TY - JOUR
T1 - Metabolome-wide association identifies ferredoxin-1 (FDX1) as a determinant of cholesterol metabolism and cardiovascular risk in Asian populations
AU - Sadhu, Nilanjana
AU - Dalan, Rinkoo
AU - Jain, Pritesh R.
AU - Lee, Chang Jie Mick
AU - Pakkiri, Leroy Sivappiragasam
AU - Tay, Kai Yi
AU - Mina, Theresia H.
AU - Low, Dorrain
AU - Min, Yilin
AU - Ackers-Johnson, Matthew
AU - Thi, Thi Tun
AU - Kota, Vishnu Goutham
AU - Shi, Yu
AU - Liu, Yan
AU - Yu, Hanry
AU - Lai, Vicky
AU - Yang, Yang
AU - Tay, Darwin
AU - Ng, Hong Kiat
AU - Wang, Xiaoyan
AU - Wong, Kari E.
AU - Lam, Max
AU - Guan, Xue Li
AU - Bertin, Nicolas
AU - Wong, Eleanor
AU - Best, James
AU - Sarangarajan, Rangaprasad
AU - Elliott, Paul
AU - Riboli, Elio
AU - Lee, Jimmy
AU - Lee, Eng Sing
AU - Ngeow, Joanne
AU - Tan, Patrick
AU - Cheung, Christine
AU - Drum, Chester Lee
AU - Foo, Roger S.Y.
AU - Michelotti, Gregory A.
AU - Yu, Haojie
AU - Sheridan, Patricia A.
AU - Loh, Marie
AU - Chambers, John C.
N1 - Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature Limited 2025.
PY - 2025
Y1 - 2025
N2 - The burden of cardiovascular disease is rising in the Asia-Pacific region, in contrast to falling cardiovascular disease mortality rates in Europe and North America. Here we perform quantification of 883 metabolites by untargeted mass spectroscopy in 8,124 Asian adults and investigate their relationships with carotid intima media thickness, a marker of atherosclerosis. Plasma concentrations of 3beta-hydroxy-5-cholestenoate (3BH5C), a cholesterol metabolite, were inversely associated with carotid intima media thickness, and Mendelian randomization studies supported a causal relationship between 3BH5C and coronary artery disease. The observed effect size was 5- to 6-fold higher in Asians than Europeans. Colocalization analyses indicated the presence of a shared causal variant between 3BH5C plasma levels and messenger RNA and protein expression of ferredoxin-1 (FDX1), a protein that is essential for sterol and bile acid synthesis. We validated FDX1 as a regulator of 3BH5C synthesis in hepatocytes and macrophages and demonstrated its role in cholesterol efflux in macrophages and aortic smooth muscle cells, using knockout and overexpression models.
AB - The burden of cardiovascular disease is rising in the Asia-Pacific region, in contrast to falling cardiovascular disease mortality rates in Europe and North America. Here we perform quantification of 883 metabolites by untargeted mass spectroscopy in 8,124 Asian adults and investigate their relationships with carotid intima media thickness, a marker of atherosclerosis. Plasma concentrations of 3beta-hydroxy-5-cholestenoate (3BH5C), a cholesterol metabolite, were inversely associated with carotid intima media thickness, and Mendelian randomization studies supported a causal relationship between 3BH5C and coronary artery disease. The observed effect size was 5- to 6-fold higher in Asians than Europeans. Colocalization analyses indicated the presence of a shared causal variant between 3BH5C plasma levels and messenger RNA and protein expression of ferredoxin-1 (FDX1), a protein that is essential for sterol and bile acid synthesis. We validated FDX1 as a regulator of 3BH5C synthesis in hepatocytes and macrophages and demonstrated its role in cholesterol efflux in macrophages and aortic smooth muscle cells, using knockout and overexpression models.
UR - http://www.scopus.com/inward/record.url?scp=105004917552&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=105004917552&partnerID=8YFLogxK
U2 - 10.1038/s44161-025-00638-w
DO - 10.1038/s44161-025-00638-w
M3 - Article
AN - SCOPUS:105004917552
SN - 2731-0590
JO - Nature Cardiovascular Research
JF - Nature Cardiovascular Research
M1 - 1417357
ER -
