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DNA methylation patterns associated with oxidative stress in an ageing population
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
Univ Tartu, Inst Biomed & Translat Med, Dept Biochem, Ctr Excellence Genom & Translat Med, Tartu, Estonia..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.ORCID iD: 0000-0003-2247-8454
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
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2016 (English)In: BMC Medical Genomics, ISSN 1755-8794, E-ISSN 1755-8794, Vol. 9, article id 72Article in journal (Refereed) Published
Abstract [en]

Background: Oxidative stress has been related to type 2 diabetes (T2D) and cardiovascular disease (CVD), the leading global cause of death. Contributions of environmental factors such as oxidative stress on complex traits and disease may be partly mediated through changes in epigenetic marks (e.g. DNA methylation). Studies relating differential methylation with intermediate phenotypes and disease endpoints may be useful in identifying additional candidate genes and mechanisms involved in disease. Methods: To investigate the role of epigenetic variation in oxidative stress marker levels and subsequent development of CVD and T2D, we performed analyses of genome-wide DNA methylation in blood, ten markers of oxidative stress (total glutathione [TGSH], reduced glutathione [GSH], oxidised glutathione [GSSG], GSSG to GSH ratio, homocysteine [HCY], oxidised low-density lipoprotein (oxLDL), antibodies against oxLDL [OLAB], conjugated dienes [CD], baseline conjugated dienes [BCD]-LDL and total antioxidant capacity [TAOC]) and incident disease in up to 966 age-matched individuals. Results: In total, we found 66 cytosine-guanine (CpG) sites associated with one or more oxidative stress markers (false discovery rate [FDR] <0.05). These sites were enriched in regulatory regions of the genome. Genes annotated to CpG sites showed enrichment in annotation clusters relating to phospho-metabolism and proteins with pleckstrin domains. We investigated the contribution of oxidative stress-associated CpGs to development of cardiometabolic disease. Methylation variation at CpGs in the 3'-UTR of HIST1H4D (cg08170869; histone cluster 1, H4d) and in the body of DVL1 (cg03465880; dishevelled-1) were associated with incident T2D events during 10 years of follow-up (all permutation p-values < 0.01), indicating a role of epigenetic regulation in oxidative stress processes leading to development or progression of diabetes. Methylation QTL (meQTL) analysis showed significant associations with genetic sequence variants in cis at 28 (42%) of oxidative stress phenotype-associated sites (FDR < 0.05). Integrating cis-meQTLs with genotype-phenotype associations indicated that genetic effects on oxidative stress phenotype at one locus (cg07547695; BCL2L11) may be mediated through DNA methylation. Conclusions: In conclusion, we report novel associations of DNA methylation with oxidative stress, some of which also show evidence of a relation with T2D incidence.

Place, publisher, year, edition, pages
2016. Vol. 9, article id 72
Keywords [en]
DNA methylation, Epigenetics, Oxidative stress, Type 2 diabetes, Cardiovascular disease
National Category
Medical Genetics
Identifiers
URN: urn:nbn:se:uu:diva-311185DOI: 10.1186/s12920-016-0235-0ISI: 000388539300001PubMedID: 27884142OAI: oai:DiVA.org:uu-311185DiVA, id: diva2:1059360
Funder
Knut and Alice Wallenberg FoundationSwedish Research Council, 2012-1397Swedish Heart Lung Foundation, 20120197EU, European Research Council, 2014-2020.4.01.15-0012Available from: 2016-12-22 Created: 2016-12-22 Last updated: 2018-01-13Bibliographically approved

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Hedman, Åsa K.Sundström, JohanLind, LarsIngelsson, Erik
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