Introduction: Women of all ethnicities have the highest rates of Acute Coronary Syndrome (ACS) misdiagnosis, delayed treatment, and ACS-related near-term mortality. Known physiologic differences and traditional risk factors have failed to fully explain these ACS disparities among women. Our knowledge gap of genomic variation underlying women’s unique ACS phenotypes means that there is no female-derived ACS risk biomarker that reflects female-specific biology and phenotype features. Among 510 women, we previously identified 122 SNPs within 14 genomic regions that significantly predicted ‘survivorship in CAD’ (all-cause mortality among coronary artery disease cases; p<10-5); none of which were significant in males or controls. Given the recent recognition of sex as a biological variable, our purpose was to identify female-specific genomic markers that predict ACS case status.
Methods: We performed secondary case-control analysis for 1,382 females (796 ACS cases/586 non-ACS controls) of the Duke Catheterization Genetics (CATHGEN) Study (Illumina Human Infinium 1.0 platform). ACS was defined as having no previous MI history plus either documented unstable angina pain type or incident myocardial infarction. We employed logistic regression models of ACS case status for each SNP separately, assuming additive genetic models, and controlling for age and 3 PCAs of ethnicity.
Results: Twenty-three SNPs among 3 biologically relevant candidates (LPAGT1, SLC9A9, & RAP1GAP2) significantly predicted women’s ACS (range p=7.43x10-5 - 0.05) with positive and negative odds ratios observed. LPGAT1 is involved in cardiolipin synthesis; SLC9A9 is involved in endosome recycling; and, RAP1GAP2 regulates secretion of dense granules from platelets at endothelial damage sites. Additionally, 74 SNPs within the 11 novel survivorship with CAD candidates significantly predicted ACS (p<0.05).
Conclusions: We demonstrate proof of principal for unique, female-specific genomic effects on ACS case status; and, shared genomic variation with ACS and survivorship in CAD among women. Validation of this work is required. Future research is needed to identify female-derived genomic markers that may uniquely characterize women’s ACS and coronary disease expression.