Metabolome-wide association of carotid intima media thickness identifies FDX1 as a determinant of cholesterol metabolism and cardiovascular risk in Asian populations.

The burden of cardiovascular disease (CVD) is rising in the Asia-Pacific region, in contrast to falling CVD mortality rates in Europe and North America. To provide new insights into the pathways influencing cardiovascular risk in Asian populations, we quantified 883 metabolites by untargeted mass spectroscopy in 8,124 Singaporean adults, and investigated their relationships to carotid intima media thickness (cIMT), a marker of atherosclerosis. We found that plasma concentrations of 3beta-hydroxy-5-cholestenoate (3BH5C), a cholesterol metabolite, associated inversely with cIMT (Beta[SE]=-0.013[0.002]). Genetic instruments support a causal relationship of 3BH5C metabolic pathways on cardiovascular risk, with a 5-6 fold higher effect size in Asians (ORGSMR[95% CI]=0.89[0.87-0.92], ORIVW[95% CI]=0.86[0.80-0.92]) compared to Europeans (ORIVW[95% CI] = 0.98[0.96-0.99]). Colocalization analyses indicate the presence of a shared causal variant between 3BH5C plasma levels and expression of ferredoxin-1 (FDX1), a protein essential for sterol and bile acid synthesis. We validated FDX1 as a key regulator of 3BH5C synthesis in hepatocytes, and macrophages, and cholesterol efflux in aortic smooth muscle cells, through knockout and overexpression models. In summary, this study makes an important contribution to our understanding of the metabolic basis for atherosclerosis in Asian populations, and identifies FDX1 as a potential therapeutic target for prevention of CVD.