The Impact of Sex on the Metabolome and CVD

Brigham And Women'S Hospital, Boston MA

Investigators

Abstract

Background: Sex has a profound effect on cardiovascular disease (CVD) occurrence and associated risk factors. Our research group, and others, have characterized metabolomic profiles associated with CVD. However, no studies have comprehensively examined the impact of sex on the metabolome and how these differences contribute to differences in CVD risk. These analyses may offer clues about sex differences in the biologic pathways related to CVD. Goal: We will examine the impact of sex on the metabolome, generate sex-specific metabolomic signatures, and evaluate their contribution to CVD risk in women and men across generations. Setting: We have assembled an exceptional team with deep expertise in women's health, cardiovascular disease, metabolomics, and biostatistics/bioinformatics. Research Plan: Our aims leverage four large, unique cohorts: (1) the UK Biobank (UKB; N=502,386 men and women, N=274,236 with metabolomics); (2) COMETS consortium (N=130,000+ men and women) (3) the Women's Health Initiative (WHI-CHD; N=2306 women with metabolomics in a CHD case-control study); and (4) Nurses' Health Studies (NHS-Stroke, N=908 women with metabolomics in a stroke case-control study). Aim 1 will use the UK Biobank (UKB, n=274,236 with metabolomics) to derive two signatures: (a) a sex metabolite score (UKB-SMS) and (b) a sex metabolite class score (UKB-SMCS). These scores will quantify molecular differences between women and men and assess which factors (eg. hormonal exposures, adiposity, etc.) partially account for them. We will then test the associations of UKB-SMS and UKB-SMCS with incident CVD, coronary heart disease (CHD), and stroke, separately in men and women and across generations. Aim 2 will extend this work to the international COMETS consortium (N=130,000+) using comprehensive metabolomic platforms. We will (a) derive a COMETS-based sex metabolite score (COM-SMS), (b) test associations of COM-SMS with incident CHD in the WHI-CHD (N=2306) and stroke in NHS-Stroke (N=908), and (c) evaluate the association of the UKB-SMCS with incident CHD and stroke in WHI-CHD and NHS-Stroke, respectively, to determine the generalizability of sex-specific metabolomic signatures across populations. Aim 3 will identify CVD-related metabolite signatures separately in men and women within UKB (N=274,236). We will develop CVD metabolite scores (CVD-MS) and metabolite class scores (CVD-MCS), compare their associations with CVD across sexes, and conduct network analyses to map shared versus sexually dimorphic pathways underlying CVD, highlighting sex-specific biological processes that may serve as novel therapeutic/preventive targets.