TY - JOUR
T1 - Epigenetic link between statin therapy and type 2 diabetes
AU - Ochoa-Rosales, Carolina
AU - Portilla-Fernandez, Eliana
AU - Nano, Jana
AU - Wilson, Rory
AU - Lehne, Benjamin
AU - Mishra, Pashupati P.
AU - Gao, Xu
AU - Ghanbari, Mohsen
AU - Rueda-Ochoa, Oscar L.
AU - Juvinao-Quintero, Diana
AU - Loh, Marie
AU - Zhang, Weihua
AU - Kooner, Jaspal S.
AU - Grabe, Hans J.
AU - Felix, Stephan B.
AU - Schöttker, Ben
AU - Zhang, Yan
AU - Gieger, Christian
AU - Müller-Nurasyid, Martina
AU - Heier, Margit
AU - Peters, Annette
AU - Lehtimäki, Terho
AU - Teumer, Alexander
AU - Brenner, Hermann
AU - Waldenberger, Melanie
AU - Ikram, M. Arfan
AU - van Meurs, Joyce B.J.
AU - Franco, Oscar H.
AU - Voortman, Trudy
AU - Chambers, John
AU - Stricker, Bruno H.
AU - Muka, Taulant
N1 - Publisher Copyright:
© 2020 by the American Diabetes Association.
PY - 2020/4/1
Y1 - 2020/4/1
N2 - 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 5 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 5 6,820) and replication (n 5 1,450) phases associated five DNAm sites with statin use: cg17901584 (1.12 3 10225 [DHCR24]), cg10177197 (3.94 3 10208 [DHCR24]), cg06500161 (2.67 3 10223 [ABCG1]), cg27243685 (6.01 3 10209 [ABCG1]), and cg05119988 (7.26 3 10212 [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.
AB - 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 5 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 5 6,820) and replication (n 5 1,450) phases associated five DNAm sites with statin use: cg17901584 (1.12 3 10225 [DHCR24]), cg10177197 (3.94 3 10208 [DHCR24]), cg06500161 (2.67 3 10223 [ABCG1]), cg27243685 (6.01 3 10209 [ABCG1]), and cg05119988 (7.26 3 10212 [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.
UR - http://www.scopus.com/inward/record.url?scp=85082147382&partnerID=8YFLogxK
U2 - 10.2337/dc19-1828
DO - 10.2337/dc19-1828
M3 - Article
C2 - 32033992
AN - SCOPUS:85082147382
SN - 0149-5992
VL - 43
SP - 875
EP - 884
JO - Diabetes Care
JF - Diabetes Care
IS - 4
ER -