Journal
DIABETES CARE
Volume 43, Issue 4, Pages 875-884Publisher
AMER DIABETES ASSOC
DOI: 10.2337/dc19-1828
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Funding
- Agencia Nacional de Investigacion y Desarrollo (ANID)/Scholarship Program/Doctorado Becas Chile/2016 [72170524]
- Academy of Finland [286284, 134309, 126925, 121584, 124282, 129378, 117787, 41071]
- Social Insurance Institution of Finland
- Competitive State Research Financing of the Expert Responsibility area of Kuopio, Tampere and Turku University Hospitals [X51001]
- Juho Vainio Foundation
- Paavo Nurmi Foundation
- Finnish Foundation for Cardiovascular Research
- Finnish Cultural Foundation
- Tampere Tuberculosis Foundation
- Emil Aaltonen Foundation
- Yrjo Jahnsson Foundation
- Signe and Ane Gyllenberg Foundation
- Diabetes Research Foundation of Finnish Diabetes Association
- EU Horizon 2020 [755320]
- Federal Ministry of Education and Research [01ZZ9603, 01ZZ0103, 01ZZ0403]
- Ministry of Cultural Affairs
- Social Ministry of the Federal State of Mecklenburg-West Pomerania
- network Greifswald Approach to Individualized Medicine (GANI_MED) - Federal Ministry of Education and Research [03IS2061A]
- DZHK [81X34000104]
- Singapore Ministry of Health's National Medical Research Council under its Singapore Translational Research Investigator (STaR) Award [NMRC/STaR/0028/2017]
- Helmholtz Zentrum Munchen (German Research Center for Environmental Health)
- German Federal Ministry of Education and Research (BMBF)
- State of Bavaria
- Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universitat, as part of LMUinnovativ
- German Research Foundation [WA 4081/1-1]
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OBJECTIVE To investigate the role of epigenetics in statins' diabetogenic effect comparing DNA methylation (DNAm) between statin users and nonusers in an epigenome-wide association study in blood. RESEARCH DESIGN AND METHODS Five cohort studies' participants (n = 8,270) were classified as statin users when they were on statin therapy at the time of DNAm assessment with Illumina 450K or EPIC array or noncurrent users otherwise. Associations of DNAm with various outcomes like incident type 2 diabetes, plasma glucose, insulin, and insulin resistance (HOMA of insulin resistance [HOMA-IR]) as well as with gene expression were investigated. RESULTS Discovery (n = 6,820) and replication (n = 1,450) phases associated five DNAm sites with statin use: cg17901584 (1.12 x 10(-25) [DHCR24]), cg10177197 (3.94 x 10(-08) [DHCR24]), cg06500161 (2.67 x 10(-23) [ABCG1]), cg27243685 (6.01 x 10(-09) [ABCG1]), and cg05119988 (7.26 x 10(-12) [SC4MOL]). Two sites were associated with at least one glycemic trait or type 2 diabetes. Higher cg06500161 methylation was associated with higher fasting glucose, insulin, HOMA-IR, and type 2 diabetes (odds ratio 1.34 [95% CI 1.22, 1.47]). Mediation analyses suggested that ABCG1 methylation partially mediates the effect of statins on high insulin and HOMA-IR. Gene expression analyses showed that statin exposure and ABCG1 methylation were associated with ABCG1 downregulation, suggesting epigenetic regulation of ABCG1 expression. Further, outcomes insulin and HOMA-IR were significantly associated with ABCG1 expression. CONCLUSIONS This study sheds light on potential mechanisms linking statins with type 2 diabetes risk, providing evidence on DNAm partially mediating statins' effects on insulin traits. Further efforts shall disentangle the molecular mechanisms through which statins may induce DNAm changes, potentially leading to ABCG1 epigenetic regulation.
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