SNVs were genome-wide significant (P<5x10(-8) ) for BP, of which 4 are new BP loci: rs9678851 (missense, SLC4A1AP), rs7437940 (AFAP1), rs13303 (missense, STAB1), and rs1055144 (7p15.2). In addition, we identified a potentially independent novel BP-associated SNV, rs3416322 (missense, SYNPO2L) at a known locus, uncorrelated with the previously reported SNVs. Two SNVs are associated with expression levels of nearby genes, and SNVs at 3 loci are associated with other traits. One SNV with a minor allele frequency <0.01, (rs3025380 at DBH) was genome-wide significant.& para;& para;Conclusions-We report 4 novel loci associated with BP regulation, and 1 independent variant at an established BP locus. This analysis highlights several candidate genes with variation that alter protein function or gene expression for potential follow-up.

  • 128. Krauskopf, Julian
    et al.
    de Kok, Theo M
    Hebels, Dennie G
    Bergdahl, Ingvar A
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Spaeth, Florentin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Kiviranta, Hannu
    Rantakokko, Panu
    Kyrtopoulos, Soterios A
    Kleinjans, Jos C
    MicroRNA profile for health risk assessment: environmental exposure to persistent organic pollutants strongly affects the human blood microRNA machinery2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 9262Article in journal (Refereed)
    Abstract [en]

    Persistent organic pollutants (POPs) are synthetic chemical substances that accumulate in our environment. POPs such as polychlorinated biphenyls (PCBs), hexachlorobenzene (HCB) and dichlorodiphenyltrichloroethane (DDT) have been classified as carcinogenic to humans and animals. Due to their resistance to biodegradation humans are still exposed to these compounds worldwide. We aim to evaluate the miRNA and transcriptomic response of a human population exposed to POPs. The miRNA and transcriptomic response was measured in blood of healthy subjects by microarray technology and associated with the serum concentrations of six PCB congeners, DDE (a common DDT metabolite), and HCB. A total of 93 miRNA levels appeared significantly associated with the POP-exposure (FDR < 0.05). The miRNA profile includes four tumor suppressor miRNAs, namely miR-193a-3p, miR-152, miR-31-5p and miR-34a-5p. Integration of the miRNA profile with the transcriptome profile suggests an interaction with oncogenes such as MYC, CCND1, BCL2 and VEGFA. We have shown that exposure to POPs is associated with human miRNA and transcriptomic responses. The identified miRNAs and target genes are related to various types of cancer and involved in relevant signaling pathways like wnt and p53. Therefore, these miRNAs may have great potential to contribute to biomarker-based environmental health risk assessment.

  • 129. Kreimer, Aimée R
    et al.
    Johansson, Mattias
    International Agency for Research on Cancer, Lyon, France.
    Waterboer, Tim
    Kaaks, Rudolf
    Chang-Claude, Jenny
    Drogen, Dagmar
    Tjønneland, Anne
    Overvad, Kim
    Quirós, J Ramón
    González, Carlos A
    Sánchez, Maria José
    Larrañaga, Nerea
    Navarro, Carmen
    Barricarte, Aurelio
    Travis, Ruth C
    Khaw, Kay-Tee
    Wareham, Nick
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Peeters, Petra H M
    Panico, Salvatore
    Masala, Giovanna
    Grioni, Sara
    Tumino, Rosario
    Vineis, Paolo
    Bueno-de-Mesquita, H Bas
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    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.
    Manjer, Jonas
    Ekström, Johanna
    Skeie, Guri
    Lund, Eiliv
    Weiderpass, Elisabete
    Ferrari, Pietro
    Byrnes, Graham
    Romieu, Isabelle
    Riboli, Elio
    Hildesheim, Allan
    Boeing, Heiner
    Pawlita, Michael
    Brennan, Paul
    Evaluation of human papillomavirus antibodies and risk of subsequent head and neck cancer2013In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 31, no 21, p. 2708-2715Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Human papillomavirus type 16 (HPV16) infection is causing an increasing number of oropharyngeal cancers in the United States and Europe. The aim of our study was to investigate whether HPV antibodies are associated with head and neck cancer risk when measured in prediagnostic sera.

    METHODS: We identified 638 participants with incident head and neck cancers (patients; 180 oral cancers, 135 oropharynx cancers, and 247 hypopharynx/larynx cancers) and 300 patients with esophageal cancers as well as 1,599 comparable controls from within the European Prospective Investigation Into Cancer and Nutrition cohort. Prediagnostic plasma samples from patients (collected, on average, 6 years before diagnosis) and control participants were analyzed for antibodies against multiple proteins of HPV16 as well as HPV6, HPV11, HPV18, HPV31, HPV33, HPV45, and HPV52. Odds ratios (ORs) of cancer and 95% CIs were calculated, adjusting for potential confounders. All-cause mortality was evaluated among patients using Cox proportional hazards regression.

    RESULTS: HPV16 E6 seropositivity was present in prediagnostic samples for 34.8% of patients with oropharyngeal cancer and 0.6% of controls (OR, 274; 95% CI, 110 to 681) but was not associated with other cancer sites. The increased risk of oropharyngeal cancer among HPV16 E6 seropositive participants was independent of time between blood collection and diagnosis and was observed more than 10 years before diagnosis. The all-cause mortality ratio among patients with oropharyngeal cancer was 0.30 (95% CI, 0.13 to 0.67), for patients who were HPV16 E6 seropositive compared with seronegative.

    CONCLUSION: HPV16 E6 seropositivity was present more than 10 years before diagnosis of oropharyngeal cancers.

  • 130. Kurbasic, Azra
    et al.
    Poveda, Alaitz
    Chen, Yan
    Ågren, Åsa
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Engberg, Elisabeth
    Umeå University, Faculty of Social Sciences, Demographic Data Base.
    Hu, Frank B
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Barroso, Ines
    Brändström, Anders
    Umeå University, Faculty of Social Sciences, Demographic Data Base.
    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.
    Renström, Frida
    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. Department of Nutrition, Harvard School of Public Health, Boston, MA, USA.
    Gene-Lifestyle Interactions in Complex Diseases: Design and Description of the GLACIER and VIKING Studies2014In: Current nutrition reports, ISSN 2161-3311, Vol. 3, no 4, p. 400-411Article in journal (Refereed)
    Abstract [en]

    Most complex diseases have well-established genetic and non-genetic risk factors. In some instances, these risk factors are likely to interact, whereby their joint effects convey a level of risk that is either significantly more or less than the sum of these risks. Characterizing these gene-environment interactions may help elucidate the biology of complex diseases, as well as to guide strategies for their targeted prevention. In most cases, the detection of gene-environment interactions will require sample sizes in excess of those needed to detect the marginal effects of the genetic and environmental risk factors. Although many consortia have been formed, comprising multiple diverse cohorts to detect gene-environment interactions, few robust examples of such interactions have been discovered. This may be because combining data across studies, usually through meta-analysis of summary data from the contributing cohorts, is often a statistically inefficient approach for the detection of gene-environment interactions. Ideally, single, very large and well-genotyped prospective cohorts, with validated measures of environmental risk factor and disease outcomes should be used to study interactions. The presence of strong founder effects within those cohorts might further strengthen the capacity to detect novel genetic effects and gene-environment interactions. Access to accurate genealogical data would also aid in studying the diploid nature of the human genome, such as genomic imprinting (parent-of-origin effects). Here we describe two studies from northern Sweden (the GLACIER and VIKING studies) that fulfill these characteristics.

  • 131. Kyro, Cecilie
    et al.
    Skeie, Guri
    Loft, Steffen
    Landberg, Rikard
    Christensen, Jane
    Lund, Eiliv
    Nilsson, Lena M.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Tjonneland, Anne
    Olsen, Anja
    Intake of whole grains from different cereal and food sources and incidence of colorectal cancer in the Scandinavian HELGA cohort2013In: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 24, no 7, p. 1363-1374Article in journal (Refereed)
    Abstract [en]

    A high intake of whole grains has been associated with a lower incidence of colorectal cancer, but few studies are available on the association with whole grains from different cereals, for example, wheat, rye and oats, and none has addressed these separately. The objective of this study was to investigate the association between whole-grain intake and colorectal cancer. We used data from the large population-based Scandinavian cohort HELGA consisting of 108,000 Danish, Swedish, and Norwegian persons, of whom 1,123 developed colorectal cancer during a median of 11 years of follow-up. Detailed information on daily intake of whole-grain products, including whole-grain bread, crispbread, and breakfast cereals, was available, and intakes of total whole grains and specific whole-grain species (wheat, rye, and oats) were estimated. Associations between these whole-grain variables and the incidence of colorectal cancer were investigated using Cox proportional hazards models. Intake of whole-grain products was associated with a lower incidence of colorectal cancer per 50-g increment (incidence rate ratio [IRR], 0.94; 95 % confidence interval [CI], 0.89, 0.99), and the same tendency was found for total whole-grain intake (IRR pr. 25-g increment, 0.94; 95 % CI, 0.88, 1.01). Intake of whole-grain wheat was associated with a lower incidence of colorectal cancer (IRR for highest versus lowest quartile of intake, 0.66; 95 % CI, 0.51, 0.85), but no statistical significant linear trend was observed (p for trend: 0.18). No significant association was found for whole-grain rye or oats. Whole-grain intake was associated with a lower incidence of colorectal cancer.

  • 132. Kyrø, Cecilie
    et al.
    Zamora-Ros, Raul
    Scalbert, Augustin
    Tjønneland, Anne
    Dossus, Laure
    Johansen, Christoffer
    Bidstrup, Pernille Envold
    Weiderpass, Elisabete
    Christensen, Jane
    Ward, Heather
    Aune, Dagfinn
    Riboli, Elio
    His, Mathilde
    Clavel-Chapelon, Françoise
    Baglietto, Laura
    Katzke, Verena
    Kühn, Tilman
    Boeing, Heiner
    Floegel, Anna
    Overvad, Kim
    Lasheras, Cristina
    Travier, Noémie
    Sánchez, Maria-José
    Amiano, Pilar
    Chirlaque, Maria-Dolores
    Ardanaz, Eva
    Khaw, Kay-Tee
    Wareham, Nick
    Perez-Cornago, Aurora
    Trichopoulou, Antonia
    Lagiou, Pagona
    Vasilopoulou, Effie
    Masala, Giovanna
    Grioni, Sara
    Berrino, Franco
    Tumino, Rosario
    Sacerdote, Carlotta
    Mattiello, Amalia
    Bueno-de-Mesquita, H B(as)
    Peeters, Petra H
    van Gils, Carla
    Borgquist, Signe
    Butt, Salma
    Zeleniuch-Jacquotte, Anne
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Hjartåker, Anette
    Skeie, Guri
    Olsen, Anja
    Romieu, Isabelle
    Pre-diagnostic polyphenol intake and breast cancer survival: the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort2015In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 154, no 2, p. 389-401Article in journal (Refereed)
    Abstract [en]

    The aim was to investigate the association between pre-diagnostic intakes of polyphenol classes (flavonoids, lignans, phenolic acids, stilbenes, and other polyphenols) in relation to breast cancer survival (all-cause and breast cancer-specific mortality). We used data from the European Prospective Investigation into Cancer and Nutrition cohort. Pre-diagnostic usual diet was assessed using dietary questionnaires, and polyphenol intakes were estimated using the Phenol-Explorer database. We followed 11,782 breast cancer cases from time of diagnosis until death, end of follow-up or last day of contact. During a median of 6 years, 1482 women died (753 of breast cancer). We related polyphenol intake to all-cause and breast cancer-specific mortality using Cox proportional hazard models with time since diagnosis as underlying time and strata for age and country. Among postmenopausal women, an intake of lignans in the highest versus lowest quartile was related to a 28 % lower risk of dying from breast (adjusted model: HR, quartile 4 vs. quartile 1, 0.72, 95 % CI 0.53; 0.98). In contrast, in premenopausal women, a positive association between lignan intake and all-cause mortality was found (adjusted model: HR, quartile 4 vs. quartile 1, 1.63, 95 % CI 1.03; 2.57). We found no association for other polyphenol classes. Intake of lignans before breast cancer diagnosis may be related to improved survival among postmenopausal women, but may on the contrary worsen the survival for premenopausal women. This suggests that the role of phytoestrogens in breast cancer survival is complex and may be dependent of menopausal status.

  • 133. Landberg, R.
    et al.
    Aman, P.
    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.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Long-term reproducibility of plasma alkylresorcinols as biomarkers of whole-grain wheat and rye intake within Northern Sweden Health and Disease Study Cohort2013In: European Journal of Clinical Nutrition, ISSN 0954-3007, E-ISSN 1476-5640, Vol. 67, no 3, p. 259-263Article in journal (Refereed)
    Abstract [en]

    BACKGROUND/OJBECTIVES: Alkylresorcinols (AR) have been suggested as specific biomarkers of whole-grain (WG) and bran intake from wheat and rye. Before using plasma AR as biomarkers in prospective cohort studies, the long-term reproducibility needs to be determined in order to judge how well a single plasma sample reflects the long-term concentration. The objective was therefore to estimate the reproducibility of plasma AR concentrations over 0.1-3.9 years. SUBJECTS/METHODS:The concentrations of AR homologues were analysed in plasma samples, drawn >8 h since last meal, 0.1-3.9 years apart (mean similar to 2 years) in 74 participants in the Swedish prospective Vasterbotten Intervention Project cohort. Reproducibility was estimated by calculating the intra class correlation coefficient (ICC). RESULTS: Fasting plasma AR concentrations were similar between the first and second measurements. The ICC for total AR was 0.54 (95% confidence interval (CI) = 0.38-0.69] overall, 0.34 (95% CI = 0.13-0.64) for men and 0.73 (95% CI = 0.56-0.85) for women, respectively. Somewhat higher ICCs were obtained for shorter AR homologues. CONCLUSION: In summary, the reproducibility of plasma AR over 0.1-3.9 years was high for women and moderate for men within this population. Together with previous data showing high validity of plasma AR as biomarkers of wheat and rye in different populations, the current finding suggest that this biomarker is stable over a long-time period and is therefore probably useful for assessment of long-term WG intake in populations with a wide intake range and a frequent intake.

  • 134. Leenders, Max
    et al.
    Bhattacharjee, Samsiddhi
    Vineis, Paolo
    Stevens, Victoria
    Bueno-de-Mesquita, H. Bas
    Shu, Xiao-Ou
    Amundadottir, Laufey
    Gross, Myron
    Tobias, Geoffrey S.
    Wactawski-Wende, Jean
    Arslan, Alan A.
    Duell, Eric J.
    Fuchs, Charles S.
    Gallinger, Steven
    Hartge, Patricia
    Hoover, Robert N.
    Holly, Elizabeth A.
    Jacobs, Eric J.
    Klein, Alison P.
    Kooperberg, Charles
    LaCroix, Andrea
    Li, Donghui
    Mandelson, Margaret T.
    Olson, Sara H.
    Petersen, Gloria
    Risch, Harvey A.
    Yu, Kai
    Wolpin, Brian M.
    Zheng, Wei
    Agalliu, Ilir
    Albanes, Demetrius
    Boutron-Ruault, Marie-Christine
    Bracci, Paige M.
    Buring, Julie E.
    Canzian, Federico
    Chang, Kenneth
    Chanock, Stephen J.
    Cotterchio, Michelle
    Gaziano, J. Michael
    Giovanucci, Edward L.
    Goggins, Michael
    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.
    Hankinson, Susan E.
    Hoffman-Bolton, Judith A.
    Hunter, David J.
    Hutchinson, Amy
    Jacobs, Kevin B.
    Jenab, Mazda
    Khaw, Kay-Tee
    Kraft, Peter
    Krogh, Vittorio
    Kurtz, Robert C.
    McWilliams, Robert R.
    Mendelsohn, Julie B.
    Patel, Alpa V.
    Rabe, Kari G.
    Riboli, Elio
    Tjonneland, Anne
    Trichopoulos, Dimitrios
    Virtamo, Jarmo
    Visvanathan, Kala
    Elena, Joanne W.
    Yu, Herbert
    Zeleniuch-Jacquotte, Anne
    Stolzenberg-Solomon, Rachael Z.
    Polymorphisms in genes related to one-carbon metabolism are not related to pancreatic cancer in PanScan and PanC42013In: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 24, no 3, p. 595-602Article in journal (Refereed)
    Abstract [en]

    The evidence of a relation between folate intake and one-carbon metabolism (OCM) with pancreatic cancer (PanCa) is inconsistent. In this study, the association between genes and single-nucleotide polymorphisms (SNPs) related to OCM and PanCa was assessed. Using biochemical knowledge of the OCM pathway, we identified thirty-seven genes and 834 SNPs to examine in association with PanCa. Our study included 1,408 cases and 1,463 controls nested within twelve cohorts (PanScan). The ten SNPs and five genes with lowest p values (< 0.02) were followed up in 2,323 cases and 2,340 controls from eight case-control studies (PanC4) that participated in PanScan2. The correlation of SNPs with metabolite levels was assessed for 649 controls from the European Prospective Investigation into Cancer and Nutrition. When both stages were combined, we observed suggestive associations with PanCa for rs10887710 (MAT1A) (OR 1.13, 95 %CI 1.04-1.23), rs1552462 (SYT9) (OR 1.27, 95 %CI 1.02-1.59), and rs7074891 (CUBN) (OR 1.91, 95 %CI 1.12-3.26). After correcting for multiple comparisons, no significant associations were observed in either the first or second stage. The three suggested SNPs showed no correlations with one-carbon biomarkers. This is the largest genetic study to date to examine the relation between germline variations in OCM-related genes polymorphisms and the risk of PanCa. Suggestive evidence for an association between polymorphisms and PanCa was observed among the cohort-nested studies, but this did not replicate in the case-control studies. Our results do not strongly support the hypothesis that genes related to OCM play a role in pancreatic carcinogenesis.

  • 135. Li, Weiqiang
    et al.
    Middha, Mridu
    Bicak, Mesude
    Sjoberg, Daniel D.
    Vertosick, Emily
    Dahlin, Anders
    Häggström, Christel
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Rönn, Ann-Charlotte
    Stattin, Par
    Melander, Olle
    Ulmert, David
    Lilja, Hans
    Klein, Robert J.
    Genome-wide Scan Identifies Role for AOX1 in Prostate Cancer Survival2018In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 74, no 6, p. 710-719Article in journal (Refereed)
    Abstract [en]

    Background: Most men diagnosed with prostate cancer have low-risk cancers. How to predict prostate cancer progression at the time of diagnosis remains challenging.

    Objective: To identify single nucleotide polymorphisms (SNPs) associated with death from prostate cancer.

    Design, setting, and participants: Blood samples from 11 506 men in Sweden were collected during 1991–1996. Of these, 1053 men were diagnosed with prostate cancer and 245 died from the disease. Stage and grade at diagnosis and outcome information were obtained, and DNA from all cases was genotyped.

    Outcome measurements and statistical analysis: A total of 6 126 633 SNPs were tested for association with prostate-cancer-specific survival time using a Cox proportional hazard model, adjusted for age, stage, and grade at diagnosis. A value of 1 × 10−6 was used as suggestive significance threshold. Positive candidate SNPs were tested for association with gene expression using expression quantitative trait locus analysis.

    Results and limitations: We found 12 SNPs at seven independent loci associated with prostate-cancer-specific survival time. One of 6 126 633 SNPs tested reached genome-wide significance (p < 5 × 10−8) and replicated in an independent cohort: rs73055188 (p = 5.27 × 10−9, per-allele hazard ratio [HR] = 2.27, 95% confidence interval [CI] 1.72–2.98) in the AOX1 gene. A second SNP reached a suggestive level of significance (p < 1 × 10−6) and replicated in an independent cohort: rs2702185 (p = 7.1 × 10−7, per-allele HR = 2.55, 95% CI = 1.76–3.69) in the SMG7 gene. The SNP rs73055188 is correlated with AOX1 expression levels, which is associated with biochemical recurrence of prostate cancer in independent cohorts. This association is yet to be validated in other ethnic groups.

    Conclusions: The SNP rs73055188 at the AOX1 locus is associated with prostate-cancer-specific survival time, and AOX1 gene expression level is correlated with biochemical recurrence of prostate cancer.

    Patient summary: We identify two genetic markers that are associated with prostate-cancer-specific survival time.

  • 136. Liedberg, Fredrik
    et al.
    Hagberg, Oskar
    Aljabery, Firas
    Gårdmark, Truls
    Hosseini, Abolfazl
    Jahnson, Staffan
    Jancke, Georg
    Jerlström, Tomas
    Malmström, Per-Uno
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Ströck, Viveka
    Häggström, Christel
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Surgical Sciences, Uppsala University, Uppsala.
    Holmberg, Lars
    Period-specific mean annual hospital volume of radical cystectomy is associated with outcome and perioperative quality of care: a nationwide population-based study2019In: BJU International, ISSN 1464-4096, E-ISSN 1464-410X, Vol. 124, no 3, p. 449-456Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To investigate the association between hospital volume and overall survival (OS), cancer-specific survival (CSS), and quality of care of patients with bladder cancer who undergo radical cystectomy (RC), defined as the use of extended lymphadenectomy (eLND), continent reconstruction, neoadjuvant chemotherapy (NAC), and treatment delay of <3 months.

    PATIENTS AND METHODS: We used the Bladder Cancer Data Base Sweden (BladderBaSe) to study survival and indicators of perioperative quality of care in all 3172 patients who underwent RC for primary invasive bladder cancer stage T1-T3 in Sweden between 1997 and 2014. The period-specific mean annual hospital volume (PSMAV) during the 3 years preceding surgery was applied as an exposure and analysed using univariate and multivariate mixed models, adjusting for tumour and nodal stage, age, gender, comorbidity, educational level, and NAC. PSMAV was either categorised in tertiles, dichotomised (at ≥25 RCs annually), or used as a continuous variable for every increase of 10 RCs annually.

    RESULTS: PSMAV in the highest tertile (≥25 RCs annually) was associated with improved OS (hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.75-1.0), whereas the corresponding HR for CSS was 0.87 (95% CI 0.73-1.04). With PSMAV as a continuous variable, OS was improved for every increase of 10 RCs annually (HR 0.95, 95% CI 0.90-0.99). Moreover, higher PSMAV was associated with increased use of eLND, continent reconstruction and NAC, but also more frequently with a treatment delay of >3 months after diagnosis.

    CONCLUSIONS: The current study supports centralisation of RC for bladder cancer, but also underpins the need for monitoring treatment delays associated with referral.

  • 137. Lindkvist, Björn
    et al.
    Johansen, Dorthe
    Stocks, Tanja
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Concin, Hans
    Bjorge, Tone
    Almquist, Martin
    Häggström, Christel
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Engeland, Anders
    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.
    Nagel, Gabriele
    Jonsson, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Selmer, Randi
    Ulmer, Hanno
    Tretli, Steinar
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Manjer, Jonas
    Metabolic risk factors for esophageal squamous cell carcinoma and adenocarcinoma: a prospective study of 580 000 subjects within the Me-Can project2014In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 14, p. 103-Article in journal (Refereed)
    Abstract [en]

    Background: Obesity is associated with an increased risk of esophageal adenocarcinoma (EAC) and a decreased risk of esophageal squamous cell carcinoma (ESCC). However, little is known about the risk of EAC and ESCC related to other metabolic risk factors. We aimed to examine the risk of EAC and ESCC in relation to metabolic risk factors, separately and combined in a prospective cohort study. Methods: The Metabolic Syndrome and Cancer cohort includes prospective cohorts in Austria, Norway and Sweden, with blood pressure, lipids, glucose and BMI available from 578 700 individuals. Relative risk (RR) for EAC and ESCC was calculated using Cox's proportional hazards analysis for metabolic risk factors categorized into quintiles and transformed into z-scores. The standardized sum of all z-scores was used as a composite score for the metabolic syndrome (MetS). Results: In total, 324 histologically verified cases of esophageal cancer were identified (114 EAC, 184 ESCC and 26 with other histology). BMI was associated with an increased risk of EAC (RR 7.34 (95% confidence interval, 2.88-18.7) top versus bottom quintile) and negatively associated with the risk of ESCC (RR 0.38 (0.23-0.62)). The mean value of systolic and diastolic blood pressure (mid blood pressure) was associated with the risk of ESCC (RR 1.77 (1.37-2.29)). The composite MetS score was associated with the risk of EAC (RR 1.56 (1.19-2.05) per one unit increase of z-score) but not ESCC. Conclusions: In accordance with previous studies, high BMI was associated with an increased risk of EAC and a decreased risk of ESCC. An association between high blood pressure and risk of ESCC was observed but alcohol consumption is a potential confounding factor that we were not able to adjust for in the analysis. The MetS was associated with EAC but not ESCC. However this association was largely driven by the strong association between BMI and EAC. We hypothesize that this association is more likely to be explained by factors directly related to obesity than the metabolic state of the MetS, considering that no other metabolic factor than BMI was associated with EAC.

  • 138. Liu, Dajiang J.
    et al.
    Peloso, Gina M.
    Yu, Haojie
    Butterworth, Adam S.
    Wang, Xiao
    Mahajan, Anubha
    Saleheen, Danish
    Emdin, Connor
    Alam, Dewan
    Alves, Alexessander Couto
    Amouyel, Philippe
    Di Angelantonio, Emanuele
    Arveiler, Dominique
    Assimes, Themistocles L.
    Auer, Paul L.
    Baber, Usman
    Ballantyne, Christie M.
    Bang, Lia E.
    Benn, Marianne
    Bis, Joshua C.
    Boehnke, Michael
    Boerwinkle, Eric
    Bork-Jensen, Jette
    Bottinger, Erwin P.
    Brandslund, Ivan
    Brown, Morris
    Busonero, Fabio
    Caulfield, Mark J.
    Chambers, John C.
    Chasman, Daniel I.
    Chen, Y. Eugene
    Chen, Yii-Der Ida
    Chowdhury, Rajiv
    Christensen, Cramer
    Chu, Audrey Y.
    Connell, John M.
    Cucca, Francesco
    Cupples, L. Adrienne
    Damrauer, Scott M.
    Davies, Gail
    Deary, Ian J.
    Dedoussis, George
    Denny, Joshua C.
    Dominiczak, Anna
    Dube, Marie-Pierre
    Ebeling, Tapani
    Eiriksdottir, Gudny
    Esko, Tonu
    Farmaki, Aliki-Eleni
    Feitosa, Mary F.
    Ferrario, Marco
    Ferrieres, Jean
    Ford, Ian
    Fornage, Myriam
    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, Massachusetts, USA.
    Frayling, Timothy M.
    Frikke-Schmidt, Ruth
    Fritsche, Lars G.
    Frossard, Philippe
    Fuster, Valentin
    Ganesh, Santhi K.
    Gao, Wei
    Garcia, Melissa E.
    Gieger, Christian
    Giulianini, Franco
    Goodarzi, Mark O.
    Grallert, Harald
    Grarup, Niels
    Groop, Leif
    Grove, Megan L.
    Gudnason, Vilmundur
    Hansen, Torben
    Harris, Tamara B.
    Hayward, Caroline
    Hirschhorn, Joel N.
    Holmen, Oddgeir L.
    Huffman, Jennifer
    Huo, Yong
    Hveem, Kristian
    Jabeen, Sehrish
    Jackson, Anne U.
    Jakobsdottir, Johanna
    Jarvelin, Marjo-Riitta
    Jensen, Gorm B.
    Jorgensen, Marit E.
    Jukema, J. Wouter
    Justesen, Johanne M.
    Kamstrup, Pia R.
    Kanoni, Stavroula
    Karpe, Fredrik
    Kee, Frank
    Khera, Amit V.
    Klarin, Derek
    Koistinen, Heikki A.
    Kooner, Jaspal S.
    Kooperberg, Charles
    Kuulasmaa, Kari
    Kuusisto, Johanna
    Laakso, Markku
    Lakka, Timo
    Langenberg, Claudia
    Langsted, Anne
    Launer, Lenore J.
    Lauritzen, Torsten
    Liewald, David C. M.
    Lin, Li An
    Linneberg, Allan
    Loos, Ruth J. F.
    Lu, Yingchang
    Lu, Xiangfeng
    Magi, Reedik
    Malarstig, Anders
    Manichaikul, Ani
    Manning, Alisa K.
    Mantyselka, Pekka
    Marouli, Eirini
    Masca, Nicholas G. D.
    Maschio, Andrea
    Meigs, James B.
    Melander, Olle
    Metspalu, Andres
    Morris, Andrew P.
    Morrison, Alanna C.
    Mulas, Antonella
    Mueller-Nurasyid, Martina
    Munroe, Patricia B.
    Neville, Matt J.
    Nielsen, Jonas B.
    Nielsen, Sune F.
    Nordestgaard, Borge G.
    Ordovas, Jose M.
    Mehran, Roxana
    O'Donnell, Christoper J.
    Orho-Melander, Marju
    Molony, Cliona M.
    Muntendam, Pieter
    Padmanabhan, Sandosh
    Palmer, Colin N. A.
    Pasko, Dorota
    Patel, Aniruddh P.
    Pedersen, Oluf
    Perola, Markus
    Peters, Annette
    Pisinger, Charlotta
    Pistis, Giorgio
    Polasek, Ozren
    Poulter, Neil
    Psaty, Bruce M.
    Rader, Daniel J.
    Rasheed, Asif
    Rauramaa, Rainer
    Reilly, Dermot F.
    Reiner, Alex P.
    Renström, Frida
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden.
    Rich, Stephen S.
    Ridker, Paul M.
    Rioux, John D.
    Robertson, Neil R.
    Roden, Dan M.
    Rotter, Jerome I.
    Rudan, Igor
    Salomaa, Veikko
    Samani, Nilesh J.
    Sanna, Serena
    Sattar, Naveed
    Schmidt, Ellen M.
    Scott, Robert A.
    Sever, Peter
    Sevilla, Raquel S.
    Shaffer, Christian M.
    Sim, Xueling
    Sivapalaratnam, Suthesh
    Small, Kerrin S.
    Smith, Albert V.
    Smith, Blair H.
    Somayajula, Sangeetha
    Southam, Lorraine
    Spector, Timothy D.
    Speliotes, Elizabeth K.
    Starr, John M.
    Stirrups, Kathleen E.
    Stitziel, Nathan
    Strauch, Konstantin
    Stringham, Heather M.
    Surendran, Praveen
    Tada, Hayato
    Tall, Alan R.
    Tang, Hua
    Tardif, Jean-Claude
    Taylor, Kent D.
    Trompet, Stella
    Tsao, Philip S.
    Tuomilehto, Jaakko
    Tybjaerg-Hansen, Anne
    van Zuydam, Natalie R.
    Varbo, Anette
    Varga, Tibor V.
    Virtamo, Jarmo
    Waldenberger, Melanie
    Wang, Nan
    Wareham, Nick J.
    Warren, Helen R.
    Weeke, Peter E.
    Weinstock, Joshua
    Wessel, Jennifer
    Wilson, James G.
    Wilson, Peter W. F.
    Xu, Ming
    Yaghootkar, Hanieh
    Young, Robin
    Zeggini, Eleftheria
    Zhang, He
    Zheng, Neil S.
    Zhang, Weihua
    Zhang, Yan
    Zhou, Wei
    Zhou, Yanhua
    Zoledziewska, Magdalena
    Howson, Joanna M. M.
    Danesh, John
    McCarthy, Mark I.
    Cowan, Chad A.
    Abecasis, Goncalo
    Deloukas, Panos
    Musunuru, Kiran
    Willer, Cristen J.
    Kathiresan, Sekar
    Exome-wide association study of plasma lipids in > 300,000 individuals2017In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 49, no 12, p. 1758-1766Article in journal (Refereed)
    Abstract [en]

    We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-densitylipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.

  • 139. Liu, Mengling
    et al.
    Lu, Wenbin
    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.
    Clendenen, Tess V.
    Zeleniuch-Jacquotte, Anne
    Estimation and selection of complex covariate effects in pooled nested case-control studies with heterogeneity2013In: Biostatistics, ISSN 1465-4644, E-ISSN 1468-4357, Vol. 14, no 4, p. 682-694Article in journal (Refereed)
    Abstract [en]

    A major challenge in cancer epidemiologic studies, especially those of rare cancers, is observing enough cases. To address this, researchers often join forces by bringing multiple studies together to achieve large sample sizes, allowing for increased power in hypothesis testing, and improved efficiency in effect estimation. Combining studies, however, renders the analysis difficult owing to the presence of heterogeneity in the pooled data. In this article, motivated by a collaborative nested case-control (NCC) study of ovarian cancer in three cohorts from United States, Sweden, and Italy, we investigate the use of penalty regularized partial likelihood estimation in the context of pooled NCC studies to achieve two goals. First, we propose an adaptive group lasso (gLASSO) penalized approach to simultaneously identify important variables and estimate their effects. Second, we propose a composite agLASSO penalized approach to identify variables with heterogeneous effects. Both methods are readily implemented with the group coordinate gradient decent algorithm and shown to enjoy the oracle property. We conduct simulation studies to evaluate the performance of our proposed approaches in finite samples under various heterogeneity settings, and apply them to the pooled ovarian cancer study.

  • 140.
    Ljungberg, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Holmgren, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Bergdahl, Ingvar A.
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Norberg, Margareta
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Näslund, Ulf
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Johansson, Bengt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Söderberg, Stefan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Lipoprotein(a) and the Apolipoprotein B/A1 Ratio Independently Associate With Surgery for Aortic Stenosis Only in Patients With Concomitant Coronary Artery Disease2017In: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, ISSN 2047-9980, E-ISSN 2047-9980, Vol. 6, no 12, article id e007160Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Aortic stenosis (AS) has different clinical phenotypes, including AS with or without concomitant coronary artery disease (CAD). It is unknown whether these phenotypes share the same risk factors. In particular, lipoprotein(a) [Lp(a)] and apolipoproteins (Apo) are associated with AS, but it is unknown whether these associations differ among phenotypes. In this prospective analysis we examined the impact of Lp(a) and Apo in subgroups of patients with AS.

    METHODS AND RESULTS: We identified 336 patients (mean age at survey 56.7 years, 48% female) who underwent surgery for AS after a median 10.9 years (interquartile range 9.3 years), participants in 1 of 3 large population surveys. For each patient, 2 matched referents were allocated. Lp(a) and Apo were analyzed in the baseline samples. Uni- and multivariable logistic regression analyses were used to estimate risks related to a 1 (ln) standard deviation increase in Lp(a) and the ratio of Apo B to Apo A1 (Apo B/A1 ratio). High levels of Lp(a) predicted surgery for AS in 203 patients with concomitant CAD (odds ratio [95% confidence intervals]) (1.29 [1.07-1.55]), but not in 132 patients without CAD (1.04 [0.83-1.29]) in the fully adjusted model. Similarly, a high Apo B/A1 ratio predicted surgery in patients with concomitant CAD (1.43 [1.16-1.76]) but not in those without CAD (0.87 [0.69-1.10]).

    CONCLUSIONS: High levels of Lp(a) and a high Apo B/A1 ratio were associated with surgery for AS in patients with concomitant CAD but not in those with isolated AS. This finding may lead to a new avenue of research for targeted risk factor interventions in this population.

  • 141.
    Ljungberg, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Janiec, Mikael
    Bergdahl, Ingvar
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Holmgren, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Johansson, Bengt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Näslund, Ulf
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Siegbahn, Agneta
    Fall, Tove
    Söderberg, Stefan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Proteomic Biomarkers for Incident Aortic Stenosis Requiring Valvular Replacement2018In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 138, no 6Article in journal (Refereed)
    Abstract [en]

    Background: Aortic valve stenosis (AS) is the most common indication for cardiac valve surgery; untreated AS is linked to high mortality. The etiological background of AS is unknown. Previous human studies were typically based on case-control studies. Biomarkers identified in prospective studies could lead to novel mechanistic insights. Methods: Within a large population survey with blood samples obtained at baseline, 334 patients were identified who later underwent surgery for AS (median age [interquartile range], 59.9 [10.4] years at survey and 68.3 [12.7] at surgery; 48% female). For each case, 2 matched referents were allocated. Plasma was analyzed with the multiplex proximity extension assay for screening of 92 cardiovascular candidate proteins. Conditional logistic regression models were used to assess associations between each protein and AS, with correction for multiple testing. A separate set of 106 additional cases with 212 matched referents was used in a validation study. Results: Six proteins (growth differentiation factor 15, galectin-4, von Willebrand factor, interleukin 17 receptor A, transferrin receptor protein 1, and proprotein convertase subtilisin/kexin type 9) were associated with case status in the discovery cohort; odds ratios ranged from 1.25 to 1.37 per SD increase in the protein signal. Adjusting the multivariable models for classical cardiovascular risk factors at baseline yielded similar results. Subanalyses of case-referent triplets (n=133) who showed no visible coronary artery disease at the time of surgery in the index person supported associations between AS and growth differentiation factor 15 (odds ratio, 1.40; 95% confidence interval, 1.10-1.78) and galectin-4 (odds ratio, 1.27; 95% confidence interval, 1.02-1.59), but these associations were attenuated after excluding individuals who donated blood samples within 5 years before surgery. In triplets (n=201), which included index individuals with concurrent coronary artery disease at the time of surgery, all 6 proteins were robustly associated with case status in all sensitivity analyses. In the validation study, the association of all but 1 (interleukin 17 receptor A) of these proteins were replicated in patients with AS with concurrent coronary artery disease but not in patients with AS without coronary artery disease. Conclusions: We provide evidence that 5 proteins were altered years before AS surgery and that the associations seem to be driven by concurrent atherosclerotic disease.

  • 142.
    Ljungberg, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Johansson, Bengt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Bergdahl, Ingvar
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Holmgren, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Näslund, Ulf
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Söderberg, Stefan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Mild impairment of renal function (shrunken pore syndrome) is associated with increased risk for future surgery for aortic stenosis2019In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 79, no 7, p. 524-530Article in journal (Refereed)
    Abstract [en]

    Recently, a new approach was proposed to detect mild impairment in renal function: a reduced ratio between estimated glomerular filtration rate (eGFR) calculated by cystatin C and eGFR calculated by creatinine. We aimed to evaluate if this ratio is associated with aortic stenosis (AS) requiring surgery. We identified 336 patients that first participated in population surveys and later underwent surgery for AS (median age [interquartile range] 59.8 [10.3] years at survey and 68.3 [12.7] at surgery, 48% females). For each patient, two matched referents were allocated. Cystatin C and creatinine were determined in stored plasma. eGFR(cystatin C) and eGFR(creatinine) and their ratio were estimated. Conditional logistic regression analyses were used to estimate the risk (odds ratio (OR) with [95% confidence interval (CI)]) related to one (ln) standard deviation increase in the ratio between eGFR(cystatin C) and eGFR(creatinine). A high ratio was associated with lower risk for AS requiring surgery (OR [95% CI]) (OR 0.84 [0.73-0.97]), especially in women (0.74 [0.60-0.92] vs. 0.93 [0.76-1.13] in men). After further stratification for coronary artery disease (CAD), the association remained in women with CAD but not in women without CAD (0.60 [0.44-0.83] and 0.89 [0.65-1.23], respectively). In conclusion, a high ratio between eGFR(cystatin C) and eGFR(creatinine) was associated with lower risk for surgery for AS, especially in women. Mild impairment of renal function is thus associated with future risk for AS requiring surgery.

  • 143.
    Ljungberg, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Johansson, Bengt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Engström, Karl Gunnar
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Albertsson, Elin
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Holmer, Paul
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Norberg, Margareta
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Bergdahl, Ingvar A.
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Söderberg, Stefan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Traditional Cardiovascular Risk Factors and Their Relation to Future Surgery for Valvular Heart Disease or Ascending Aortic Disease: A Case-Referent Study2017In: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, ISSN 2047-9980, E-ISSN 2047-9980, Vol. 6, no 5, article id e005133Article in journal (Refereed)
    Abstract [en]

    Background: Risk factors for developing heart valve and ascending aortic disease are based mainly on retrospective data. To elucidate these factors in a prospective manner, we have performed a nested case-referent study using data from large, population-based surveys. Methods and Results: A total of 777 patients operated for heart valve disease or disease of the ascending aorta had previously participated in population-based health surveys in Northern Sweden. Median time (interquartile range) from survey to surgery was 10.5 (9.0) years. Primary indications for surgery were aortic stenosis (41%), aortic regurgitation (12%), mitral regurgitation (23%), and dilatation/dissection of the ascending aorta (17%). For each case, referents were allocated, matched for age, sex, and geographical area. In multivariable models, surgery for aortic stenosis was predicted by hypertension, high cholesterol levels, diabetes mellitus, and active smoking. Surgery for aortic regurgitation was associated with a low cholesterol level, whereas a high cholesterol level predicted surgery for mitral regurgitation. Hypertension, blood pressure, and previous smoking predicted surgery for disease of the ascending aorta whereas diabetes mellitus was associated with reduced risk. After exclusion of cases with coronary atherosclerosis, only the inverse associations between cholesterol and aortic regurgitation and between diabetes mellitus and disease of the ascending aorta remained. Conclusions: This is the first truly prospective study of traditional cardiovascular risk factors and their association with valvular heart disease and disease of the ascending aorta. We confirm the strong association between traditional risk factors and aortic stenosis, but only in patients with concomitant coronary artery disease. In isolated valvular heart disease, the impact of traditional risk factors is varying.

  • 144.
    Ljungberg, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Johansson, Bengt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Engström, Karl Gunnar
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Norberg, Margareta
    Umeå University, Faculty of Medicine, Department of Epidemiology and Global Health.
    Bergdahl, Ingvar A
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Söderberg, Stefan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Arterial hypertension and diastolic blood pressure associate with aortic stenosis2019In: Scandinavian Cardiovascular Journal, ISSN 1401-7431, E-ISSN 1651-2006, Vol. 53, no 2, p. 91-97Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Due to age-related differences in aortic valve structure, it is likely that the pathophysiology of aortic stenosis (AS) and associated risk factors differ between age groups. Here we prospectively studied the influence of traditional cardiovascular risk factors on AS development requiring surgery among patients without concomitant coronary artery disease (CAD) and stratified for age.

    DESIGN: This study included 322 patients, who had prior to surgery for AS participated in population-based surveys, and 131 of them had no visible CAD upon preoperative coronary angiogram. For each case, we selected four referents matched for age, gender, and geographic area. To identify predictors for surgery, we used multivariable conditional logistic regression with a model including arterial hypertension (or measured blood pressure and antihypertensive medication), cholesterol levels, diabetes, body mass index (BMI), and smoking.

    RESULTS: In patients without CAD, future surgery for AS was associated with arterial hypertension and elevated levels of diastolic blood pressure in patients younger than 60 years at surgery (odds ratio [95% confidence interval]), (3.40 [1.45-7.93] and 1.60 [1.09-2.37], respectively), and with only impaired fasting glucose tolerance in patients 60 years or older at surgery (3.22 [1.19-8.76]).

    CONCLUSION: Arterial hypertension and elevated diastolic blood pressure are associated with a risk for AS requiring surgery in subjects below 60 years of age. Strict blood pressure control in this group is strongly advocated to avoid other cardiovascular diseases correlated to hypertension. If hypertension and elevated diastolic blood pressure are risk factors for developing AS requiring surgery need further investigations. Notably, elevated fasting glucose levels were related to AS requiring surgery in older adults without concomitant CAD.

  • 145.
    Ljungberg, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Johansson, Bengt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Engström, Karl Gunnar
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Norberg, Margareta
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Bergdahl, Ingvar A.
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Söderberg, Stefan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Arterial hypertension and elevated diastolic blood pressure is associated with developing aortic stenosis requiring surgery in persons less than 60 years of ageManuscript (preprint) (Other academic)
    Abstract [en]

    Background:  Due to age-related differences in aortic valve structure, it is likely that the pathophysiology of aortic stenosis and associated risk factors differ between age groups. Here we prospectively studied the influence of traditional cardiovascular risk factors on aortic stenosis development among patients without concomitant coronary artery disease, and stratified for age. 

    Methods: This study included 131 patients from previous population-based surveys, who underwent surgery for aortic stenosis and had no visible coronary arteriosclerosis upon preoperative coronary angiogram. The younger group included 49 patients of <60 years old at surgery: median age, 54.4 years; median follow-up, 8.7 years. The older group included 82 patients of ≥60 years old at surgery: median age, 71.3 years; median follow-up, 11.0 years. For each case, we selected four referents matched for age, gender, and geographic area. To identify predictors for surgery, we used multivariable conditional logistic regression with a model including arterial hypertension, cholesterol levels, diabetes, BMI, and smoking. 

    Results:  Future surgery for aortic stenosis was associated with arterial hypertension and elevated levels of diastolic blood pressure in the younger group (odds ratio, 3.40; 95% confidence interval, 1.45–7.93, and odds ratio 1,60; 95% confidence interval, 1.09–2.37, respectively), and with only impaired fasting glucose tolerance in the older group (odds ratio, 3.22; 95% confidence interval, 1.19–8.76). 

    Conclusion: Arterial hypertension and elevated diastolic blood pressure are associated with a risk for aortic stenosis development in subjects below 60 years of age. Strict blood pressure control in this group are strongly advocated to avoid other cardiovascular diseases correlated to hypertension. If hypertension and elevated diastolic blood pressure are risk for developing aortic stenosis need further investigations. Notably, elevated fasting glucose levels were related to aortic stenosis in older adults without concomitant coronary artery disease. 

  • 146. Locke, Adam E.
    et al.
    Kahali, Bratati
    Berndt, Sonja I.
    Justice, Anne E.
    Pers, Tune H.
    Day, Felix R.
    Powell, Corey
    Vedantam, Sailaja
    Buchkovich, Martin L.
    Yang, Jian
    Croteau-Chonka, Damien C.
    Esko, Tonu
    Fall, Tove
    Ferreira, Teresa
    Gustafsson, Stefan
    Kutalik, Zoltan
    Luan, Jian'an
    Maegi, Reedik
    Randall, Joshua C.
    Winkler, Thomas W.
    Wood, Andrew R.
    Workalemahu, Tsegaselassie
    Faul, Jessica D.
    Smith, Jennifer A.
    Zhao, Jing Hua
    Zhao, Wei
    Chen, Jin
    Fehrmann, Rudolf
    Hedman, Asa K.
    Karjalainen, Juha
    Schmidt, Ellen M.
    Absher, Devin
    Amin, Najaf
    Anderson, Denise
    Beekman, Marian
    Bolton, Jennifer L.
    Bragg-Gresham, L.
    Buyske, Steven
    Demirkan, Ayse
    Deng, Guohong
    Ehret, Georg B.
    Feenstra, Bjarke
    Feitosa, Mary F.
    Fischer, Krista
    Goel, Anuj
    Gong, Jian
    Jackson, Anne U.
    Kanoni, Stavroula
    Kleber, Marcus E.
    Kristiansson, Kati
    Lim, Unhee
    Lotay, Vaneet
    Mangino, Massimo
    Leach, Irene Mateo
    Medina-Gomez, Carolina
    Medland, Sarah E.
    Nalls, Michael A.
    Palmer, Cameron D.
    Pasko, Dorota
    Pechlivanis, Sonali
    Peters, Marjolein J.
    Prokopenko, Inga
    Shungin, Dmitry
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Umeå University, Faculty of Medicine, Department of Odontology.
    Stancakova, Alena
    Strawbridge, Rona J.
    Sung, Yun Ju
    Tanaka, Toshiko
    Teumer, Alexander
    Trompet, Stella
    van der Laan, Sander W.
    van Settee, Jessica
    Van Vliet-Ostaptchouk, Jana V.
    Wang, Zhaoming
    Yengo, Loic
    Zhang, Weihua
    Isaacs, Aaron
    Albrecht, Eva
    Arnlov, Johan
    Arscott, Gillian M.
    Attwood, Antony P.
    Bandinelli, Stefania
    Barrett, Amy
    Bas, Isabelita N.
    Bellis, Claire
    Bennett, Amanda J.
    Berne, Christian
    Blagieva, Roza
    Blueher, Matthias
    Bohringer, Stefan
    Bonnycastle, Lori L.
    Boettcher, Yvonne
    Boyd, Heather A.
    Bruinenberg, Marcel
    Caspersen, Ida H.
    Chen, Yii-Der Ida
    Clarke, Robert
    Daw, E. Warwick
    de Craen, Anton J. M.
    Delgado, Graciela
    Dimitriou, Maria
    Doney, Alex S. F.
    Eklund, Niina
    Estrada, Karol
    Eury, Elodie
    Folkersen, Lasse
    Fraser, Ross M.
    Garcia, Melissa E.
    Geller, Frank
    Giedraitis, Vilmantas
    Gigante, Bruna
    Go, Alan S.
    Golay, Alain
    Goodall, Alison H.
    Gordon, Scott D.
    Gorski, Mathias
    Grabe, Hans-Joergen
    Grallert, Harald
    Grammer, Tanja B.
    Graessler, Jurgen
    Gronberg, Henrik
    Groves, Christopher J.
    Gusto, Gaeelle
    Haessler, Jeffrey
    Hall, Per
    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
    Heard-Costa, Nancy L.
    Helmer, Qinta
    Hengstenberg, Christian
    Holmen, Oddgeir
    Hottenga, Jouke-Jan
    James, Alan L.
    Jeff, Janina M.
    Johansson, Asa
    Jolley, Jennifer
    Juliusdottir, Thorhildur
    Kinnunen, Leena
    Koenig, Wolfgang
    Koskenvuo, Markku
    Kratzer, Wolfgang
    Laitinen, Jaana
    Lamina, Claudia
    Leander, Karin
    Lee, Nanette R.
    Lichtner, Peter
    Lind, Lars
    Lindstrom, Jaana
    Lo, Ken Sin
    Lobbens, Stephane
    Lorbeer, Roberto
    Lu, Yingchang
    Mach, Francois
    Magnusson, Patrik K. E.
    Mahajan, Anubha
    McArdle, Wendy L.
    McLachlan, Stela
    Menni, Cristina
    Merger, Sigrun
    Mihailov, Evelin
    Milani, Lili
    Moayyeri, Alireza
    Monda, Keri L.
    Morken, Mario A.
    Mulas, Antonella
    Mueller, Gabriele
    Mueller-Nurasyid, Martina
    Musk, Arthur W.
    Nagaraja, Ramaiah
    Noethen, Markus M.
    Nolte, Ilja M.
    Pilz, Stefan
    Rayner, Nigel W.
    Renstrom, Frida
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Rettig, Rainer
    Ried, Janina S.
    Ripke, Stephan
    Robertson, Neil R.
    Rose, Lynda M.
    Sanna, Serena
    Scharnagl, Hubert
    Scholtens, Salome
    Schumacher, Fredrick R.
    Scott, William R.
    Seufferlein, Thomas
    Shi, Jianxin
    Smith, Albert Vernon
    Smolonska, Joanna
    Stanton, Alice V.
    Steinthorsdottir, Valgerdur
    Stirrups, Kathleen
    Stringham, Heather M.
    Sundstrom, Johan
    Swertz, Morris A.
    Swift, Amy J.
    Syvanen, Ann-Christine
    Tan, Sian-Tsung
    Tayo, Bamidele O.
    Thorand, Barbara
    Thorleifsson, Gudmar
    Tyrer, Jonathan P.
    Uh, Hae-Won
    Vandenput, Liesbeth
    Verhulst, Frank C.
    Vermeulen, Sita H.
    Verweij, Niek
    Vonk, Judith M.
    Waite, Lindsay L.
    Warren, Helen R.
    Waterworth, Dawn
    Weedon, Michael N.
    Wilkens, Lynne R.
    Willenborg, Christina
    Wilsgaard, Tom
    Wojczynski, Mary K.
    Wong, Andrew
    Wrightl, Alan F.
    Zhang, Qunyuan
    Brennan, Eoin P.
    Choi, Murim
    Dastani, Zari
    Drong, Alexander W.
    Eriksson, Per
    Franco-Cereceda, Anders
    Gadin, Jesper R.
    Gharavi, Ali G.
    Goddard, Michael E.
    Handsaker, Robert E.
    Huang, Jinyan
    Karpe, Fredrik
    Kathiresan, Sekar
    Keildson, Sarah
    Kiryluk, Krzysztof
    Kubo, Michiaki
    Lee, Jong-Young
    Liang, Liming
    Lifton, Richard P.
    Ma, Baoshan
    McCarroll, Steven A.
    McKnight, Amy J.
    Min, Josine L.
    Moffatt, Miriam F.
    Montgomery, Grant W.
    Murabito, Joanne M.
    Nicholson, George
    Nyholt, Dale R.
    Okada, Yukinori
    Perry, John R. B.
    Dorajoo, Rajkumar
    Reinmaa, Eva
    Salem, Rany M.
    Sandholm, Niina
    Scott, Robert A.
    Stolk, Lisette
    Takahashi, Atsushi
    Tanaka, Toshihiro
    van 't Hooft, Ferdinand M.
    Vinkhuyzen, Anna A. E.
    Westra, Harm-Jan
    Zheng, Wei
    Zondervan, Krina T.
    Heath, Andrew C.
    Arveiler, Dominique
    Bakker, Stephan J. L.
    Beilby, John
    Bergman, Richard N.
    Blangero, John
    Bovet, Pascal
    Campbell, Harry
    Caulfield, Mark J.
    Cesana, Giancarlo
    Chakravarti, Aravinda
    Chasman, Daniel I.
    Chines, Peter S.
    Collins, Francis S.
    Crawford, Dana C.
    Cupples, L. Adrienne
    Cusi, Daniele
    Danesh, John
    de Faire, Ulf
    den Ruijter, Hester M.
    Dominiczak, Anna F.
    Erbel, Raimund
    Erdmann, Jeanette
    Eriksson, Johan G.
    Farrall, Martin
    Felix, Stephan B.
    Ferrannini, Ele
    Ferrieres, Jean
    Ford, Ian
    Forouhi, Nita G.
    Forrester, Terrence
    Franco, Oscar H.
    Gansevoort, Ron T.
    Gejman, Pablo V.
    Gieger, Christian
    Gottesman, Omri
    Gudnason, Vilmundur
    Gyllensten, Ulf
    Hall, Alistair S.
    Harris, Tamara B.
    Hattersley, Andrew T.
    Hicks, Andrew A.
    Hindorff, Lucia A.
    Hingorani, Aroon D.
    Hofman, Albert
    Homuth, Georg
    Hovingh, G. Kees
    Humphries, Steve E.
    Hunt, Steven C.
    Hypponen, Elina
    Illig, Thomas
    Jacobs, Kevin B.
    Jarvelin, Marjo-Riitta
    Joeckel, Karl-Heinz
    Johansen, Berit
    Jousilahti, Pekka
    Jukema, J. Wouter
    Jula, Antti M.
    Kaprio, Jaakko
    Kastelein, John J. P.
    Keinanen-Kiukaanniemi, Sirkka M.
    Kiemeney, Lambertus A.
    Knekt, Paul
    Kooner, Jaspal S.
    Kooperberg, Charles
    Kovacs, Peter
    Kraja, Aldi T.
    Kumari, Meena
    Kuusisto, Johanna
    Lakka, Timo A.
    Langenberg, Claudia
    Le Marchand, Laic
    Lehtimaki, Terho
    Lyssenko, Valeriya
    Mannisto, Satu
    Marette, Andre
    Matise, Tara C.
    McKenzie, Colin A.
    McKnight, Barbara
    Moll, Frans L.
    Morris, Andrew D.
    Morris, Andrew P.
    Murray, Jeffrey C.
    Nelis, Mari
    Ohlsson, Claes
    Oldehinkel, Albertine J.
    Ong, Ken K.
    Madden, Pamela A. F.
    Pasterkamp, Gerard
    Peden, John F.
    Peters, Annette
    Postma, Dirkje S.
    Pramstaller, Peter P.
    Price, Jackie F.
    Qi, Lu
    Raitakari, Olli T.
    Rankinen, Tuomo
    Rao, D. C.
    Rice, Treva K.
    Ridker, Paul M.
    Rioux, John D.
    Ritchie, Marylyn D.
    Rudan, Igor
    Salomaa, Veikko
    Samani, Nilesh J.
    Saramines, Jouko
    Sarzynski, Mark A.
    Schunkert, Heribert
    Schwarz, Peter E. H.
    Sever, Peter
    Shuldiner, Alan R.
    Sinisalo, Juha
    Stolk, Ronald P.
    Strauch, Konstantin
    Toenjes, Anke
    Tregouet, David-Alexandre
    Tremblay, Angelo
    Tremoli, Elena
    Virtamo, Jarmo
    Vohl, Marie-Claude
    Voelker, Uwe
    Waeber, Gerard
    Willemsen, Gonneke
    Witteman, Jacqueline C.
    Zillikens, M. Carola
    Adair, Linda S.
    Amouyel, Philippe
    Asselbergs, Folkert W.
    Assimes, Themistocles L.
    Bochud, Murielle
    Boehm, Bernhard O.
    Boerwinkle, Eric
    Bornstein, Stefan R.
    Bottinger, Erwin P.
    Bouchard, Claude
    Cauchi, Stephane
    Chambers, John C.
    Chanock, Stephen J.
    Cooper, Richard S.
    de Bakker, Paul I. W.
    Dedoussis, George
    Ferrucci, Luigi
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Froguel, Philippe
    Groop, Leif C.
    Haiman, Christopher A.
    Hamsten, Anders
    Hui, Jennie
    Hunter, David J.
    Hveem, Kristian
    Kaplan, Robert C.
    Kivimaki, Mika
    Kuh, Diana
    Laakso, Markku
    Liu, Yongmei
    Martin, Nicholas G.
    Maerz, Winfried
    Melbve, Mads
    Metspalu, Andres
    Moebus, Susanne
    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
    Sattar, Naveed
    Schadt, Eric E.
    Schlessinger, David
    Slagboom, P. Eline
    Snieder, Harold
    Spector, Tim D.
    Thorsteinsdottir, Unnu R.
    Stumvoll, Michael
    Tuomilehto, Jaakko
    Uitterlinden, Andre G.
    Uusitupa, Matti
    van der Harst, Pim
    Walker, Mark
    Wallaschofski, Henri
    Wareham, Nicholas J.
    Watkins, Hugh
    Weir, David R.
    Wichmann, H-Erich
    Wilson, James F.
    Zanen, Pieter
    Borecki, Ingrid B.
    Deloukas, Panos
    Fox, Caroline S.
    Heid, Iris M.
    O'Connell, Jeffrey R.
    Strachan, David P.
    Stefansson, Kari
    van Duijri, Cornelia M.
    Abecasis, Goncalo R.
    Franke, Lude
    Frayling, Timothy M.
    McCarthy, Mark I.
    Visscher, Peter M.
    Scherag, Andre
    Willer, Cristen J.
    Boehnke, Michael
    Mohlke, Karen L.
    Lindgren, Cecilia M.
    Beckmann, Jacques S.
    Barroso, Ines
    North, Kari E.
    Ingelsson, Erik
    Hirschhorn, Joel N.
    Loos, Ruth J. F.
    Speliotes, Elizabeth K.
    Genetic studies of body mass index yield new insights for obesity biology2015In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 518, no 7538, p. 197-U401Article in journal (Refereed)
    Abstract [en]

    Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in upto 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 x 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for similar to 2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous systemin obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

  • 147. Lu, Yunxia
    et al.
    Cross, Amanda J
    Murphy, Neil
    Freisling, Heinz
    Travis, Ruth C
    Ferrari, Pietro
    Katzke, Verena A
    Kaaks, Rudolf
    Olsson, Åsa
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology. 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, Skåne University Hospital Malmö, Malmö, Sweden.
    Panico, Salvatore
    Pala, Valeria
    Palli, Domenico
    Tumino, Rosario
    Peeters, Petra H
    Siersema, Peter D
    Bueno-de-Mesquita, H B
    Trichopoulou, Antonia
    Klinaki, Eleni
    Tsironis, Christos
    Agudo, Antonio
    Navarro, Carmen
    Sánchez, María-José
    Barricarte, Aurelio
    Boutron-Ruault, Marie-Christine
    Fagherazzi, Guy
    Racine, Antoine
    Weiderpass, Elisabete
    Gunter, Marc J
    Riboli, Elio
    Comparison of abdominal adiposity and overall obesity in relation to risk of small intestinal cancer in a European Prospective Cohort2016In: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 27, no 7, p. 919-927Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The etiology of small intestinal cancer (SIC) is largely unknown, and there are very few epidemiological studies published to date. No studies have investigated abdominal adiposity in relation to SIC.

    METHODS: We investigated overall obesity and abdominal adiposity in relation to SIC in the European Prospective Investigation into Cancer and Nutrition (EPIC), a large prospective cohort of approximately half a million men and women from ten European countries. Overall obesity and abdominal obesity were assessed by body mass index (BMI), waist circumference (WC), hip circumference (HC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR). Multivariate Cox proportional hazards regression modeling was performed to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs). Stratified analyses were conducted by sex, BMI, and smoking status.

    RESULTS: During an average of 13.9 years of follow-up, 131 incident cases of SIC (including 41 adenocarcinomas, 44 malignant carcinoid tumors, 15 sarcomas and 10 lymphomas, and 21 unknown histology) were identified. WC was positively associated with SIC in a crude model that also included BMI (HR per 5-cm increase = 1.20, 95 % CI 1.04, 1.39), but this association attenuated in the multivariable model (HR 1.18, 95 % CI 0.98, 1.42). However, the association between WC and SIC was strengthened when the analysis was restricted to adenocarcinoma of the small intestine (multivariable HR adjusted for BMI = 1.56, 95 % CI 1.11, 2.17). There were no other significant associations.

    CONCLUSION: WC, rather than BMI, may be positively associated with adenocarcinomas but not carcinoid tumors of the small intestine.

    IMPACT: Abdominal obesity is a potential risk factor for adenocarcinoma in the small intestine.

  • 148. Lujan-Barroso, Leila
    et al.
    González, Carlos Alberto
    Slimani, Nadia
    Obón-Santacana, Mireia
    Ferrari, Pietro
    Freisling, Heinz
    Overvad, Kim
    Clavel-Chapelon, Françoise
    Boutron-Ruault, Marie-Christine
    Racine, Antoine
    Katzke, Verena
    Kühn, Tilman
    Tjønneland, Anne
    Olsen, Anja
    Quirós, J Ramón
    Sánchez-Cantalejo, Emilio
    Amiano, Pilar
    Navarro, Carmen
    Barricarte, Aurelio
    Khaw, Kay-Tee
    Wareham, Nick
    Travis, Ruth C
    Trichopoulou, Antonia
    Bamia, Christina
    Benetou, Vassiliki
    Saieva, Calogero
    Grioni, Sara
    Tumino, Rosario
    Vineis, Paolo
    Mattiello, Amalia
    Bueno-de-Mesquita, H Bas
    Siersema, Peter D
    Numans, Mattijs E
    Peeters, Petra H
    Ericson, Ulrika
    Wirfält, Elisabet
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Weiderpass, Elisabete
    Skeie, Guri
    Riboli, Elio
    Boeing, Heiner
    Duell, Eric J
    Dietary intake of acrylamide and esophageal cancer risk in the European Prospective Investigation into Cancer and Nutrition cohort2014In: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 25, no 5, p. 639-646Article in journal (Refereed)
    Abstract [en]

    PURPOSE: The relation between dietary acrylamide intake and esophageal cancer (EC) risk, including esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC), has not been consistent. We evaluated the association between dietary acrylamide intake and EAC, ESCC, and overall EC in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.

    METHODS: Multivariate Cox proportional hazards models were used to estimate the HR and 95 % confidence interval (95 % CI). Since nonlinear relations were observed, HRs were displayed for quartiles of acrylamide intake in μg per day.

    RESULTS: After a mean follow-up of 11 years, 341 EC were identified, 142 of which were EAC, 176 ESCC, and 23 other histological types or not specified. An increase in EC risk was observed in the second and third quartiles (HRQ2vsQ1 1.75, 95 % CI 1.12-2.74; HRQ3vsQ1 1.66, 95 % CI 1.05-2.61), but not in the fourth quartile, and there was no evidence for a linear dose-response trend. HRs were similarly elevated but not statistically significant when ESCC and EAC were analyzed separately, due to the small number of cases observed. No associations were observed when quartiles were based on energy-adjusted acrylamide intake.

    CONCLUSIONS: In the EPIC cohort, an association between estimated dietary acrylamide intake and an increased risk of developing EC was observed in the middle quartiles but not in the highest quartile; however, results from other larger cohorts or consortia, and results from biomarker studies, might add to the evidence provided by this analysis, suggesting that acrylamide is not an important risk factor for EC.

  • 149. Lumme, Sonja
    et al.
    Tenkanen, Leena
    Langseth, Hilde
    Gislefoss, Randi
    Hakama, Matti
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Adlercreutz, Herman
    Saikku, Pekka
    Stenman, Ulf-Hakan
    Tuohimaa, Pentti
    Luostarinen, Tapio
    Dillner, Joakim
    Longitudinal biobanks-based study on the joint effects of infections, nutrition and hormones on risk of prostate cancer2016In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 55, no 7, p. 839-845Article in journal (Refereed)
    Abstract [en]

    Background To evaluate the individual and combined effects of enterolactone, vitamin D, free testosterone, Chlamydia trachomatis and HPV-18 on the risk of prostate cancer in a large population-based biochemical material that combined three Nordic serum sample banks. Material and methods A joint cohort of 209000 healthy men was followed using cancer registry linkages. From this cohort altogether 699 incident cases of prostate cancer were identified. Four controls were selected by incidence density sampling and matching for country, age and date of the blood sampling. Complete data for all investigated exposures was available for 483 eligible cases and 1055 eligible controls. Multivariate regression analyses were performed to investigate the solitary and combined effects. Results The solitary effects were small. Significantly increased risk [rate ratio 1.6 (95% CI 1.0-2.5)] was found in those seronegative for C. trachomatis infection. The joint effect in risk levels of enterolactone and vitamin D was antagonistic [observed rate ratio (RR) 1.4 (1.0-2.1), expected RR 2.0 (1.0-4.1)] as well as that of HPV-18 and C. trachomatis [observed RR 1.9 (0.8-4.5), expected RR 9.9 (1.1-87.0)]. Conclusion A large follow-up study combining data from several previously investigated exposures to investigate joint effects found no evidence that exposure to two risk factors would increase the risk of prostate cancer from that expected on basis of exposure to one risk factor. If anything, the results were consistent with antagonistic interactions.

  • 150. Löfstedt, Alexandra
    et al.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Tesi, Bianca
    Bergdahl, Ingvar
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Nordenskjöld, Magnus
    Bryceson, Yenan T.
    Henter, Jan-Inge
    Meeths, Marie
    Haploinsufficiency of UNC13D increases the risk of lymphoma2019In: Cancer, ISSN 0008-543X, E-ISSN 1097-0142, Vol. 125, no 11, p. 1848-1854Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Experimental models have demonstrated that immune surveillance by cytotoxic lymphocytes can protect from spontaneous neoplasms and cancer. In humans, defective lymphocyte cytotoxicity is associated with the development of hemophagocytic lymphohistiocytosis, a hyperinflammatory syndrome. However, to the best of the authors' knowledge, the degree to which human lymphocyte cytotoxicity protects from cancer remains unclear. In the current study, the authors examined the risk of lymphoma attributable to haploinsufficiency in a gene required for lymphocyte cytotoxicity.

    METHODS: The authors exploited a founder effect of an UNC13D inversion, which abolishes Munc13-4 expression and causes hemophagocytic lymphohistiocytosis in an autosomal recessive manner. Within 2 epidemiological screening programs in northern Sweden, an area demonstrating a founder effect of this specific UNC13D mutation, all individuals with a diagnosis of lymphoma (487 patients) and matched controls (1844 controls) were assessed using polymerase chain reaction for carrier status.

    RESULTS: Among 487 individuals with lymphoma, 15 (3.1%) were heterozygous carriers of the UNC13D inversion, compared with 18 controls (1.0%) (odds ratio, 3.0; P = .002). It is interesting to note that a higher risk of lymphoma was attributed to female carriers (odds ratio, 3.7; P = .004).

    CONCLUSIONS: Establishing a high regional prevalence of the UNC13D inversion, the authors have reported an overrepresentation of this mutation in individuals with lymphoma. Therefore, the results of the current study indicate that haploinsufficiency of a gene required for lymphocyte cytotoxicity can predispose patients to lymphoma, suggesting the importance of cytotoxic lymphocyte-mediated surveillance of cancer. Furthermore, the results of the current study suggest that female carriers are more susceptible to lymphoma.

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