Post-genomic update on a classical candidate gene for coronary artery disease: ESR1

Abstract

Background: After age, sex is the most important risk factor for coronary artery disease (CAD). The mechanism through which women are protected from CAD is still largely unknown, but the observed sex difference suggests the involvement of the reproductive steroid hormone signaling system. Genetic association studies of the gene-encoding Estrogen Receptor α (ESR1) have shown conflicting results, although only a limited range of variation in the gene has been investigated.

Methods and results: We exploited information made available by advanced new methods and resources in complex disease genetics to revisit the question of ESR1's role in risk of CAD. We performed a meta-analysis of 14 genome-wide association studies (CARDIoGRAM discovery analysis, N=≈87,000) to search for population-wide and sex-specific associations between CAD risk and common genetic variants throughout the coding, noncoding, and flanking regions of ESR1. In addition to samples from the MIGen (N=≈6000), WTCCC (N=≈7400), and Framingham (N=≈3700) studies, we extended this search to a larger number of common and uncommon variants by imputation into a panel of haplotypes constructed using data from the 1000 Genomes Project. Despite the widespread expression of ERα in vascular tissues, we found no evidence for involvement of common or low-frequency genetic variation throughout the ESR1 gene in modifying risk of CAD, either in the general population or as a function of sex.

Conclusions: We suggest that future research on the genetic basis of sex-related differences in CAD risk should initially prioritize other genes in the reproductive steroid hormone biosynthesis system.

Figure 1

Regional association results for the ESR1 gene region. Results of CARDIoGRAM global and gender-stratified meta-analysis and fine mapping analysis for a region of chromosome 6 containing the coding and non-coding exons of ESR1 and 50kb of the upstream and downstream flanking regions (−log₁₀(p-value) shown as black points). Results shown are for a fixed or random effects meta-analysis in the absence or presence of between-study heterogeneity, respectively (see Methods). The position of the ESR1 gene is shown at the bottom of the plot (dotted line), with coding and non-coding exons shown as long and short vertical bars, respectively. Regional recombination rate (HapMap II) is shown as a grey line in plot A. A). Regional association plot of global meta-analysis results from the CARDIoGRAM study. B). Regional association plot of gender-stratified meta-analysis results from the CARDIoGRAM study. Results for the test for SNP-gender interaction are shown in the top panel; results for the association test in females and males are shown in the middle and bottom panels, respectively. C). Regional association plot of results from fine-mapping meta-analysis (MIGen, WTCCC and Framingham studies). Results for SNPs that were previously analyzed in the CARDIoGRAM study are shown as black points (i.e. SNPs that were directly genotyped or imputed using a reference panel of haplotypes generated from the Phase II HapMap CEU genotypes). Results for additional SNPs that were imputed using a reference panel of haplotypes generated using data from the 1000 Genomes project (August 2010 release) are shown as grey points.