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

• Published in: American heart journal plus Vol. 17; p. 100152
• Main Authors: Dungan, Jennifer R., Qin, Xue, Gregory, Simon G., Cooper-Dehoff, Rhonda, Duarte, Julio D., Qin, Huaizhen, Gulati, Martha, Taylor, Jacquelyn Y., Pepine, Carl J., Hauser, Elizabeth R., Kraus, William E.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.05.2022; Elsevier
• Subjects: Coronary artery disease; Genome-wide association study; Sex differences; Sex dimorphism; Survival analysis; Survival analysis; ACS; GWAS; Sex dimorphism; Genome-wide association study; IHD; SNP; MACE; CAD; Sex differences; MI; Coronary artery disease
• ISSN: 2666-6022; 2666-6022
• DOI: 10.1016/j.ahjo.2022.100152

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). 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. 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. 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. [Display omitted] •Genetic variation is a presumed factor underlying sex differences in MACE, yet the field lacks sex-stratified GWAS of longitudinal events.•We identified unique sex-associated candidate genes, adjusted for cardiovascular risk factors, for all-cause mortality among people with CAD.•Candidate genes among males (EMP2, KCNJ6) and females (LPGAT1, PDE9A, PRKD1, RAP1GAP2) have biologic relevance to CAD and/or mortality.•Future genetic research using sex-as-a-biological variable may help to explain how sex differences contribute to disparate CAD outcomes.