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 - Funding Information:
C.O.-R. reports receiving grant support from Agencia Nacional de Investigación y Desarrollo (ANID)/Scholarship Program/Doctorado Becas Chile/2016 - 72170524. P.P.M. and T.L. reported receiving financial support from the Academy of Finland [grants 286284, 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi), and 41071 (Skidi)], the Social Insurance Institution of Finland, Competitive State Research Financing of the Expert Responsibility area of Kuopio, Tampere and Turku University Hospitals (grant X51001), Juho Vainio Foundation, Paavo Nurmi Foundation, Finnish Foundation for Cardiovascular Research, Finnish Cultural Foundation, Tampere Tuberculosis Foundation, Emil Aaltonen Foundation, Yrjö Jahnsson Foundation, Signe and Ane Gyllenberg Foundation, Diabetes Research Foundation of Finnish Diabetes Association, and EU Horizon 2020 (grant 755320 for TAXINOMISIS Project). H.J.G., S.B.F., and A.T. report receiving financial support from the Federal Ministry of Education and Research (grants 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania, and the network “Greifswald Approach to Individualized Medicine (GANI_MED)” funded by the Federal Ministry of Education and Research (grant 03IS2061A) and the DZHK (grant 81X34000104). J.C. is supported by the Singapore Ministry of Health’s National Medical Research Council under its Singapore Translational Research Investigator (STaR) Award (NMRC/STaR/0028/ 2017). KORA was initiated and financed by Helmholtz Zentrum München (German Research Center for Environmental Health), which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Furthermore, KORA research has been supported within the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ. This work was supported by a grant (WA 4081/1-1) from the German Research Foundation.
Funding Information:
under its Singapore Translational Research Investigator (STaR) Award (NMRC/STaR/0028/ 2017). KORA was initiated and financed by Helmholtz Zentrum München (German Research Center for Environmental Health), which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Furthermore, KORA research has been supported within the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ. This work was supported by a grant (WA 4081/1-1) from the German Research Foundation. Duality of Interest. H.J.G. has received travel grants and speakers honoraria from Fresenius Medical Care, Neuraxpharm, Servier, and Janssen Cilag, as well as research funding from Fresenius Medical Care. O.H.F. reports receiving grants or research support from Metagenics, Inc., and Nestlé Nutrition (Nestec Ltd.). No other potential conflicts of interest relevant to this article were reported. Author Contributions. T.M. and C.O.-R. contributed to the study concept and design. C.O.-R., R.W.,B.L.,P.P.M.,X.G.,M.L.,D.J.-Q.,J.B.J.v.M.,W.Z., J.S.K., H.J.G., S.B.F., B.S., Y.Z., C.G., M.M.-N., M.H., A.P., and A.T. contributed to data generation and analyses.C.O.-R.,T.M.,R.W.,B.L.,P.P.M.,X.G.,D.J.-Q., M.L., E.P.-F., J.N., O.H.F., M.G., O.L.R.-O., A.T., H.B., M.W., M.A.I., J.B.J.v.M., T.V., J.C., and B.H.S. contributed to drafting of the manuscript. O.H.F., M.G., O.L.R.-O., T.L., A.T., H.B., M.W., M.A.I., J.B.J.v.M., T.V., J.C., B.H.S., and T.M. contributed to critical revision of the manuscript for important intellectual content. All authors approved the final version of the manuscript. C.O.-R. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Prior Presentation. Parts of this study were presented in abstract form at the 78th Scientific Sessions of the American Diabetes Association, Orlando, FL, 22–26 June 2018, and at EuroPre-vent 2019, Lisbon, Portugal, 11–13 April 2019.
Funding Information:
Funding. C.O.-R. reports receiving grant support from Agencia Nacional de Investigación y De-sarrollo (ANID)/Scholarship Program/Doctorado Becas Chile/2016 - 72170524. P.P.M. and T.L. reported receiving financial support from the Academy of Finland [grants 286284, 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi), and 41071 (Skidi)], the Social Insurance Institution of Finland, Competitive State Research Financing of the Expert Responsibility area of Kuopio, Tampere and Turku University Hospitals (grant X51001), Juho Vainio Foundation, Paavo Nurmi Foundation, Finnish Foundation for Cardiovascular Research, Finnish Cultural Foundation, Tampere Tuberculosis Foundation, Emil Aaltonen Foundation, Yrjö Jahnsson Foundation, Signe and Ane Gyllenberg Foundation, Diabetes Research Foundation of Finnish Diabetes Association, and EU Horizon 2020 (grant 755320 for TAXINOMISIS Project). H.J.G., S.B.F., and A.T. report receiving financial support from the Federal Ministry of Education and Research (grants 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania, and the network “Greifswald Approach to Individualized Medicine (GANI_MED)” funded by the Federal Ministry of Education and Research (grant 03IS2061A) and the DZHK (grant 81X34000104). J.C. is supported by the Singapore Ministry of Health’s National Medical Research Council
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 -