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

Abstract

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. 12/26 genes were also discovered in studies that conducted sex-stratified analyses. 12/26 genes were classified as having a role in lipid synthesis, metabolism and/or lipoprotein mechanisms, while 11/26 were classified as having a role in vascular integrity, and 3/26 were classified as having a role in thrombosis.

Discussion: This study provides further evidence of the relationship between estrogen, genetic risk and the development of CAD. More sex-stratified research will need to be conducted to further characterize estrogen's relation to sex differences in the pathology and progression of CAD.

Keywords: coronary artery disease; estrogen; gene candidates; genome wide association study; sex differences.

Figure 1

Abstract screening of CAD GWAS studies included shown through PRISMA flow diagram. “Significant” refers to genome-wide significance of p < 5 * 10⁻⁸ and “data” refer to SNPs.

Figure 2

Representation of key characteristics of the GWASs that had genome-wide significant SNPs mapped to genes (n = 36). (A) Frequency of studies that did sex-stratified analyses and/or sex-combined analyses; (B) frequency of phenotype definitions used for inclusion criteria cases; (C) frequency of inclusion of the large ancestral supergroups of participants in the studies. Percents do not add up to 100% because multiple CAD definitions or ancestries may have been reported per study.

Figure 3

Venn diagram mapped genes from significant SNPs identified in CAD GWASs. Genes emphasized by bold and underscore were identified to have evidence of estrogen modulation of gene expression and/or translated protein activity. No SNPs were identified to be significant just in females.

Figure 4

Mechanism diagram of the gene products identified in lipid synthesis, metabolism and/or lipoprotein mechanisms that have evidence for estrogen modulation. Genes described in text are in blue boxes with arrows identifying their gene product.

Figure 5

Mechanism diagram of the gene products identified in vascular integrity through roles in the vascular endothelium and/or smooth muscle cells that have evidence for estrogen modulation. Genes described in text are in blue boxes with arrows identifying their gene product.

Figure 6

Mechanism diagram of the gene products identified in thrombosis roles that have evidence for estrogen modulation. Genes described in text are in blue boxes with arrows identifying their gene product.