Abstract | 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: RESULTS: Discovery (n = 6,820) and replication (n = 1,450) phases associated five DNAm sites with statin use: cg17901584 (1.12 × 10-25 [DHCR24]), cg10177197 (3.94 × 10-08 [DHCR24]), cg06500161 (2.67 × 10-23 [ABCG1]), cg27243685 (6.01 × 10-09 [ABCG1]), and cg05119988 (7.26 × 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.
|
Authors | Carolina Ochoa-Rosales, Eliana Portilla-Fernandez, Jana Nano, Rory Wilson, Benjamin Lehne, Pashupati P Mishra, Xu Gao, Mohsen Ghanbari, Oscar L Rueda-Ochoa, Diana Juvinao-Quintero, Marie Loh, Weihua Zhang, Jaspal S Kooner, Hans J Grabe, Stephan B Felix, Ben Schöttker, Yan Zhang, Christian Gieger, Martina Müller-Nurasyid, Margit Heier, Annette Peters, Terho Lehtimäki, Alexander Teumer, Hermann Brenner, Melanie Waldenberger, M Arfan Ikram, Joyce B J van Meurs, Oscar H Franco, Trudy Voortman, John Chambers, Bruno H Stricker, Taulant Muka |
Journal | Diabetes care
(Diabetes Care)
Vol. 43
Issue 4
Pg. 875-884
(04 2020)
ISSN: 1935-5548 [Electronic] United States |
PMID | 32033992
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Copyright | © 2020 by the American Diabetes Association. |
Chemical References |
- Blood Glucose
- Hydroxymethylglutaryl-CoA Reductase Inhibitors
- Insulin
|
Topics |
- Adult
- Aged
- Blood Glucose
(metabolism)
- Cohort Studies
- CpG Islands
(drug effects, genetics)
- DNA Methylation
(drug effects, physiology)
- Diabetes Mellitus, Type 2
(blood, drug therapy, genetics)
- Epigenesis, Genetic
(drug effects)
- Female
- Follow-Up Studies
- Humans
- Hydroxymethylglutaryl-CoA Reductase Inhibitors
(therapeutic use)
- Insulin
(blood)
- Insulin Resistance
(genetics)
- Male
- Middle Aged
- Phenotype
|
|
Join CureHunter, for free Research Interface BASIC access!
Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease.
Find out why thousands of doctors, pharma researchers and patient activists
around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!
|