Theresia Mina

Background Carotid-intima media-thickness (cIMT) predicts cardiovascular events and informs mechanistic research on cardiovascular diseases. However, cardiovascular disease research remains Eurocentric despite etiological differences across ancestries. Incorporating Asian populations who face substantial cardiovascular disease burden with distinct etiological landscape can enhance our understanding of cIMT biology and subclinical processes linked to CVD. This study aims to elucidate methylation-based mechanisms of cIMT through DNA methylation profiling integrated with multi-omics data and clinically informative cIMT thresholds, leveraging an Asian cohort to enhance discovery. Methods We conducted an epigenome-wide association study (EWAS) of cIMT using peripheral blood DNA methylation at ~ 850,000 CpG sites in the Asian Health for Life in Singapore (HELIOS) cohort (n = 1,357), followed by targeted trans-ancestry meta-analysis with European cohorts (overall n = 2,765). Causal inference analyses (summary data-based Mendelian Randomisation [SMR] and colocalisation) evaluated methylation-mediated effects on cIMT, cardiovascular disease and proximal gene expression. We derived a methylation risk score (MRS) and tested its association with cIMT thresholds indicative of elevated cardiovascular risk (≥ 75th percentile for age, sex and ethnicity). Results Three novel CpG-cIMT associations were identified (P < 9.35E-07). Causal analyses supported cg08227773 methylation-mediated effects on both coronary artery disease risk (P _SMR =2.91E-05, coloc PP.H4 = 0.91) and NBEAL2 (Neurobeachin-like 2) expression (P _SMR =9.13E-08, coloc PP.H4 = 0.69), a gene implicated in immune dysregulation. MRS of cIMT aggregating the three sentinel CpGs was associated with clinically-informative cIMT elevation (Odds Ratio = 2.75 for Q4 vs Q1, 95% CI: 1.47–5.13). Conclusions Through Asian-led discovery, this study identifies three novel DNA methylation markers for cIMT that are linked to cIMT elevation above clinically meaningful risk thresholds. Causal inference analyses suggest methylation-mediated coronary artery disease risk via NBEAL2 regulation, nominating biologically relevant targets while underscoring the need for larger multi-omics resources to refine mechanisms.

The gut microbiome composition varies across human populations, but its characteristics and determinants in a multi-ethnic setting remain incompletely understood. Singapore, a multicultural city-state, provides a context in which culturally diverse groups share a broadly similar built environment. Using the Health for Life in Singapore (HELIOS) cohort, we profiled the gut microbiome of ethnic Chinese, Indian, and Malay participants (n=861) who resided in the country. Despite substantial overlap in the overall microbial compositions, each group displayed distinct microbial signatures that paralleled culturally rooted dietary habits. Specifically, ethnic Indian participants showed enrichment of multiple Bifidobacterium species associated with greater intake of traditional grain-based staples such as idli and thosai; ethnic Malay participants exhibited higher abundance of Ruminococcaceae associated with coconut-and rice-based dishes; and ethnic Chinese participants had greater levels of Bacteroides associated with seafood- and meat-rich diets. These ethnicity-diet-microbiome relationships were further corroborated by additional data from two independent Malaysian cohorts (n=544), a cohort from the United States (n=210), and an in vitro microbial culture model showing selective Bifidobacterium expansion by a fermented rice-based batter. Analysis of fecal microbiome-based risk scores revealed ethnic gradients in colorectal neoplasia scores that mirrored population-level cancer incidence patterns. Together, these findings characterize gut microbiome variations across major Asian ethnicities residing in a shared urban environment, providing a reference for precision health strategies relevant to over two billion ethnically relevant people in the Asia-Pacific region and beyond.

Background: Obesity is a global public health challenge, with increasing burden especially in emerging Asian economies. While the effectiveness of behavioural interventions for weight management has been extensively studied in the Western Hemisphere, it remains inadequately evaluated in Asian populations. Therefore, we performed a systematic review and meta-analysis to assess the efficacy of behavioural interventions in weight management in Asian adults living with overweight and obesity.Methods: We searched 6 databases and included randomized controlled trials (RCTs) published between 2008 to 2023 which compared behavioural interventions with usual care in Asian adults. We considered 3 adiposity indices: body weight, BMI and waist circumference. We i) conducted meta-analyses using random-effects models; ii) analysed the network of Behaviour Change Techniques (BCT) implemented and iii) performed stratified meta-regressions adjusting for 13 demographic and behavioural factors to identify factors associated with changes in adiposity.Results: Of 25,950 records screened, only 56 RCTs (0·22%, 11,191 participants) were conducted in Asia. The most frequently utilized BCT components were shaping knowledge (19·7%), feedback with monitoring (18·5%), and goals setting with planning (18·1%). Behavioural interventions promoted significant albeit modest improvement across adiposity indices, with reduced weight, BMI and waist circumferences (unadjusted: -2·12 Kg [-2·38; -1·85], -0·81 Kg/m2 [-0·93; -0·68] and -2·63 cm [-3·08; -2·18], respectively). In stratified meta-regressions, behavioural interventions incorporating both diet and physical activity show slightly higher adiposity loss (-3·03 Kg [-4·37; -1·69], -0·92 Kg/m2 [-1·34; -0·51] and -2·28 cm [-3·05; -1·5], respectively).Conclusions: Behavioural interventions in Asian adults living with overweight and obesity were associated with only modest (3-5%) improvements in adiposity. Greater success is linked to combined diet–exercise strategies, and targeted behaviour change techniques. Future research should prioritise culturally tailored, theory-driven interventions that can better meet the unique needs of Asian populations.

Obesity, diabetes and cardiovascular disease are rising rapidly in Asia. Population-based data consistently show that Asians are at higher risk for these non-communicable diseases than their European counterparts, especially when living in urban and migrant settings. Contrary to initial hypotheses, genetic susceptibility factors only partially explain globally divergent health outcomes. In this Perspective, we discuss potential additional mechanisms to explain this divergence. We review the global disparities in the cardiometabolic disease burden and the role of genetic variation. We then summarize potential pathways linking prenatal and postnatal adversity with unfavourable nutrition, increased adiposity and altered metabolic well-being in Asian populations. In parallel, molecular epidemiological studies are providing insights into how life-course exposures and environmental adversity intersect with adverse nutrition to establish the functional genomic changes that may drive cardiometabolic risk in global Asian populations. We highlight opportunities in precision health studies to advance Asian health through the identification of underlying aetiology critical to the development of effective interventions to promote and maintain metabolic health in current and future generations of Asian individuals worldwide.

Asian people are under-represented in population-based, clinical, and genomic research. To address this gap, we have initiated the Health for Life in Singapore (HELIOS) longitudinal cohort study, comprising comprehensive behavioural, phenotypic, and genomic measurements from 10,004 Asian men and women of Chinese, Indian or Malay background. Phenotyping has been carried out using validated approaches, that are internationally interoperable. Health record linkage enriches both baseline phenotyping and evaluation of prospective outcomes. The integrated multi-omics data include whole-genome and RNA sequencing, quantification of DNA methylation, and metabolomic profiling. Our data reveal extensive lifestyle, physiological, genomic, and molecular diversity between the distinct Asian ethnic groups, and the biological interconnectivity between functional layers. This includes characterisation of divergent patterns of genome regulation between Asian individuals, that correlate with differences in educational attainment, dietary quality, and adiposity, and which overlap transcription factors and DNA methylation sites linked to the development of diabetes and other chronic diseases. Our unique HELIOS Asian Precision Medicine cohort study represents a state-of-the-art platform to enable biomedical researchers to understand the aetiology and pathogenesis of diverse disease outcomes in Asia, and to generate insights that have the potential to improve health outcomes for Asian populations globally.