Sexually dimorphic DNA-methylation in cardiometabolic health: A systematic review.

Eralda Asllanaj, Xiaofang Zhang, Carolina Ochoa Rosales, Jana Nano, Wichor M Bramer, Eliana Portilla-Fernandez, Kim V E Braun, Valentina Gonzalez-Jaramillo, Wolfgang Ahrens, Arfan Ikram, Mohsen Ghanbari, Trudy Voortman, Oscar H Franco, Taulant Muka, Marija Glisic

Journal: Maturitas 2020;135():6-26

PMID: 32252966

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Abstract

Sex is a major determinant of cardiometabolic risk. DNA methylation (DNAm), an important epigenetic mechanism that differs between sexes, has been associated with cardiometabolic diseases. Therefore, we aimed to systematically review studies in adults investigating sex-specific associations of DNAm with intermediate cardiometabolic traits and incident cardiovascular disease including stroke, myocardial infarction (MI) and coronary heart disease (CHD). Five bibliographic databases were searched from inception to 15 July 2019. We selected 35 articles (based on 30 unique studies) from 17,023 references identified, with a total of 14,020 participants of European, North American or Asian ancestry. Four studies reported sex differences between global DNAm and blood lipid levels and stroke risk. In 25 studies that took a genome wide or candidate gene approach, DNAm at 31 gene sites was associated with sex differences in cardiometabolic diseases. The identified genes were PLA2G7, BCL11A, KDM6A, LIPC, ABCG1, PLTP, CETP, ADD1, CNN1B, HOOK2, GFBP-7,PTPN1, GCK, PTX3, ABCG1, GALNT2, CDKN2B, APOE, CTH, GNASAS, INS, PON1, TCN2, CBS, AMT, KDMA6A, FTO, MAP3K13, CCDC8, MMP-2 and ER-α. Prioritized pathway connectivity analysis associated these genes with biological pathways such as vitamin B12 metabolism, statin pathway, plasma lipoprotein, plasma lipoprotein assembly, remodeling and clearance and cholesterol metabolism. Our findings suggest that DNAm might be a promising molecular strategy for understanding sex differences in the pathophysiology of cardiometabolic diseases and that future studies should investigate the effects of sex on epigenetic mechanisms in cardiometabolic risk. In addition, we emphasize the gap between the translational potential and the clinical utilization of cardiometabolic epigenetics.

Address: Department of Epidemiology, Erasmus MC, University Medical Centre, Rotterdam, the Netherlands; Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany. Electronic address: [email protected].; Department of Epidemiology, Erasmus MC, University Medical Centre, Rotterdam, the Netherlands.; Department of Epidemiology, Erasmus MC, University Medical Centre, Rotterdam, the Netherlands; Centro de Vida Saludable de la Universidad de Concepción, Concepción, Chile.; Institute of Epidemiology, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany; German Centre for Diabetes Research, Neuherberg, Germany.; Medical Library, Erasmus MC, University Medical Centre, Rotterdam, the Netherlands.; Department of Epidemiology, Erasmus MC, University Medical Centre, Rotterdam, the Netherlands; Division of Pharmacology, Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands.; Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.; Leibniz Institute for Prevention Research and Epidemiology-BIPS, Bremen, Germany.; Department of Epidemiology, Erasmus MC, University Medical Centre, Rotterdam, the Netherlands; Department of Neurology, Erasmus MC, University Medical Centre, Rotterdam, the Netherlands.; Department of Epidemiology, Erasmus MC, University Medical Centre, Rotterdam, the Netherlands; Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.; Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland; Swiss Paraplegic Research, Nottwil, Switzerland.

DOI: 10.1016/j.maturitas.2020.02.005