Sex‐Associated Metabolites and Incident Stroke, Incident Coronary Heart Disease, Hypertension, and Chronic Kidney Disease in the REGARDS Cohort

Abstract

Background Sex disparities exist in cardiometabolic diseases. Metabolomic profiling offers insight into disease mechanisms, as the metabolome is influenced by environmental and genetic factors. We identified metabolites associated with sex and determined if sex‐associated metabolites are associated with incident stoke, incident coronary heart disease, prevalent hypertension, and prevalent chronic kidney disease. Methods and Results Targeted metabolomics was conducted for 357 metabolites in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) case‐cohort substudy for incident stroke. Weighted logistic regression models were used to identify metabolites associated with sex in REGARDS. Sex‐associated metabolites were replicated in the HyperGEN (Hypertension Genetic Epidemiology Network) and using the literature. Weighted Cox proportional hazard models were used to evaluate associations between metabolites and incident stroke. Cox proportional hazard models were used to evaluate associations between metabolites and incident coronary heart disease. Weighted logistic regression models were used to evaluate associations between metabolites and hypertension and chronic kidney disease. Fifty‐one replicated metabolites were associated with sex. Higher levels of 6 phosphatidylethanolamines were associated with incident stroke. No metabolites were associated with incident coronary heart disease. Higher levels of uric acid and leucine and lower levels of a lysophosphatidylcholine were associated with hypertension. Higher levels of indole‐3‐lactic acid, 7 phosphatidylethanolamines, and uric acid, and lower levels of betaine and bilirubin were associated with chronic kidney disease. Conclusions These findings suggest that the sexual dimorphism of the metabolome may contribute to sex differences in stroke, hypertension, and chronic kidney disease.