Dissect the sex-specific role of the CYP17A1 locus in cardiovascular and metabolic diseases

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Genetic factors can modulate blood pressure and obesity and increase coronary artery disease (CAD) and its related risk factors. CAD is partially heritable, and our recent genome-wide association studies (GWAS) identified over 300 loci associated with elevated risk for CAD. CYP17A1 is among the CAD GWAS loci and was initially identified to be associated with myocardial infarction. CYP17A1 gene encodes the cytochrome P450 17A1 enzyme, a determinant in steroid metabolism. Studies from other groups demonstrated the association of the CYP17A1 locus with other cardiovascular-related risk factors, including blood pressure and fat distribution. Recently sex-stratified GWAS (in male or female only) for cardiovascular disease revealed strong evidence of a sex-specific effect of the CYP17A1 locus in fat distribution, blood pressure regulation, and atherosclerosis, the underlying cause of CAD. Similar to the human data, our Cyp17a1 knockout mice results pinpointed a risk of atherosclerosis in males and obesity in females. The XY Cyp17a1 KO mice revealed a lack of testosterone, while the XX Cyp17a1 KO mice lack estrogen and display a marked progesterone accumulation. However, the functional link and exact molecular mechanisms underlying the association between the CYP17A1 sex-biased effect and CAD and other cardiovascular-related diseases are missing. In this proposal, we aim to investigate the exact mechanism by which CYP17A1, and thus its related sex steroid hormones, influence blood pressure, metabolism, and atherosclerosis (CAD) in humans and mice in a sex manner. Especially we aim to 1) identify and validate the causal genetic variants associated with CYP17A1 gene expression changes differently in males and females, 2) test whether sex hormone supplementation, including testosterone and estrogen, can prevent atherosclerosis in XY Cyp17a1 KO and obesity in XX Cyp17a1 KO mice, 3) test the effect of a progesterone receptor inhibitor on obesity in females; and 4) to determine the importance of AT1 receptor blocker therapy in XX and XY Cyp17a1 KO mice, as it is known that the Renin Angiotensin Aldosterone System (RAAS) influences steroid biosynthesis via Cyp17a1 regulation and that therapeutic RAAS intervention has an antiadipose effect and reduces the risk of atherosclerosis and CAD. All these will help to develop sex-specific therapies and diagnostic methods for males and females at high risk for cardiovascular diseases.