Epigenetic Link Between Statin Therapy and Type 2 Diabetes

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

doi:10.2337/dc19-1828

Epigenetic Link Between Statin Therapy and Type 2 Diabetes

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 HeierAnnette 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

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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: 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 × 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 regulations 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.

Original language	English
Journal	Diabetes Care
Early online date	7 Feb 2020
DOIs	https://doi.org/10.2337/dc19-1828
Publication status	E-pub ahead of print - 7 Feb 2020

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Ochoa-Rosales, C., Portilla-Fernandez, E., Nano, J., Wilson, R., Lehne, B., Mishra, P. P., Gao, X., Ghanbari, M., Rueda-Ochoa, O. L., Juvinao-Quintero, D., Loh, M., Zhang, W., Kooner, J. S., Grabe, H. J., Felix, S. B., Schöttker, B., Zhang, Y., Gieger, C., Müller-Nurasyid, M., ... Muka, T. (2020). Epigenetic Link Between Statin Therapy and Type 2 Diabetes. Diabetes Care. Advance online publication. https://doi.org/10.2337/dc19-1828

@article{93302438111744eca010d5bcc0988be6,

title = "Epigenetic Link Between Statin Therapy and Type 2 Diabetes",

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: 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 × 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 regulations 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.",

author = "Carolina Ochoa-Rosales and Eliana Portilla-Fernandez and Jana Nano and Rory Wilson and Benjamin Lehne and Mishra, {Pashupati P} and Xu Gao and Mohsen Ghanbari and Rueda-Ochoa, {Oscar L} and Diana Juvinao-Quintero and Marie Loh and Weihua Zhang and Kooner, {Jaspal S} and Grabe, {Hans J} and Felix, {Stephan B} and Ben Sch{\"o}ttker and Yan Zhang and Christian Gieger and Martina M{\"u}ller-Nurasyid and Margit Heier and Annette Peters and Terho Lehtim{\"a}ki and Alexander Teumer and Hermann Brenner and Melanie Waldenberger and Ikram, {M Arfan} and {van Meurs}, {Joyce B J} and Franco, {Oscar H} and Trudy Voortman and John Chambers and Stricker, {Bruno H} and Taulant Muka",

note = "{\textcopyright} 2020 by the American Diabetes Association.",

year = "2020",

month = feb,

day = "7",

doi = "10.2337/dc19-1828",

language = "English",

journal = "Diabetes Care",

issn = "0149-5992",

publisher = "American Diabetes Association Inc.",

}

Ochoa-Rosales, C, Portilla-Fernandez, E, Nano, J, Wilson, R, Lehne, B, Mishra, PP, Gao, X, Ghanbari, M, Rueda-Ochoa, OL, Juvinao-Quintero, D, Loh, M, Zhang, W, Kooner, JS, Grabe, HJ, Felix, SB, Schöttker, B, Zhang, Y, Gieger, C, Müller-Nurasyid, M, Heier, M, Peters, A, Lehtimäki, T, Teumer, A, Brenner, H, Waldenberger, M, Ikram, MA, van Meurs, JBJ, Franco, OH, Voortman, T, Chambers, J, Stricker, BH & Muka, T 2020, 'Epigenetic Link Between Statin Therapy and Type 2 Diabetes', Diabetes Care. https://doi.org/10.2337/dc19-1828

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

PY - 2020/2/7

Y1 - 2020/2/7

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 = 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 × 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 regulations 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 = 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 × 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 regulations 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.

U2 - 10.2337/dc19-1828

DO - 10.2337/dc19-1828

M3 - Article (Academic Journal)

C2 - 32033992

SN - 0149-5992

JO - Diabetes Care

JF - Diabetes Care

ER -

Epigenetic Link Between Statin Therapy and Type 2 Diabetes

Abstract

Bibliographical note

UN SDGs

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