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

The HELIOS cohort (short for Health for Life in Singapore or sometimes referred to as HELIOS Study) is a large-scale biomedical research project based in Singapore, aimed at understanding how genetic, lifestyle, and environmental factors influence health and disease in Asian populations. The rates of cardiovascular disease in the Asia-Pacific region are increasing, despite a decline in Europe and North America. To better understand the reasons behind this, researchers studied blood samples from over 8,000 adults in Singapore. They measured hundreds of small molecules in the blood and looked at how these related to early signs of atherosclerosis.

One molecule in particular, 3beta-hydroxy-5-cholestenoate (3BH5C), which comes from cholesterol—stood out. People with higher levels of this molecule tended to have healthier arteries. The connection was especially strong in Asian individuals, suggesting that this molecule may play a bigger role in heart health for them compared to people of European background.

The researchers also discovered that a protein called FDX1 helps control the levels of this helpful molecule. In lab tests, they showed that changing the amount of FDX1 in certain cells affected how cholesterol was processed and moved out of cells in the arteries.

Overall, this study provides new insight into how metabolism affects heart disease risk in Asian populations—and points to FDX1 as a possible target for new treatments to prevent heart disease.

Abstract

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.

Author Publications List
Key recent publications include:

Wang X*, Mina T*, Sadhu N, Jain PR, Ng HK, Low D, Tay D, Tong T, Choo W, Kerk SK, Low GL, The HELIOS Study Team, Lam B, Dalan R, Wanseicheong G, Yew YW, Leow E, Brage S, Michelotti GA, Wong KE, Sheridan PA, Low PY, Yeo ZX, Bertin N, Bellis C, Hebrard M, Goy PV, Tsilidis KK, Sanikini H, Guan XL, Lim TH, Lee L, Best JD, Lee J, Ngeow J, Riboli E, Lam M, Loh M, Chambers JC. The Health for Life in Singapore (HELIOS) Study: delivering Precision Medicine research for Asian populations (revise &resubmit, preprint on medRxiv).

Low DY, Mina T, Sadhu N, Wong K, Jain PR, Dalan R, Ng HK, Xie W, Lam B, Tay D, Wang X, Yew YW, Best J, Sarangarajan R, Elliott P, Riboli E, Lee J, Lee ES, Ngeow J, Sheridan P, Michelotti G, Loh M, Chambers J. Metabolic variation reflects dietary intake in a multi-ethnic Asian population (revise &resubmit, preprint on medRxiv).

Mina T, Xie W, Low DY, Wang X, Lam B, Sadhu N, Ng HK, Azizah N, Tong T, Kim KS, Choo WL, Low GL, Halimah I, Lim L, Wansaicheong G, Dalan R, Yew YW, Elliott P, Riboli E, Loh M, Ngeow J, Lee ES, Lee J, Best J, Chambers J. Adiposity and metabolic health in Asian populations: An epidemiological study using Dual X-Ray Absorptiometry. The Lancet Diabetes & Endocrinology, 2024.

Smith HM, Ng HK, Moodie JE, Gadd DA, McCartney DL, Bernabeu E, Campbell A, Redmond P, Taylor A, Danielle Page 3, Janie Corley 3, Sarah E Harris 3, Darwin Tay 2, Ian J Deary 3, Kathryn L Evans 1, Matthew R Robinson 4, John C Chambers JC, Loh M, Cox SR, Marioni RE, Hillary RF. Am J Hum Genet. 2025 Jan 2;112(1):106-115. DNA methylation-based predictors of metabolic traits in Scottish and Singaporean cohorts.

In This Webinar You Will Learn:

  • How ethnicity impacts cardiovascular disease risk
  • How metabolomics and genomics are integrated to identify atherosclerosis disease mechanisms
  • How findings from the HELIOS cohort were translated and confirmed in in vitro models
  • About Metabolomics and genomic integration

Integrating metabolomics data with genomics provides a comprehensive understanding of the biological mechanisms underlying health and disease by linking genetic variation to metabolic phenotypes. Metabolomics enhances genomic data by identifying the functional consequences of genetic variants, offering direct insight into biochemical activity that genomics alone cannot provide. This integration improves biomarker discovery, reveals novel therapeutic targets, and supports more precise and personalized approaches to medicine by uncovering gene-environment interactions that shape individual metabolic responses.

Program

Time
Presenter
Title/Abstract
5 min
Kari Wong, Ph.D.
Welcome and Introductions
10 min
John Chambers, Ph.D.
Importance of the paper and partnership
20 min
Nilanjana Sadhu, Ph.D.
Study outcomes, findings and next steps
5 min
John Chambers, Ph.D.
Wrap up
10 min
Greg Michelotti, Ph.D.
Metabolon Product
10 min
Kari Wong, Ph.D.
Questions and Answers

Guest Speakers

K
L

John Chambers, Ph.D.

Professor, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore

Professor Chambers is Chief Scientific Officer (CSO) of PRECISE, the central entity established to implement Phase II of Singapore’s National Precision Medicine strategy. Prof Chambers is the lead investigator of the PRECISE-SG100K population cohort study, a multi-institutional effort that aims to study the genetic makeup of 100,000 healthy Singaporeans and specific disease cohorts. The genetic data will be integrated with detailed lifestyle, environmental, and clinical data to yield rich insights into factors that contribute to Asian diseases and conditions.

John is also Distinguished Professor of Cardiovascular Epidemiology at LKCMedicine, where he leads research focused on identification of mechanisms underlying the high rate of cardiovascular disease and diabetes in Asian populations, along with clinical translation to improve prevention and control of these major diseases. He has been closely involved in large-scale prospective population studies in Europe, South Asia and Singapore. His research has contributed to the discovery of novel genetic and epigenetic pathways associated with coronary heart disease, type-2 diabetes, obesity, and related metabolic disturbances implicating new molecular pathways underlying these diseases.

As Program Lead, he aims to inspire a new generation of researchers to become future leaders, who will build innovative research programs that build on the foundational SG100K resource, and the international partnerships established.

K
L

Nilanjana Sadhu, Ph.D.

Doctor, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore

LinkedIn | X | HELIOS | Featured Publication

Dr. Nilanjana Sadhu received her Ph.D. in 2020 from the University of Illinois at Chicago, USA, after which she joined the Human Genetics group at Biogen, USA. She is currently a Research Fellow at the Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, where she is working with Professor John C. Chambers and leading the PRECISE-SG100K Flagship Proteomics Project.
Dr. Sadhu holds a Bachelor's and Master's degree in Pharmacy from the Birla Institute of Technology and Science (BITS Pilani), India. She uses computational approaches to investigate molecular mechanisms underlying human diseases. Her work is motivated by her passion for translational research. Currently, her research focuses on leveraging and integrating genetic, metabolomic, and proteomic data to gain insights into cardiovascular and metabolic disease risk and health outcomes in Asian populations.

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