Sex-dimorphic gene effects on survival outcomes in people with coronary artery disease

Abstract

Background: Ischemic coronary heart disease (IHD) is the leading cause of death worldwide. Genetic variation is presumed to be a major factor underlying sex differences for IHD events, including mortality. The purpose of this study was to identify sex-specific candidate genes associated with all-cause mortality among people diagnosed with coronary artery disease (CAD).

Methods: We performed a sex-stratified, exploratory genome-wide association (GWAS) screen using existing data from CAD-diagnosed males (n = 510) and females (n = 174) who reported European ancestry from the Duke Catheterization Genetics biorepository. Extant genotype data for 785,945 autosomal SNPs generated with the Human Omni1-Quad BeadChip (Illumina, CA, USA) were analyzed using an additive inheritance model. We estimated instantaneous risk of all-cause mortality by genotype groups across the 11-year follow-up using Cox multivariate regression, covarying for age and genomic ancestry.

Results: The top GWAS hits associated with all-cause mortality among people with CAD included 8 SNPs among males and 15 among females (p = 1 × 10^-6 or 10^-7), adjusted for covariates. Cross-sex comparisons revealed distinct candidate genes. Biologically relevant candidates included rs9932462 (EMP2/TEKT5) and rs2835913 (KCNJ6) among males and rs7217169 (RAP1GAP2), rs8021816 (PRKD1), rs8133010 (PDE9A), and rs12145981 (LPGAT1) among females.

Conclusions: We report 20 sex-specific candidate genes having suggestive association with all-cause mortality among CAD-diagnosed subjects. Findings demonstrate proof of principle for identifying sex-associated genetic factors that may help explain differential mortality risk in people with CAD. Replication and meta-analyses in larger studies with more diverse samples will strengthen future work in this area.

Keywords: Coronary artery disease; Genome-wide association study; Sex differences; Sex dimorphism; Survival analysis.

Graphical abstract

Fig. 1

Exemplar Kaplan-Meier curves of survival time in days (x-axis) and all-cause survival probability (y-axis) by genotype category among males with CAD. The solid black line represents wild-type homozygous (AA) genotype carriers, the blue dashed line represents heterozygous (GA) genotype carriers, and the red dotted line represents carriers with two copies of the minor (“risk”) allele (GG; risk homozygous genotype). A) The frequency of rs9932462 risk homozygous genotype was extremely low in this group. Males with CAD having the heterozygous genotype had a 4.92-fold increased risk of all-cause mortality compared to males having the wild-type homozygous genotype (95 % CI [2.57, 9.40], p = 1.41e−06). B) The frequency of rs2835913 risk homozygous carriers was also very low; males with CAD having the heterozygous genotype had a 3.5-fold increase in risk of all-cause mortality compared to wild-type homozygous genotype carriers (HR = 3.46, 95 % CI [2.03, 5.90], p = 4.81e−06). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Exemplar Kaplan-Meier curves of survival time in days (x-axis) and all-cause survival probability (y-axis) by genotype category among females with CAD. A) rs7217169 (RAP1GAP2); B) rs8021816 (PRKD1); C) rs8133010 (PDE9A); and D) rs12145981 (LPGAT1). The black solid line represents wild-type homozygous genotype carriers, the blue dashed line represents heterozygous genotype carriers, and the red dotted line represents carriers with two copies of the minor (“risk”) allele (risk homozygous genotype). The frequency of rs7217169 and rs8021816 risk homozygous genotype was low. Compared to wild-type homozygous genotype carriers, A) each copy of the RAP1GAP2 rs7217169 G (risk) allele was associated with a 4.06-fold increased risk of all-cause mortality among females with CAD (95 % CI [2.22, 7.41], p = 4.98e−06); B) each copy of the PRKD1 rs8021816 C (risk) allele was associated with a 5.86-fold increased risk of all-cause mortality (95 % CI [2.71, 12.65], p = 6.76e−06); C) each copy of the PDE9A rs8133010 G (risk) allele was associated with a 3.22-fold increased event risk (95 % CI [1.94, 5.33], p = 5.57e−06); and D) each copy of the LPGAT1 rs12145981 G (risk) allele was associated with a 3.40-fold increased event risk (95 % CI [2.03, 5.68], p = 3.18e−06). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 3

Venn diagram of top candidate genes and shared genetic variation, by sex. Genes in bold have biological relevance to cardiovascular disease or survival. ^†Top male SNP that also shows p < .05 among females (does not appear in list of top candidates for females).

Fig. 4

Forest plot of top SNP effect sizes. Circles indicate hazard ratio (HR), by male (blue) and female (pink). Horizontal lines indicate the 95 % confidence interval (CI), also provided in brackets, far right. Vertical dotted line indicates HR threshold value of 1. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)