Exploring associations between estrogen and gene candidates identified by coronary artery disease genome-wide association studies

Ava Parissa Aminbakhsh ¹ Emilie T Théberge ¹ Ellizabeth Burden ^1,2 Cindy Kalenga Adejumo ^1,2 Annabel Katherine Gravely ¹ Anna Lehman ^1,2 Tara Sedlak ^1,2*

• ¹ University of British Columbia, Vancouver, Canada
• ² Vancouver Coastal Health, Vancouver, British Columbia, Canada

Introduction: Coronary artery disease (CAD) is the leading cause of death around the world, with epidemiological sex and gender differences in prevalence, pathophysiology and outcomes. It has been hypothesized that sex steroids, like estrogen, may contribute to these sex differences. There is a relatively large genetic component to developing CAD, with heritability estimates ranging between 40-60%. In the last two decades, genome-wide association studies (GWAS) have contributed substantially to advancing the understanding of genetic candidates contributing to CAD. The aim of this study was to determine if genes discovered in CAD GWASs are affected by estrogen via direct modulation or indirect down-stream targets.Methods: A scoping review was conducted using MEDLINE and EMBASE for studies of atherosclerotic coronary artery disease and a genome-wide association study (GWAS) design. Analysis was limited to candidate genes with corresponding single nucleotide polymorphisms (SNPs) surpassing genome-wide significance and had been mapped to genes by study authors. The number of studies that conducted sex-stratified analyses with significant genes were quantified. A literature search of the final gene lists was done to examine any evidence suggesting estrogen may modulate the genes and/or gene products.Results: There were 60 eligible CAD GWASs meeting inclusion criteria for data extraction. Of these 60, only 36 had genome-wide significant SNPs reported, and only 3 of these had significant SNPs from sex-stratified analyses mapped to genes. From these 36 studies, a total of 61 genes were curated, of which 26 genes (43%) were found to have modulation by estrogen. All 26 were discovered in studies that adjusted for sex.