umu.sePublications
Change search
Refine search result
1 - 31 of 31
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the Create feeds function.
  • 1.
    Bodén, Stina
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Myte, Robin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Wennberg, Maria
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    Harlid, Sophia
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology, School of Dentistry. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    Shivappa, Nitin
    Hébert, James R
    van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Nilsson, Lena Maria
    Umeå University, Arctic Research Centre at Umeå University. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    The inflammatory potential of diet in determining cancer risk: a prospective investigation of two dietary pattern scores2019In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 4, article id e0214551Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Inflammation-related mechanisms may contribute to the link between diet and cancer. We sought to investigate the inflammatory impact of diet on cancer risk using the Dietary inflammatory index (DII) and an adapted Mediterranean diet score (MDS).

    METHODS: This population-based, prospective cohort study used self-reported dietary data from the Västerbotten Intervention Programme, including 100,881 participants, of whom 35,393 had repeated measures. Associations between dietary patterns and cancer risk were evaluated using Cox proportional hazards regression. We also used restricted cubic splines to test for potential non-linear associations.

    RESULTS: A total of 9,250 incident cancer cases were diagnosed during a median follow-up of 15 years. The two dietary patterns were moderately correlated to each other and had similar associations with cancer risk, predominantly lung cancer in men (DII per tertile decrease: Hazard ratio (HR) 0.81 (0.66-0.99), MDS per tertile increase: HR 0.86 (0.72-1.03)), and gastric cancer in men (DII: 0.73 (0.53-0.99), MDS: 0.73 (0.56-0.96)). Associations were, in general, found to be linear. We found no longitudinal association between 10-year change in diet and cancer risk.

    CONCLUSION: We confirm small, but consistent and statistically significant associations between a more anti-inflammatory or healthier diet and reduced risk of cancer, including a lower risk of lung and gastric cancer in men. The dietary indexes produced similar associations with respect to the risk of cancer.

  • 2. Butt, Salma
    et al.
    Harlid, Sophia
    Lund University, Department of Laboratory Sciences.
    Borgquist, Signe
    Ivarsson, Malin
    Landberg, Göran
    Dillner, Joakim
    Carlson, Joyce
    Manjer, Jonas
    Genetic predisposition, parity, age at first childbirth and risk for breast cancer.2012In: BMC Research Notes, ISSN 1756-0500, E-ISSN 1756-0500, Vol. 5, article id 414Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Recent studies have identified several single-nucleotide polymorphisms (SNPs) associated with the risk of breast cancer and parity and age at first childbirth are well established and important risk factors for breast cancer. The aim of the present study was to examine the interaction between these environmental factors and genetic variants on breast cancer risk.

    METHODS: The Malmö Diet and Cancer Study (MDCS) included 17 035 female participants, from which 728 incident breast cancer cases were matched to 1448 controls. The associations between 14 SNPs and breast cancer risk were investigated in different strata of parity and age at first childbirth. A logistic regression analysis for the per allele risk, adjusted for potential confounders yielded odds ratios (OR) with 95% confidence intervals (CI).

    RESULTS: Six of the previously identified SNPs showed a statistically significant association with breast cancer risk: rs2981582 (FGFR2), rs3803662 (TNRC9), rs12443621 (TNRC9), rs889312 (MAP3K1), rs3817198 (LSP1) and rs2107425 (H19). We could not find any statistically significant interaction between the effects of tested SNPs and parity/age at first childbirth on breast cancer risk after adjusting for multiple comparisons.

    CONCLUSIONS: The results of this study are in agreement with previous studies of null interactions between tested SNPs and parity/age at first childbirth with regard to breast cancer risk.

  • 3. Christakoudi, Sofia
    et al.
    Kakourou, Artemisia
    Markozannes, Georgios
    Tzoulaki, Ioanna
    Weiderpass, Elisabete
    Brennan, Paul
    Gunter, Marc
    Dahm, Christina C.
    Overvad, Kim
    Olsen, Anja
    Tjønneland, Anne
    Boutron-Ruault, Marie-Christine
    Madika, Anne-Laure
    Severi, Gianluca
    Katzke, Verena
    Kühn, Tilman
    Bergmann, Manuela M.
    Boeing, Heiner
    Karakatsani, Anna
    Martimianaki, Georgia
    Thriskos, Paschalis
    Masala, Giovanna
    Sieri, Sabina
    Panico, Salvatore
    Tumino, Rosario
    Ricceri, Fulvio
    Agudo, Antonio
    Redondo-Sánchez, Daniel
    Colorado-Yohar, Sandra M.
    Mokoroa, Olatz
    Melander, Olle
    Stocks, Tanja
    Häggström, Christel
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
    Harlid, Sophia
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Bueno-de-Mesquita, Bas
    van Gils, Carla H.
    Vermeulen, Roel C. H.
    Khaw, Kay-Tee
    Wareham, Nicholas J.
    Tong, Tammy Y. N.
    Freisling, Heinz
    Johansson, Mattias
    Lennon, Hannah
    Aune, Dagfinn
    Riboli, Elio
    Trichopoulos, Dimitrios
    Trichopoulou, Antonia
    Tsilidis, Konstantinos K.
    Blood pressure and risk of cancer in the European Prospective Investigation into Cancer and Nutrition2019In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215Article in journal (Refereed)
    Abstract [en]

    Several studies have reported associations of hypertension with cancer, but not all results were conclusive. We examined the association of systolic (SBP) and diastolic (DBP) blood pressure with the development of incident cancer at all anatomical sites in the European Prospective Investigation into Cancer and Nutrition (EPIC). Hazard ratios (HRs) (95% confidence intervals) were estimated using multivariable Cox proportional hazards models, stratified by EPIC-participating center and age at recruitment, and adjusted for sex, education, smoking, body mass index, physical activity, diabetes and dietary (in women also reproductive) factors. The study included 307,318 men and women, with an average follow-up of 13.7 (standard deviation 4.4) years and 39,298 incident cancers. We confirmed the expected positive association with renal cell carcinoma: HR = 1.12 (1.08-1.17) per 10 mm Hg higher SBP and HR = 1.23 (1.14-1.32) for DBP. We additionally found positive associations for esophageal squamous cell carcinoma (SCC): HR = 1.16 (1.07-1.26) (SBP), HR = 1.31 (1.13-1.51) (DBP), weaker for head and neck cancers: HR = 1.08 (1.04-1.12) (SBP), HR = 1.09 (1.01-1.17) (DBP) and, similarly, for skin SCC, colon cancer, postmenopausal breast cancer and uterine adenocarcinoma (AC), but not for esophageal AC, lung SCC, lung AC or uterine endometroid cancer. We observed weak inverse associations of SBP with cervical SCC: HR = 0.91 (0.82-1.00) and lymphomas: HR = 0.97 (0.93-1.00). There were no consistent associations with cancers in other locations. Our results are largely compatible with published studies and support weak associations of blood pressure with cancers in specific locations and morphologies.

  • 4. Costas, Laura
    et al.
    Lujan-Barroso, Leila
    Benavente, Yolanda
    Allen, Naomi E.
    Amiano, Pilar
    Ardanaz, Eva
    Besson, Caroline
    Boeing, Heiner
    Bueno-de-Mesquita, Bas
    Cervenka, Iris
    Fortner, Renee T.
    Fournier, Agnes
    Gunter, Marc
    Harlid, Sophia
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Maria Huerta, Jose
    Jerkeman, Mats
    Jirstrom, Karin
    Kaaks, Rudolf
    Karakatsani, Anna
    Khaw, Kay-Tee
    Kotanidou, Anastasia
    Lund, Eiliv
    Masala, Giovanna
    Mattiello, Amalia
    Melin, Beatrice S.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Menendez, Virginia
    Murphy, Neil
    Nieters, Alexandra
    Overvad, Kim
    Riboli, Elio
    Sacerdote, Carlotta
    Sanchez, Maria-Jose
    Schmidt, Julie A.
    Sieri, Sabina
    Tjonneland, Anne
    Trichopoulou, Antonia
    Tumino, Rosario
    Vermeulen, Roel
    Weiderpass, Elisabete
    de Sanjose, Silvia
    Agudo, Antonio
    Casabonne, Delphine
    Reproductive Factors, Exogenous Hormone Use, and Risk of B-Cell Non-Hodgkin Lymphoma in a Cohort of Women From the European Prospective Investigation Into Cancer and Nutrition2019In: American Journal of Epidemiology, ISSN 0002-9262, E-ISSN 1476-6256, Vol. 188, no 2, p. 274-281Article in journal (Refereed)
    Abstract [en]

    The role of hormonal factors in the etiology of lymphoid neoplasms remains unclear. Previous studies have yielded conflicting results, have lacked sufficient statistical power to assess many lymphoma subtypes, or have lacked detailed information on relevant exposures. Within the European Prospective Investigation Into Cancer and Nutrition cohort, we analyzed comprehensive data on reproductive factors and exogenous hormone use collected at baseline (1992-2000) among 343,458 women, including data on 1,427 incident cases of B-cell non-Hodgkin lymphoma (NHL) and its major subtypes identified after a mean follow-up period of 14 years (through 2015). We estimated hazard ratios and 95% confidence intervals using multivariable proportional hazards modeling. Overall, we observed no statistically significant associations between parity, age at first birth, breastfeeding, oral contraceptive use, or ever use of postmenopausal hormone therapy and risk of B-cell NHL or its subtypes. Women who had undergone surgical menopause had a 51% higher risk of B-cell NHL (based on 67 cases) than women with natural menopause (hazard ratio = 1.51, 95% confidence interval: 1.17, 1.94). Given that this result may have been due to chance, our results provide little support for the hypothesis that sex hormones play a role in lymphomagenesis.

  • 5. Fedirko, Veronika
    et al.
    Jenab, Mazda
    Meplan, Catherine
    Jones, Jeb S.
    Zhu, Wanzhe
    Schomburg, Lutz
    Siddiq, Afshan
    Hybsier, Sandra
    Overvad, Kim
    Tjonneland, Anne
    Omichessan, Hanane
    Perduca, Vittorio
    Boutron-Ruault, Marie-Christine
    Kuehn, Tilman
    Katzke, Verena
    Aleksandrova, Krasimira
    Trichopoulou, Antonia
    Karakatsani, Anna
    Kotanidou, Anastasia
    Tumino, Rosario
    Panico, Salvatore
    Masala, Giovanna
    Agnoli, Claudia
    Naccarati, Alessio
    Bueno-de-Mesquita, Bas
    Vermeulen, Roel C. H.
    Weiderpass, Elisabete
    Skeie, Guri
    Nost, Therese Haugdahl
    Lujan-Barroso, Leila
    Ramon Quiros, J.
    Maria Huerta, Jose
    Rodriguez-Barranco, Miguel
    Barricarte, Aurelio
    Gylling, Björn
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Harlid, Sophia
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bradbury, Kathryn E.
    Wareham, Nick
    Khaw, Kay-Tee
    Gunter, Marc
    Murphy, Neil
    Freisling, Heinz
    Tsilidis, Kostas
    Aune, Dagfinn
    Riboli, Elio
    Hesketh, John E.
    Hughes, David J.
    Association of Selenoprotein and Selenium Pathway Genotypes with Risk of Colorectal Cancer and Interaction with Selenium Status2019In: Nutrients, ISSN 2072-6643, E-ISSN 2072-6643, Vol. 11, no 4, article id 935Article in journal (Refereed)
    Abstract [en]

    Selenoprotein genetic variations and suboptimal selenium (Se) levels may contribute to the risk of colorectal cancer (CRC) development. We examined the association between CRC risk and genotype for single nucleotide polymorphisms (SNPs) in selenoprotein and Se metabolic pathway genes. Illumina Goldengateassays were designed and resulted in the genotyping of 1040 variants in 154 genes from 1420 cases and 1421 controls within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Multivariable logistic regression revealed an association of 144 individual SNPs from 63 Se pathway genes with CRC risk. However, regarding the selenoprotein genes, only TXNRD1 rs11111979 retained borderline statistical significance after adjustment for correlated tests (PACT = 0.10; PACT significance threshold was P < 0.1). SNPs in Wingless/Integrated (Wnt) and Transforming growth factor (TGF) beta-signaling genes (FRZB, SMAD3, SMAD7) from pathways affected by Se intake were also associated with CRC risk after multiple testing adjustments. Interactions with Se status (using existing serum Se and Selenoprotein P data) were tested at the SNP, gene, and pathway levels. Pathway analyses using the modified Adaptive Rank Truncated Product method suggested that genes and gene x Se status interactions in antioxidant, apoptosis, and TGF-beta signaling pathways may be associated with CRC risk. This study suggests that SNPs in the Se pathway alone or in combination with suboptimal Se status may contribute to CRC development.

  • 6. Hair, Brionna Y
    et al.
    Xu, Zongli
    Kirk, Erin L
    Harlid, Sophia
    Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA.
    Sandhu, Rupninder
    Robinson, Whitney R
    Wu, Michael C
    Olshan, Andrew F
    Conway, Kathleen
    Taylor, Jack A
    Troester, Melissa A
    Body mass index associated with genome-wide methylation in breast tissue.2015In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 151, no 2, p. 453-63Article in journal (Refereed)
    Abstract [en]

    Gene expression studies indicate that body mass index (BMI) is associated with molecular pathways involved in inflammation, insulin-like growth factor activation, and other carcinogenic processes in breast tissue. The goal of this study was to determine whether BMI is associated with gene methylation in breast tissue and to identify pathways that are commonly methylated in association with high BMI. Epigenome-wide methylation profiles were determined using the Illumina HumanMethylation450 BeadChip array in the non-diseased breast tissue of 81 women undergoing breast surgery between 2009 and 2013 at the University of North Carolina Hospitals. Multivariable, robust linear regression was performed to identify methylation sites associated with BMI at a false discovery rate q value <0.05. Gene expression microarray data was used to identify which of the BMI-associated methylation sites also showed correlation with gene expression. Gene set enrichment analysis was conducted to assess which pathways were enriched among the BMI-associated methylation sites. Of the 431,568 methylation sites analyzed, 2573 were associated with BMI (q value <0.05), 57 % of which showed an inverse correlation with BMI. Pathways enriched among the 2573 probe sites included those involved in inflammation, insulin receptor signaling, and leptin signaling. We were able to map 1251 of the BMI-associated methylation sites to gene expression data, and, of these, 226 (18 %) showed substantial correlations with gene expression. Our results suggest that BMI is associated with genome-wide methylation in non-diseased breast tissue and may influence epigenetic pathways involved in inflammatory and other carcinogenic processes.

  • 7.
    Harlid, S.
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Umeå University.
    Myte, Robin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    The metabolic syndrome, inflammation and colorectal cancer risk: an evaluation of large panels of plasma protein markers using repeated, pre-diagnostic samples2017In: Mediators of Inflammation, article id 4803156Article in journal (Refereed)
    Abstract [en]

    Metabolic syndrome (MetS), a set of metabolic risk factors including obesity, dysglycemia, and dyslipidemia, is associated with increased colorectal cancer (CRC) risk. A putative biological mechanism is chronic, low-grade inflammation, both a feature of MetS and a CRC risk factor. However, excess body fat also induces a proinflammatory state and increases CRC risk. In order to explore the relationship between MetS, body size, inflammation, and CRC, we studied large panels of inflammatory and cancer biomarkers. We included 138 participants from the Västerbotten Intervention Programme with repeated sampling occasions, 10 years apart. Plasma samples were analyzed for 178 protein markers by proximity extension assay. To identify associations between plasma protein levels and MetS components, linear mixed models were fitted for each protein. Twelve proteins were associated with at least one MetS component, six of which were associated with MetS score. MetS alone was not related to any protein. Instead, BMI displayed by far the strongest associations with the biomarkers. One of the 12 MetS score-related proteins (FGF-21), also associated with BMI, was associated with an increased CRC risk (OR 1.71, 95% CI 1.19–2.47). We conclude that overweight and obesity, acting through both inflammation and other mechanisms, likely explain the MetS-CRC connection.

  • 8.
    Harlid, Sophia
    et al.
    Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA.
    Adgent, Margaret
    Jefferson, Wendy N.
    Panduri, Vijayalakshmi
    Umbach, David M.
    Xu, Zongli
    Stallings, Virginia A.
    Williams, Carmen J.
    Rogan, Walter J.
    Taylor, Jack A.
    Soy formula and epigenetic modifications: analysis of vaginal epithelial cells from infant girls in the IFED study2017In: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 125, no 3, p. 447-452Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Early-life exposure to estrogenic compounds affects the development of the reproductive system in rodent models and humans. Soy products, which contain phytoestrogens such as genistein, are one source of exposure in infants fed soy formula, and they result in high serum concentrations.

    OBJECTIVES: Our goal was to determine whether soy exposure is associated with differential DNA methylation in vaginal cells from soy-fed infant girls.

    METHODS: Using the Illumina HumanMethylation450 BeadChip, we evaluated epigenome-wide DNA methylation in vaginal cells from four soy formula-fed and six cow formula-fed girls from the Infant Feeding and Early Development (IFED) study. Using pyrosequencing we followed up the two most differentially methylated sites in 214 vaginal cell samples serially collected between birth and 9 months of age from 50 girls (28 soy formula-fed and 22 cow formula-fed). With a mouse model, we examined the effect of neonatal exposure to genistein on gene specific mRNA levels in vaginal tissue.

    RESULTS: The epigenome-wide scan suggested differences in methylation between soy formula-fed and cow formula-fed infants at three CpGs in the gene proline rich 5 like (PRR5L) (p < 10(4)). Pyrosequencing of the two feeding groups found that methylation levels progressively diverged with age, with pointwise differences becoming statistically significant after 126 days. Genistein-exposed mice showed a 50% decrease in vaginal Prr5l mRNA levels compared to controls.

    CONCLUSIONS: Girls fed soy formula have altered DNA methylation in vaginal cell DNA which may be associated with decreased expression of an estrogen-responsive gene.

  • 9.
    Harlid, Sophia
    et al.
    Lund University, Department of Laboratory Sciences.
    Butt, Salma
    Ivarsson, Malin I L
    Eyfjörd, Jorunn Erla
    Lenner, Per
    Manjer, Jonas
    Dillner, Joakim
    Carlson, Joyce
    Interactive effect of genetic susceptibility with height, body mass index, and hormone replacement therapy on the risk of breast cancer.2012In: BMC Women's Health, ISSN 1472-6874, E-ISSN 1472-6874, Vol. 12, article id 17Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Breast cancer today has many established risk factors, both genetic and environmental, but these risk factors by themselves explain only part of the total cancer incidence. We have investigated potential interactions between certain known genetic and phenotypic risk factors, specifically nine single nucleotide polymorphisms (SNPs) and height, body mass index (BMI) and hormone replacement therapy (HRT).

    METHODS: We analyzed samples from three different study populations: two prospectively followed Swedish cohorts and one Icelandic case-control study. Totally 2884 invasive breast cancer cases and 4508 controls were analysed in the study. Genotypes were determined using Mass spectrometry-Maldi-TOF and phenotypic variables were derived from measurements and/or questionnaires. Odds Ratios and 95% confidence intervals were calculated using unconditional logistic regression with the inclusion of an interaction term in the logistic regression model.

    RESULTS: One SNP (rs851987 in ESR1) tended to interact with height, with an increasingly protective effect of the major allele in taller women (p = 0.007) and rs13281615 (on 8q24) tended to confer risk only in non users of HRT (p-for interaction = 0.03). There were no significant interactions after correction for multiple testing.

    CONCLUSIONS: We conclude that much larger sample sets would be necessary to demonstrate interactions between low-risk genetic polymorphisms and the phenotypic variables height, BMI and HRT on the risk for breast cancer. However the present hypothesis-generating study has identified tendencies that would be of interest to evaluate for gene-environment interactions in independent materials.

  • 10.
    Harlid, Sophia
    et al.
    Lund University, Department of Laboratory Sciences.
    Ivarsson, Malin I. L.
    Butt, Salma
    Grzybowska, Eva
    Eyfjord, Jorunn E.
    Lenner, Per
    Forsti, Asta
    Hemminki, Kari
    Manjer, Jonas
    Dillner, Joakim
    Carlson, Joyce
    Combined effect of low-penetrant SNPs on breast cancer risk2012In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 106, no 2, p. 389-396Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Although many low-penetrant genetic risk factors for breast cancer have been discovered, knowledge about the effect of multiple risk alleles is limited, especially in women <50 years. We therefore investigated the association between multiple risk alleles and breast cancer risk as well as individual effects according to age-approximated pre- and post-menopausal status.

    METHODS: Ten previously described breast cancer-associated single-nucleotide polymorphisms (SNPs) were analysed in a joint European biobank-based study comprising 3584 breast cancer cases and 5063 cancer-free controls. Genotyping was performed using MALDI-TOF mass spectrometry, and odds ratios were estimated using logistic regression.

    RESULTS: Significant associations with breast cancer were confirmed for 7 of the 10 SNPs. Analysis of the joint effect of the original 10 as well as the statistically significant 7 SNPs (rs2981582, rs3803662, rs889312, rs13387042, rs13281615, rs3817198 and rs981782) found a highly significant trend for increasing breast cancer risk with increasing number of risk alleles (P-trend 5.6 x 10(-20) and 1.5 x 10(-25), respectively). Odds ratio for breast cancer of 1.84 (95% confidence interval (CI): 1.59-2.14; 10 SNPs) and 2.12 (95% CI: 1.80-2.50; 7 SNPs) was seen for the maximum vs the minimum number of risk alleles. Additionally, one of the examined SNPs (rs981782 in HCN1) had a protective effect that was significantly stronger in premenopausal women (P-value: 7.9 x 10(-4)).

    CONCLUSION: The strongly increasing risk seen when combining many low-penetrant risk alleles supports the polygenic inheritance model of breast cancer. British Journal of Cancer (2012) 106, 389-396. doi:10.1038/bjc.2011.461 www.bjcancer.com Published online 1 November 2011 (C) 2012 Cancer Research UK

  • 11.
    Harlid, Sophia
    et al.
    Lund University, Department of Laboratory Sciences.
    Ivarsson, Malin I L
    Butt, Salma
    Hussain, Shehnaz
    Grzybowska, Ewa
    Eyfjörd, Jorunn Erla
    Lenner, Per
    Försti, Asta
    Hemminki, Kari
    Manjer, Jonas
    Dillner, Joakim
    Carlson, Joyce
    A candidate CpG SNP approach identifies a breast cancer associated ESR1-SNP2011In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 129, no 7, p. 1689-1698Article in journal (Refereed)
    Abstract [en]

    Altered DNA methylation is often seen in malignant cells, potentially contributing to carcinogenesis by suppressing gene expression. We hypothesized that heritable methylation potential might be a risk factor for breast cancer and evaluated possible association with breast cancer for single nucleotide polymorphisms (SNPs) either involving CpG sequences in extended 5'-regulatory regions of candidate genes (ESR1, ESR2, PGR, and SHBG) or CpG and missense coding SNPs in genes involved in methylation (MBD1, MECP2, DNMT1, MGMT, MTHFR, MTR, MTRR, MTHFD1, MTHFD2, BHMT, DCTD, and SLC19A1). Genome-wide searches for genetic risk factors for breast cancers have in general not investigated these SNPs, because of low minor allele frequency or weak haplotype associations. Genotyping was performed using Mass spectrometry-Maldi-Tof in a screening panel of 538 cases and 1,067 controls. Potential association to breast cancer was identified for 15 SNPs and one of these SNPs (rs7766585 in ESR1) was found to associate strongly with breast cancer, OR 1.30 (95% CI 1.17-1.45; p-value 2.1 × 10(-6) ), when tested in a verification panel consisting of 3,211 unique breast cancer cases and 4,223 unique controls from five European biobank cohorts. In conclusion, a candidate gene search strategy focusing on methylation-related SNPs did identify a SNP that associated with breast cancer at high significance.

  • 12.
    Harlid, Sophia
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Myte, Robin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Replication of Epigenome-wide Associations Related to Body Mass Index Using the Infinium MethylationEPIC BeadChip on Repeated Samples2017In: Genetic Epidemiology, ISSN 0741-0395, E-ISSN 1098-2272, Vol. 41, no 7, p. 680-680Article in journal (Other academic)
  • 13.
    Harlid, Sophia
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Myte, Robin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    The metabolic syndrome, inflammation, and colorectal cancer risk: an evaluation of large panels of plasma protein markers using erepeated, prediagnostic samples2017In: Mediators of Inflammation, ISSN 0962-9351, E-ISSN 1466-1861, article id 4803156Article in journal (Refereed)
    Abstract [en]

    Metabolic syndrome (MetS), a set of metabolic risk factors including obesity, dysglycemia, and dyslipidemia, is associated with increased colorectal cancer (CRC) risk. A putative biological mechanism is chronic, low-grade inflammation, both a feature of MetS and a CRC risk factor. However, excess body fat also induces a proinflammatory state and increases CRC risk. In order to explore the relationship between MetS, body size, inflammation, and CRC, we studied large panels of inflammatory and cancer biomarkers. We included 138 participants from the Vasterbotten Intervention Programme with repeated sampling occasions, 10 years apart. Plasma samples were analyzed for 178 protein markers by proximity extension assay. To identify associations between plasma protein levels and MetS components, linear mixed models were fitted for each protein. Twelve proteins were associated with at least one MetS component, six of which were associated with MetS score. MetS alone was not related to any protein. Instead, BMI displayed by far the strongest associations with the biomarkers. One of the 12 MetS score-related proteins (FGF-21), also associated with BMI, was associated with an increased CRC risk (OR 1.71, 95% CI 1.19-2.47). We conclude that overweight and obesity, acting through both inflammation and other mechanisms, likely explain the MetS-CRC connection.

  • 14.
    Harlid, Sophia
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Epigenetics & Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
    Xu, Zongli
    Kirk, Erin
    Wilson, Lauren E.
    Troester, Melissa A.
    Taylor, Jack A.
    Hormone therapy use and breast tissue DNA methylation: analysis of epigenome wide data from the normal breast study2019In: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 14, no 2, p. 146-157Article in journal (Refereed)
    Abstract [en]

    Hormone therapy (HT) is associated with increased risk of breast cancer, strongly dependent on type, duration, and recency of use. HT use could affect cancer risk by changing breast tissue transcriptional programs. We hypothesize that these changes are preceded by changes in DNA methylation. To explore this hypothesis we used histologically normal-appearing breast tissue from the Normal Breast Study (NBS). DNA methylation β-values were obtained using the Illumina HumanMethylation 450 BeadChips for 90 samples including all NBS-participants who used HT within 5 y before surgery. Data were analyzed using the reference-free cell mixture method. Cancer Genome Atlas (TCGA) mRNA-Seq data were used to assess correlation between DNA methylation and gene expression. We identified 527 CpG sites in 403 genes that were associated with ever using HT at genome wide significance (FDR q < 0.05), of these, 68 sites were also significantly associated with duration of use or recency of use. Twelve sites reached significance in all analyses one of which was cg01382688 in ARHGEF4 (p < 1.2x10-7). Mutations in ARHGEF4 have been reported in breast tumors, but this is the first report of possible breast cancer-related DNA methylation changes. In addition, 22 genes included more than one significant CpG site and a majority of these sites were significantly correlated with gene expression. Although based on small numbers, these findings support the hypothesis that HT is associated with epigenetic alterations in breast tissue, and identifies genes with altered DNA methylation states which could be linked to breast cancer development.

  • 15.
    Harlid, Sophia
    et al.
    Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA.
    Xu, Zongli
    Panduri, Vijayalakshmi
    D'Aloisio, Aimee A
    DeRoo, Lisa A
    Sandler, Dale P
    Taylor, Jack A
    In utero exposure to diethylstilbestrol and blood DNA methylation in women ages 40-59 years from the sister study.2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 3, article id e0118757Article in journal (Refereed)
    Abstract [en]

    In utero exposure to diethylstilbestrol (DES) has been associated with increased risk of adverse health outcomes such as fertility problems and vaginal as well as breast cancer. Animal studies have linked prenatal DES exposure to lasting DNA methylation changes. We investigated genome-wide DNA methylation and in utero DES exposure in a sample of non-Hispanic white women aged 40-59 years from the Sister Study, a large United States cohort study of women with a family history of breast cancer. Using questionnaire information from women and their mothers, we selected 100 women whose mothers reported taking DES while pregnant and 100 control women whose mothers had not taken DES. DNA methylation in blood was measured at 485,577 CpG sites using the Illumina HumanMethylation450 BeadChip. Associations between CpG methylation and DES exposure status were analyzed using robust linear regression with adjustment for blood cell composition and multiple comparisons. Although four CpGs had p<105, after accounting for multiple comparisons using the false discovery rate (FDR), none reached genome-wide significance. In conclusion, adult women exposed to DES in utero had no evidence of large persistent changes in blood DNA methylation.

  • 16.
    Harlid, Sophia
    et al.
    Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA.
    Xu, Zongli
    Panduri, Vijayalakshmi
    Sandler, Dale P
    Taylor, Jack A
    CpG sites associated with cigarette smoking: analysis of epigenome-wide data from the Sister Study.2014In: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 122, no 7, p. 673-8Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Smoking increases the risk of many diseases, and it is also linked to blood DNA methylation changes that may be important in disease etiology.

    OBJECTIVES: We sought to identify novel CpG sites associated with cigarette smoking.

    METHODS: We used two epigenome-wide data sets from the Sister Study to identify and confirm CpG sites associated with smoking. One included 908 women with methylation measurements at 27,578 CpG sites using the HumanMethylation27 BeadChip; the other included 200 women with methylation measurements for 473,844 CpG sites using the HumanMethylation450 BeadChip. Significant CpGs from the second data set that were not included in the 27K assay were validated by pyrosequencing in a subset of 476 samples from the first data set.

    RESULTS: Our study successfully confirmed smoking associations for 9 previously established CpGs and identified 2 potentially novel CpGs: cg26764244 in GNG12 (p = 9.0 × 10-10) and cg22335340 in PTPN6 (p = 2.9 × 10-05). We also found strong evidence of an association between smoking status and cg02657160 in CPOX (p = 7.3 × 10-7), which has not been previously reported. All 12 CpGs were undermethylated in current smokers and showed an increasing percentage of methylation in former and never-smokers.

    CONCLUSIONS: We identified 2 potentially novel smoking related CpG sites, and provided independent replication of 10 previously reported CpGs sites related to smoking, one of which is situated in the gene CPOX. The corresponding enzyme is involved in heme biosynthesis, and smoking is known to increase heme production. Our study extends the evidence base for smoking-related changes in DNA methylation.

  • 17. Huyghe, Jeroen R.
    et al.
    Bien, Stephanie A.
    Harrison, Tabitha A.
    Kang, Hyun Min
    Chen, Sai
    Schmit, Stephanie L.
    Conti, David V.
    Qu, Conghui
    Jeon, Jihyoun
    Edlund, Christopher K.
    Greenside, Peyton
    Wainberg, Michael
    Schumacher, Fredrick R.
    Smith, Joshua D.
    Levine, David M.
    Nelson, Sarah C.
    Sinnott-Armstrong, Nasa A.
    Albanes, Demetrius
    Alonso, M. Henar
    Anderson, Kristin
    Arnau-Collell, Coral
    Arndt, Volker
    Bamia, Christina
    Banbury, Barbara L.
    Baron, John A.
    Berndt, Sonja I.
    Bezieau, Stephane
    Bishop, D. Timothy
    Boehm, Juergen
    Boeing, Heiner
    Brenner, Hermann
    Brezina, Stefanie
    Buch, Stephan
    Buchanan, Daniel D.
    Burnett-Hartman, Andrea
    Butterbach, Katja
    Caan, Bette J.
    Campbell, Peter T.
    Carlson, Christopher S.
    Castellvi-Bel, Sergi
    Chan, Andrew T.
    Chang-Claude, Jenny
    Chanock, Stephen J.
    Chirlaque, Maria-Dolores
    Cho, Sang Hee
    Connolly, Charles M.
    Cross, Amanda J.
    Cuk, Katarina
    Curtis, Keith R.
    de la Chapelle, Albert
    Doheny, Kimberly F.
    Duggan, David
    Easton, Douglas F.
    Elias, Sjoerd G.
    Elliott, Faye
    English, Dallas R.
    Feskens, Edith J. M.
    Figueiredo, Jane C.
    Fischer, Rocky
    FitzGerald, Liesel M.
    Forman, David
    Gala, Manish
    Gallinger, Steven
    Gauderman, W. James
    Giles, Graham G.
    Gillanders, Elizabeth
    Gong, Jian
    Goodman, Phyllis J.
    Grady, William M.
    Grove, John S.
    Gsur, Andrea
    Gunter, Marc J.
    Haile, Robert W.
    Hampe, Jochen
    Hampel, Heather
    Harlid, Sophia
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hayes, Richard B.
    Hofer, Philipp
    Hoffmeister, Michael
    Hopper, John L.
    Hsu, Wan-Ling
    Huang, Wen-Yi
    Hudson, Thomas J.
    Hunter, David J.
    Ibanez-Sanz, Gemma
    Idos, Gregory E.
    Ingersoll, Roxann
    Jackson, Rebecca D.
    Jacobs, Eric J.
    Jenkins, Mark A.
    Joshi, Amit D.
    Joshu, Corinne E.
    Keku, Temitope O.
    Key, Timothy J.
    Kim, Hyeong Rok
    Kobayashi, Emiko
    Kolonel, Laurence N.
    Kooperberg, Charles
    Kuehn, Tilman
    Kury, Sebastien
    Kweon, Sun-Seog
    Larsson, Susanna C.
    Laurie, Cecelia A.
    Le Marchand, Loic
    Leal, Suzanne M.
    Lee, Soo Chin
    Lejbkowicz, Flavio
    Lemire, Mathieu
    Li, Christopher I.
    Li, Li
    Lieb, Wolfgang
    Lin, Yi
    Lindblom, Annika
    Lindor, Noralane M.
    Ling, Hua
    Louie, Tin L.
    Mannisto, Satu
    Markowitz, Sanford D.
    Martin, Vicente
    Masala, Giovanna
    McNeil, Caroline E.
    Melas, Marilena
    Milne, Roger L.
    Moreno, Lorena
    Murphy, Neil
    Myte, Robin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Naccarati, Alessio
    Newcomb, Polly A.
    Offit, Kenneth
    Ogino, Shuji
    Onland-Moret, N. Charlotte
    Pardini, Barbara
    Parfrey, Patrick S.
    Pearlman, Rachel
    Perduca, Vittorio
    Pharoah, Paul D. P.
    Pinchev, Mila
    Platz, Elizabeth A.
    Prentice, Ross L.
    Pugh, Elizabeth
    Raskin, Leon
    Rennert, Gad
    Rennert, Hedy S.
    Riboli, Elio
    Rodriguez-Barranco, Miguel
    Romm, Jane
    Sakoda, Lori C.
    Schafmayer, Clemens
    Schoen, Robert E.
    Seminara, Daniela
    Shah, Mitul
    Shelford, Tameka
    Shin, Min-Ho
    Shulman, Katerina
    Sieri, Sabina
    Slattery, Martha L.
    Southey, Melissa C.
    Stadler, Zsofia K.
    Stegmaier, Christa
    Su, Yu-Ru
    Tangen, Catherine M.
    Thibodeau, Stephen N.
    Thomas, Duncan C.
    Thomas, Sushma S.
    Toland, Amanda E.
    Trichopoulou, Antonia
    Ulrich, Cornelia M.
    Van den Berg, David J.
    van Duijnhoven, Franzel J. B.
    van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    van Kranen, Henk
    Vijai, Joseph
    Visvanathan, Kala
    Vodicka, Pavel
    Vodickova, Ludmila
    Vymetalkova, Veronika
    Weigl, Korbinian
    Weinstein, Stephanie J.
    White, Emily
    Win, Aung Ko
    Wolf, C. Roland
    Wolk, Alicja
    Woods, Michael O.
    Wu, Anna H.
    Zaidi, Syed H.
    Zanke, Brent W.
    Zhang, Qing
    Zheng, Wei
    Scacheri, Peter C.
    Potter, John D.
    Bassik, Michael C.
    Kundaje, Anshul
    Casey, Graham
    Moreno, Victor
    Abecasis, Goncalo R.
    Nickerson, Deborah A.
    Gruber, Stephen B.
    Hsu, Li
    Peters, Ulrike
    Discovery of common and rare genetic risk variants for colorectal cancer2019In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 51, no 1, p. 76-+Article in journal (Refereed)
    Abstract [en]

    To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 x 10(-8), bringing the number of known independent signals for CRC to similar to 100. New signals implicate lower-frequency variants, Kruppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.

  • 18. Johansson, Stefan
    et al.
    Buchmayer, Susanne
    Harlid, Sophia
    Department of Medical Microbiology, Lund University, Malmö University Hospital, Sweden.
    Iliadou, Anastasia
    Sjöholm, Malin
    Grillner, Lena
    Norman, Mikael
    Sparén, Per
    Dillner, Joakim
    Cnattingius, Sven
    Infection with Parvovirus B19 and Herpes viruses in early pregnancy and risk of second trimester miscarriage or very preterm birth2008In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 26, no 3-4, p. 298-302Article in journal (Refereed)
    Abstract [en]

    We investigated whether infections with Parvovirus B19 and Herpes viruses in early pregnancy increase risks of second trimester miscarriage or delivery before 32 gestational weeks. Blood samples taken in early pregnancy were analyzed for Parvovirus B19 or Herpes viruses. Viremia was found in blood samples of 11 (4.7%) women with second trimester miscarriage and 10 (3.7%) women with very preterm birth, compared to 5 (1.7%) women who delivered at term, corresponding to adjusted odds ratios [95% CI] of 3.32 [0.93, 11.8] and 2.21 [0.71, 6.84], respectively. In stratified analyses, Parvovirus B19 viremia was associated with adjusted odds ratios of 3.76 [0.77, 18.3] for second trimester miscarriage and 2.66 [0.64, 11.1] for very preterm birth. Corresponding odds ratios for Human Herpes virus 6 viremia was 2.52 [0.33, 19.5] and 1.08 [0.14, 8.08], respectively. In conclusion, this study lends some support to the hypothesis that women with viremia in early pregnancy may face an increased risk of second trimester miscarriage or very preterm birth. Studies with larger sample sizes are needed.

  • 19. Markunas, Christina A.
    et al.
    Wilcox, Allen J.
    Xu, Zongli
    Joubert, Bonnie R.
    Harlid, Sophia
    Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina, United States of America.
    Panduri, Vijayalakshmi
    Håberg, Siri E.
    Nystad, Wenche
    London, Stephanie J.
    Sandler, Dale P.
    Lie, Rolv T.
    Wade, Paul A.
    Taylor, Jack A.
    Maternal Age at Delivery Is Associated with an Epigenetic Signature in Both Newborns and Adults2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 7, article id e0156361Article in journal (Refereed)
    Abstract [en]

    Offspring of older mothers are at increased risk of adverse birth outcomes, childhood cancers, type 1 diabetes, and neurodevelopmental disorders. The underlying biologic mechanisms for most of these associations remain obscure. One possibility is that maternal aging may produce lasting changes in the epigenetic features of a child's DNA. To test this, we explored the association of mothers' age at pregnancy with methylation in her offspring, using blood samples from 890 Norwegian newborns and measuring DNA methylation at more than 450,000 CpG sites across the genome. We examined replication of a maternal-age finding in an independent group of 1062 Norwegian newborns, and then in 200 US middle-aged women. Older maternal age was significantly associated with reduced methylation at four adjacent CpGs near the 2nd exon of KLHL35 in newborns (p-values ranging from 3x10-6 to 8x10-7). These associations were replicated in the independent set of newborns, and replicated again in women 40 to 60 years after their birth. This study provides the first example of parental age permanently affecting the epigenetic profile of offspring. While the specific functions of the affected gene are unknown, this finding opens the possibility that a mother's age at pregnancy could affect her child's health through epigenetic mechanisms.

  • 20. Markunas, Christina A
    et al.
    Xu, Zongli
    Harlid, Sophia
    Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA.
    Wade, Paul A
    Lie, Rolv T
    Taylor, Jack A
    Wilcox, Allen J
    Identification of DNA methylation changes in newborns related to maternal smoking during pregnancy.2014In: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 122, no 10, p. 1147-53Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Maternal smoking during pregnancy is associated with significant infant morbidity and mortality, and may influence later disease risk. One mechanism by which smoking (and other environmental factors) might have long-lasting effects is through epigenetic modifications such as DNA methylation.

    OBJECTIVES: We conducted an epigenome-wide association study (EWAS) investigating alterations in DNA methylation in infants exposed in utero to maternal tobacco smoke, using the Norway Facial Clefts Study.

    METHODS: The Illumina HumanMethylation450 BeadChip was used to assess DNA methylation in whole blood from 889 infants shortly after delivery. Of 889 mothers, 287 reported smoking-twice as many smokers as in any previous EWAS of maternal smoking. CpG sites related to maternal smoking during the first trimester were identified using robust linear regression.

    RESULTS: We identified 185 CpGs with altered methylation in infants of smokers at genome-wide significance (q-value < 0.05; mean Δβ = ± 2%). These correspond to 110 gene regions, of which 7 have been previously reported and 10 are newly confirmed using publicly available results. Among these 10, the most noteworthy are FRMD4A, ATP9A, GALNT2, and MEG3, implicated in processes related to nicotine dependence, smoking cessation, and placental and embryonic development.

    CONCLUSIONS: Our study identified 10 genes with newly established links to maternal smoking. Further, we note differences between smoking-related methylation changes in newborns and adults, suggesting possible distinct effects of direct versus indirect tobacco smoke exposure as well as potential differences due to age. Further work would be needed to determine whether these small changes in DNA methylation are biologically or clinically relevant. The methylation changes identified in newborns may mediate the association between in utero maternal smoking exposure and later health outcomes.

  • 21.
    Myte, Robin
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Umeå University.
    Harlid, Sophia
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Sundkvist, Anneli
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Gylling, Björn
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Häggström, Jenny
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Zingmark, Carl
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Löfgren Burström, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Metabolic biomarkers and the risk of molecular subtypes of colorectal cancerManuscript (preprint) (Other academic)
    Abstract [en]

    Background: Body fatness measured as high body mass index (BMI) increase the risk for colorectal cancer (CRC). The mechanisms behind the relationship are not fully understood, but might include insulin resistance and changes in adipokine concentrations produced by adipose tissue. Yet, associations between circulating biomarkers related to these mechanisms and CRC risk have been somewhat inconsistent, possibly due to CRC heterogeneity. To better understand the role of insulin resistance and adipokines in CRC development, we therefore investigated circulating biomarkers related to these mechanisms in relation to molecular subtypes of CRC.

    Methods: This was a prospective case-control study of 1010 cases and 1:1 matched controls nested within the population-based Northern Sweden Health and Disease Study (NSHDS). Concentrations of insulin, C-peptide, adiponectin, and leptin were quantified in prediagnostic plasma using immunoassays and related to CRC and CRC subtypes defined by mutations in BRAF and KRAS, and microsatellite instability (MSI) status analyzed in tumor tissue. Odds ratios (ORs) and 95% confidence intervals (CIs) for CRC by metabolic biomarker levels were calculated with conditional logistic regression.

    Results: Higher C-peptide and lower adiponectin were associated with an increased CRC risk (ORs per 1 standard deviation increase (95% CI): 1.11 (1.01, 1.23) and 0.91 (0.83, 1.00), respectively). The associations were attenuated when adjusting for BMI (ORs (95% CI): 1.07 (0.96, 1.19) and 0.93 (0.84, 1.03), respectively), with the potential exception of the association of C-peptide in women. Circulating insulin and leptin were not associated with CRC risk. We found no clear differences in the association between any biomarkers and CRC risk by molecular subtypes defined by KRAS and BRAF mutation status (Pheterogeneity>0.6), or MSI status (Pheterogeneity>0.3).

    Conclusion: Circulating biomarkers of insulin resistance and adipokines were not associated with CRC or specific molecular subtypes of CRC defined by KRAS and BRAF mutation or MSI status.

  • 22.
    Myte, Robin
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Sundkvist, Anneli
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Harlid, Sophia
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Circulating levels of inflammatory markers and DNA methylation, an analysis of repeated samples from a population based cohort2019In: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 14, no 7, p. 649-659Article in journal (Refereed)
    Abstract [en]

    DNA methylation in blood may adapt to conditions affecting our health, such as inflammation, and multiple studies have identified differential DNA methylation related to smoking, obesity and various diseases. The purpose of this study was to evaluate previously reported, and explore possible new, associations between levels of inflammatory markers and DNA methylation in blood. We used a well-characterized study population consisting of 127 individuals, all of whom were participants in the population-based Vasterbotten Intervention Programme cohort and had provided two blood samples, ten years apart. Levels of CRP and 160 other proteins were measured in plasma, and DNA methylation levels (assessed using the 850K Illumina Infinium MethylationEPIC BeadChip) were measured in white blood cell DNA. Associations between CpG methylation and protein levels were estimated using linear mixed models. In the study we were able to confirm the direction for 85 of 102 previously reported protein-methylation associations. Depicting associations in a network allowed us to identify CpG sites with associations to multiple proteins, and ten CpG sites were each associated with three or more inflammatory markers. Furthermore, two genetic regions included nine additional unreported CpG sites that may represent trans-acting methylation sites. Our study supports a complex interaction between DNA methylation and circulating proteins involved in the inflammatory response. The notion of trans-acting methylation sites affecting, or being affected by, the expression of genes on completely different chromosomes should be taken into account when interpreting results from epigenome-wide association studies.

  • 23. Perrier, Flavie
    et al.
    Novoloaca, Alexei
    Ambatipudi, Srikant
    Baglietto, Laura
    Ghantous, Akram
    Perduca, Vittorio
    Barrdahl, Myrto
    Harlid, Sophia
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Ong, Ken K.
    Cardona, Alexia
    Polidoro, Silvia
    Haugdahl Nøst, Therese
    Overvad, Kim
    Omichessan, Hanane
    Dollé, Martijn
    Bamia, Christina
    Huerta, José Marìa
    Vineis, Paolo
    Herceg, Zdenko
    Romieu, Isabelle
    Ferrari, Pietro
    Identifying and correcting epigenetics measurements for systematic sources of variation2018In: Clinical Epigenetics, E-ISSN 1868-7083, Vol. 10, article id 38Article in journal (Refereed)
    Abstract [en]

    Background: Methylation measures quantified by microarray techniques can be affected by systematic variation due to the technical processing of samples, which may compromise the accuracy of the measurement process and contribute to bias the estimate of the association under investigation. The quantification of the contribution of the systematic source of variation is challenging in datasets characterized by hundreds of thousands of features.In this study, we introduce a method previously developed for the analysis of metabolomics data to evaluate the performance of existing normalizing techniques to correct for unwanted variation. Illumina Infinium HumanMethylation450K was used to acquire methylation levels in over 421,000 CpG sites for 902 study participants of a case-control study on breast cancer nested within the EPIC cohort. The principal component partial R-square (PC-PR2) analysis was used to identify and quantify the variability attributable to potential systematic sources of variation. Three correcting techniques, namely ComBat, surrogate variables analysis (SVA) and a linear regression model to compute residuals were applied. The impact of each correcting method on the association between smoking status and DNA methylation levels was evaluated, and results were compared with findings from a large meta-analysis.

    Results:  A sizeable proportion of systematic variability due to variables expressing 'batch' and 'sample position' within 'chip' was identified, with values of the partial R-2 statistics equal to 9.5 and 11.4% of total variation, respectively. After application of ComBat or the residuals' methods, the contribution was 1.3 and 0.2%, respectively. The SVA technique resulted in a reduced variability due to 'batch' (1.3%) and 'sample position' (0.6%), and in a diminished variability attributable to 'chip' within a batch (0.9%). After ComBat or the residuals' corrections, a larger number of significant sites (k = 600 and k = 427, respectively) were associated to smoking status than the SVA correction (k = 96).

    Conclusions: The three correction methods removed systematic variation in DNA methylation data, as assessed by the PC-PR2, which lent itself as a useful tool to explore variability in large dimension data. SVA produced more conservative findings than ComBat in the association between smoking and DNA methylation.

  • 24. Schmit, Stephanie L.
    et al.
    Edlund, Christopher K.
    Schumacher, Fredrick R.
    Gong, Jian
    Harrison, Tabitha A.
    Huyghe, Jeroen R.
    Qu, Chenxu
    Melas, Marilena
    Van den Berg, David J.
    Wang, Hansong
    Tring, Stephanie
    Plummer, Sarah J.
    Albanes, Demetrius
    Alonso, M. Henar
    Amos, Christopher I.
    Anton, Kristen
    Aragaki, Aaron K.
    Arndt, Volker
    Barry, Elizabeth L.
    Berndt, Sonja I.
    Bezieau, Stephane
    Bien, Stephanie
    Bloomer, Amanda
    Boehm, Juergen
    Boutron-Ruault, Marie-Christine
    Brenner, Hermann
    Brezina, Stefanie
    Buchanan, Daniel D.
    Butterbach, Katja
    Caan, Bette J.
    Campbell, Peter T.
    Carlson, Christopher S.
    Castelao, Jose E.
    Chan, Andrew T.
    Chang-Claude, Jenny
    Chanock, Stephen J.
    Cheng, Iona
    Cheng, Ya-Wen
    Chin, Lee Soo
    Church, James M.
    Church, Timothy
    Coetzee, Gerhard A.
    Cotterchio, Michelle
    Correa, Marcia Cruz
    Curtis, Keith R.
    Duggan, David
    Easton, Douglas F.
    English, Dallas
    Feskens, Edith J. M.
    Fischer, Rocky
    FitzGerald, Liesel M.
    Fortini, Barbara K.
    Fritsche, Lars G.
    Fuchs, Charles S.
    Gago-Dominguez, Manuela
    Gala, Manish
    Gallinger, Steven J.
    Gauderman, W. James
    Giles, Graham G.
    Giovannucci, Edward L.
    Gogarten, Stephanie M.
    Gonzalez-Villalpando, Clicerio
    Gonzalez-Villalpando, Elena M.
    Grady, William M.
    Greenson, Joel K.
    Gsur, Andrea
    Gunter, Marc
    Haiman, Christopher A.
    Hampe, Jochen
    Harlid, Sophia
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Harju, John F.
    Hayes, Richard B.
    Hofer, Philipp
    Hoffmeister, Michael
    Hopper, John L.
    Huang, Shu-Chen
    Huerta, Jose Maria
    Hudson, Thomas J.
    Hunter, David J.
    Idos, Gregory E.
    Iwasaki, Motoki
    Jackson, Rebecca D.
    Jacobs, Eric J.
    Jee, Sun Ha
    Jenkins, Mark A.
    Jia, Wei-Hua
    Jiao, Shuo
    Joshi, Amit D.
    Kolonel, Laurence N.
    Kono, Suminori
    Kooperberg, Charles
    Krogh, Vittorio
    Kuehn, Tilman
    Kury, Sebastien
    LaCroix, Andrea
    Laurie, Cecelia A.
    Lejbkowicz, Flavio
    Lemire, Mathieu
    Lenz, Heinz-Josef
    Levine, David
    Li, Christopher I.
    Li, Li
    Lieb, Wolfgang
    Lin, Yi
    Lindor, Noralane M.
    Liu, Yun-Ru
    Loupakis, Fotios
    Lu, Yingchang
    Luh, Frank
    Ma, Jing
    Mancao, Christoph
    Manion, Frank J.
    Markowitz, Sanford D.
    Martin, Vicente
    Matsuda, Koichi
    Matsuo, Keitaro
    McDonnell, Kevin J.
    McNeil, Caroline E.
    Milne, Roger
    Molina, Antonio J.
    Mukherjee, Bhramar
    Murphy, Neil
    Newcomb, Polly A.
    Offit, Kenneth
    Omichessan, Hanane
    Palli, Domenico
    Cotore, Jesus P. Paredes
    Perez-Mayoral, Julyann
    Pharoah, Paul D.
    Potter, John D.
    Qu, Conghui
    Raskin, Leon
    Rennert, Gad
    Rennert, Hedy S.
    Riggs, Bridget M.
    Schafmayer, Clemens
    Schoen, Robert E.
    Sellers, Thomas A.
    Seminara, Daniela
    Severi, Gianluca
    Shi, Wei
    Shibata, David
    Shu, Xiao-Ou
    Siegel, Erin M.
    Slattery, Martha L.
    Southey, Melissa
    Stadler, Zsofia K.
    Stern, Mariana C.
    Stintzing, Sebastian
    Taverna, Darin
    Thibodeau, Stephen N.
    Thomas, Duncan C.
    Trichopoulou, Antonia
    Tsugane, Shoichiro
    Ulrich, Cornelia M.
    van Duijnhoven, Franzel J. B.
    van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Vijai, Joseph
    Virtamo, Jarmo
    Weinstein, Stephanie J.
    White, Emily
    Win, Aung Ko
    Wolk, Alicja
    Woods, Michael
    Wu, Anna H.
    Wu, Kana
    Xiang, Yong-Bing
    Yen, Yun
    Zanke, Brent W.
    Zeng, Yi-Xin
    Zhang, Ben
    Zubair, Niha
    Kweon, Sun-Seog
    Figueiredo, Jane C.
    Zheng, Wei
    Le Marchand, Loic
    Lindblom, Annika
    Moreno, Victor
    Peters, Ulrike
    Casey, Graham
    Hsu, Li
    Conti, David V.
    Gruber, Stephen B.
    Novel Common Genetic Susceptibility Loci for Colorectal Cancer2019In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 111, no 2, p. 146-157Article in journal (Refereed)
    Abstract [en]

    Background: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5x10(-8)) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk.

    Methods: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5x10(-8)) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided.

    Results: The discovery GWAS identified 11 variants associated with CRC at P < 5x10(-8), of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0.

    Conclusions: This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.

  • 25. Smith, Todd
    et al.
    Muller, David C.
    Moons, Karel G. M.
    Cross, Amanda J.
    Johansson, Mattias
    Ferrari, Pietro
    Fagherazzi, Guy
    Peeters, Petra H. M.
    Severi, Gianluca
    Hüsing, Anika
    Kaaks, Rudolf
    Tjonneland, Anne
    Olsen, Anja
    Overvad, Kim
    Bonet, Catalina
    Rodriguez-Barranco, Miguel
    Huerta, Jose Maria
    Barricarte Gurrea, Aurelio
    Bradbury, Kathryn E.
    Trichopoulou, Antonia
    Bamia, Christina
    Orfanos, Philippos
    Palli, Domenico
    Pala, Valeria
    Vineis, Paolo
    Bueno-de-Mesquita, Bas
    Ohlsson, Bodil
    Harlid, Sophia
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Skeie, Guri
    Weiderpass, Elisabete
    Jenab, Mazda
    Murphy, Neil
    Riboli, Elio
    Gunter, Marc J.
    Aleksandrova, Krasimira Jekova
    Tzoulaki, Ioanna
    Comparison of prognostic models to predict the occurrence of colorectal cancer in asymptomatic individuals: a systematic literature review and external validation in the EPIC and UK Biobank prospective cohort studies2019In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 68, p. 672-683Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To systematically identify and validate published colorectal cancer risk prediction models that do not require invasive testing in two large population-based prospective cohorts.

    DESIGN: Models were identified through an update of a published systematic review and validated in the European Prospective Investigation into Cancer and Nutrition (EPIC) and the UK Biobank. The performance of the models to predict the occurrence of colorectal cancer within 5 or 10 years after study enrolment was assessed by discrimination (C-statistic) and calibration (plots of observed vs predicted probability).

    RESULTS: The systematic review and its update identified 16 models from 8 publications (8 colorectal, 5 colon and 3 rectal). The number of participants included in each model validation ranged from 41 587 to 396 515, and the number of cases ranged from 115 to 1781. Eligible and ineligible participants across the models were largely comparable. Calibration of the models, where assessable, was very good and further improved by recalibration. The C-statistics of the models were largely similar between validation cohorts with the highest values achieved being 0.70 (95% CI 0.68 to 0.72) in the UK Biobank and 0.71 (95% CI 0.67 to 0.74) in EPIC.

    CONCLUSION: Several of these non-invasive models exhibited good calibration and discrimination within both external validation populations and are therefore potentially suitable candidates for the facilitation of risk stratification in population-based colorectal screening programmes. Future work should both evaluate this potential, through modelling and impact studies, and ascertain if further enhancement in their performance can be obtained.

  • 26. Sonestedt, Emily
    et al.
    Ivarsson, Malin I L
    Harlid, Sophia
    Lund University, Department of Laboratory Sciences.
    Ericson, Ulrika
    Gullberg, Bo
    Carlson, Joyce
    Olsson, Håkan
    Adlercreutz, Herman
    Wirfält, Elisabet
    The protective association of high plasma enterolactone with breast cancer is reasonably robust in women with polymorphisms in the estrogen receptor alpha and beta genes2009In: Journal of Nutrition, ISSN 0022-3166, E-ISSN 1541-6100, Vol. 139, no 5, p. 993-1001Article in journal (Refereed)
    Abstract [en]

    It is plausible that polymorphisms in the estrogen receptor alpha and beta genes (ESR1 and ESR2) may modulate the association between enterolactone and breast cancer. Seven polymorphisms in ESR1 (rs827422, rs1709184, rs2347867, rs3020328, rs72207, rs2982896, and rs2234693) and 5 polymorphisms in ESR2 (rs915057, rs1269056, rs1256033, rs3020450, and rs3020443) were selected. The risk of breast cancer for these polymorphisms was estimated among 542 cases and 1076 matched controls from the population-based Malmö Diet and Cancer cohort. The joint effect of these polymorphisms and enterolactone was estimated among those individuals about whom we had information on enterolactone blood concentration (365 cases and 728 controls). Breast cancer risk was not significantly associated with any of the selected polymorphisms. We found a tendency for an interaction between a polymorphism in intron 3 of ESR1 (rs2347867) and enterolactone concentration (P = 0.07). Breast cancer and enterolactone concentration were not associated among those homozygous for the major allele (A) (P = 0.93), whereas we found an inverse association among carriers of the minor allele (G) (P = 0.007). None of the other polymorphisms seem to modify the association between enterolactone and breast cancer. This study suggests that the protective association of enterolactone is reasonably robust across the investigated genotypes. The suggested interaction between enterolactone concentration and rs2347867 needs to be confirmed in larger samples.

  • 27.
    Sundkvist, Anneli
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Myte, Robin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bodén, Stina
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Enroth, Stefan
    Gyllensten, Ulf
    Harlid, Sophia
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Umeå University.
    van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Targeted plasma proteomics identifies a novel, robust association between cornulin and Swedish moist snuff2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, no 1, article id 2320Article in journal (Refereed)
    Abstract [en]

    Lifestyle behaviors are believed to influence the body's inflammatory state. Chronic low-grade inflammation contributes to the development of major non-communicable diseases such as diabetes, cardiovascular disease and cancer. Inflammation may thus be an important link between lifestyle and disease. We evaluated self-reported physical activity, tobacco use and alcohol consumption in relation to plasma levels of 160 validated inflammatory and cancer biomarkers. The study included 138 participants from a population-based cohort, all with repeated sampling of plasma and data ten years apart, allowing consideration of both intra- and inter-individual variation. Of 17 relationships identified, the strongest was an independent, positive association between cornulin (CRNN) and Swedish moist snuff (snus) use. We replicated the finding in a second cohort of 501 individuals, in which a dose-response relationship was also observed. Snus explained approximately one fifth of the variance in CRNN levels in both sample sets (18% and 23%). In conclusion, we identified a novel, independent, dose-dependent association between CRNN and snus use. Further study is warranted, to evaluate the performance of CRNN as a potential snus biomarker. The putative importance of lifestyle behaviors on a wide range of protein biomarkers illustrates the need for more personalized biomarker cut-offs.

  • 28.
    Sundkvist, Anneli
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Myte, Robin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Harlid, Sophia
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Plasma ghrelin is probably not a useful biomarker for risk prediction or early detection of colorectal cancer2019In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 68, no 2, p. 373-374Article in journal (Refereed)
  • 29. Wilson, Lauren E
    et al.
    Harlid, Sophia
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA.
    Xu, Zongli
    Sandler, Dale P
    Taylor, Jack A
    An epigenome-wide study of body mass index and DNA methylation in blood using participants from the Sister Study cohort2017In: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 41, no 1, p. 194-199Article in journal (Refereed)
    Abstract [en]

    BACKGROUND/OBJECTIVES: The relationship between obesity and chronic disease risk is well-established; the underlying biological mechanisms driving this risk increase may include obesity-related epigenetic modifications. To explore this hypothesis, we conducted a genome-wide analysis of DNA methylation and body mass index (BMI) using data from a subset of women in the Sister Study.

    SUBJECTS/METHODS: The Sister Study is a cohort of 50 884 US women who had a sister with breast cancer but were free of breast cancer themselves at enrollment. Study participants completed examinations which included measurements of height and weight, and provided blood samples. Blood DNA methylation data generated with the Illumina Infinium HumanMethylation27 BeadChip array covering 27,589 CpG sites was available for 871 women from a prior study of breast cancer and DNA methylation. To identify differentially methylated CpG sites associated with BMI, we analyzed this methylation data using robust linear regression with adjustment for age and case status. For those CpGs passing the false discovery rate significance level, we examined the association in a replication set comprised of a non-overlapping group of 187 women from the Sister Study who had DNA methylation data generated using the Infinium HumanMethylation450 BeadChip array. Analysis of this expanded 450 K array identified additional BMI-associated sites which were investigated with targeted pyrosequencing.

    RESULTS: Four CpG sites reached genome-wide significance (false discovery rate (FDR) q<0.05) in the discovery set and associations for all four were significant at strict Bonferroni correction in the replication set. An additional 23 sites passed FDR in the replication set and five were replicated by pyrosequencing in the discovery set. Several of the genes identified including ANGPT4, RORC, SOCS3, FSD2, XYLT1, ABCG1, STK39, ASB2 and CRHR2 have been linked to obesity and obesity-related chronic diseases.

    CONCLUSIONS: Our findings support the hypothesis that obesity-related epigenetic differences are detectable in blood and may be related to risk of chronic disease.

  • 30. Wilson, Lauren E
    et al.
    Kim, Sangmi
    Xu, Zongli
    Harlid, Sophia
    Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA.
    Sandler, Dale P
    Taylor, Jack A
    Non-Steroidal Anti-Inflammatory Drug Use and Genomic DNA Methylation in Blood.2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 9, article id e0138920Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Non-steroidal anti-inflammatory drug (NSAID) use is associated with decreased risk of some cancers. NSAID use modulates the epigenetic profile of normal colonic epithelium and may reduce risk of colon cancer through this pathway; however, the effect of NSAID use on the DNA methylation profile of other tissues including whole blood has not yet been examined.

    FINDINGS: Using the Sister Study cohort, we examined the association between NSAID usage and whole genome methylation patterns in blood DNA. Blood DNA methylation status across 27,589 CpG sites was evaluated for 871 women using the Illumina Infinium HumanMethylation27 Beadchip, and in a non-overlapping replication sample of 187 women at 485,512 CpG sites using the Infinium HumanMethylation450 Beadchip. We identified a number of CpG sites that were differentially methylated in regular, long-term users of NSAIDs in the discovery group, but none of these sites were statistically significant in our replication group.

    CONCLUSIONS: We found no replicable methylation differences in blood related to NSAID usage. If NSAID use does effect blood DNA methylation patterns, differences are likely small.

  • 31. Wilson, Lauren E.
    et al.
    Xu, Zongli
    Harlid, Sophia
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    White, Alexandra J.
    Troester, Melissa A.
    Sandler, Dale P.
    Taylor, Jack A.
    Alcohol and DNA Methylation: An Epigenome-Wide Association Study in Blood and Normal Breast Tissue2019In: American Journal of Epidemiology, ISSN 0002-9262, E-ISSN 1476-6256, Vol. 188, no 6, p. 1055-1065Article in journal (Refereed)
    Abstract [en]

    The biological mechanisms driving associations between alcohol consumption and chronic diseases might include epigenetic modification of DNA methylation. We explored the hypothesis that alcohol consumption is associated with methylation in an epigenome-wide association study of blood and normal breast tissue DNA. Infinium HumanMethylation450 BeadChip (Illumina Inc., San Diego, California) array data on blood DNA methylation was examined in a discovery set of 2,878 non-Hispanic white women from the Sister Study (United States, 2004-2015) who provided detailed questionnaire information on lifetime alcohol use. Robust linear regression modeling was used to identify significant associations (false discovery rate of Q < 0.05) between the number of alcoholic drinks per week and DNA methylation at 5,458 cytosine-phosphate-guanine (CpG) sites. Associations were replicated (P < 0.05) for 677 CpGs in an independent set of 187 blood DNA samples from the Sister Study and for 628 CpGs in an independent set of 171 normal breast DNA samples; 1,207 CpGs were replicated in either blood or normal breast, with 98 CpGs replicated in both tissues. Individual gene effects were notable for phosphoglycerate dehydrogenase (PGHDH), peptidyl-prolyl cis-trans isomerase (PPIF), solute carrier 15 (SLC15), solute carrier family 43 member 1 (SLC43A1), and solute carrier family 7 member 11 (SLC7A11). We also found that high alcohol consumption was associated with significantly lower global methylation as measured by the average of CpGs on the entire array.

1 - 31 of 31
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf