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One of the promises of precision medicine is to understand and act on inter-individual genetic differences in drug responses. SNPdrug3D contains the complete genomic landscape of missense single nucleotide variants (SNV) across the human proteome and at population-wide level that could affect drug binding. In the Singapore SG10K Health and global gnomAD cohorts, comprising variations in over 80,000 individuals, we identified ~ 1.17 million variants mapped to residues near bound drug molecules in protein-drug complexes relative to ~ 6000 drug molecules and experimentally verified effects of selected SNVs, including previously uncharacterized variants, on drug binding in relevant proteins ranging from kinases to cytochrome P450s (CYPs). The latter led to a specific predictor for interpreting variants in the CYP family that vastly outperforms existing tools in the prediction of pharmacogenetic effects. By placing variants and drugs in structural context, SNPdrug3D aids drug development by early flagging of resistance potential through population-specific variability.

Background: Obesity and related metabolic disturbances including diabetes, hypertension and hyperlipidemia predict future cognitive decline. Asia has a high prevalence of both obesity and metabolic disease, potentially amplifying the future burden of dementia in the region. We aimed to investigate the impact of adiposity and metabolic risk on cognitive function in Asian populations, using an epidemiological analysis and a two-sample Mendelian Randomization (MR) study. Methods: The Health for Life in Singapore (HELIOS) Study is a population-based cohort of South-East-Asian men and women in Singapore, aged 30–84 years. We analyzed 8769 participants with metabolic and cognitive data collected between 2018 and 2021. Whole-body fat mass was quantified with Dual X-Ray Absorptiometry (DEXA). Cognition was assessed using a computerized cognitive battery. An index of general cognition ‘g’ was derived through factor analysis. We tested the relationship of fat mass indices and metabolic measures with ‘g’ using regression approaches. We then performed inverse-variance-weighted MR of adiposity and metabolic risk factors on ‘g’, using summary statistics for genome-wide association studies of BMI, visceral adipose tissue (VAT), waist-hip-ratio (WHR), blood pressure, HDL cholesterol, triglycerides, fasting glucose, HbA1c, and general cognition. Findings: Participants were 58.9% female, and aged 51.4 (11.3) years. In univariate analysis, all 29 adiposity and metabolic measures assessed were associated with ‘g’ at P < 0.05. In multivariable analyses, reduced ‘g’ was consistently associated with increased visceral fat mass index and lower HDL cholesterol (P < 0.001), but not with blood pressure, triglycerides, or glycemic indices. The reduction in ‘g’ associated with 1SD higher visceral fat, or 1SD lower HDL cholesterol, was equivalent to a 0.7 and 0.9-year increase in chronological age respectively (P < 0.001). Inverse variance MR analyses showed that reduced ‘g’ is associated with genetically determined elevation of VAT, BMI and WHR (all P < 0.001). In contrast, MR did not support a causal role for blood pressure, lipid, or glycemic indices on cognition. Interpretation: We show an independent relationship between adiposity and cognition in a multi-ethnic Asian population. MR analyses suggest that both visceral adiposity and raised BMI are likely to be causally linked to cognition. Our findings have important implications for preservation of cognitive health, including further motivation for action to reverse the rising burden of obesity in the Asia–Pacific region. Agency for Science, Technology and Research (A*STAR) Ministry of Education (MOE) Ministry of Health (MOH) Nanyang Technological University National Medical Research Council (NMRC) Published version This work was supported by intramural funding from Nanyang Technological University, Lee Kong Chian School of Medicine, and the National Healthcare Group. J.C. is supported by: the Singapore Ministry of Health and National Medical Research Council STaR funding scheme [NMRC/StaR/0028/2017], LCG funding [MOH-000271], and Phase 2 National Precision Medicine Programme (Research Platform and Data Enablers) [NMRC/PRECISE/2020]; and the Singapore Agency for Science Technology and Research IAF-PP National Precision Medicine Program Phase 1A (A Population Level Genomic Infrastructure) [H17/ 01/a0/007] and IAF-PP Asian Skin Microbiome Programme [H18/01/ a0/016]. T.M. received postdoctoral fellowship from the Singapore Ministry of Education – Research Scholarship Block and Lee Kong Chian School of Medicine.

Polygenic risk scores (PRS), commonly referred to as genetic or genomic risk scores, aggregate the effects of multiple genetic variants into a single composite estimate of genetic risk. PRS scores are typically used to predict the risk of developing a disease or to explain the phenotypic variation, and are derived from the effect sizes observed in large-scale genome-wide association studies (GWAS). Unlike rare monogenic diseases such as cystic fibrosis, which are attributable to genetic variants in single genes, with large effects on disease status, common complex diseases such as type 2 diabetes mellitus (T2DM) are polygenic, with risk contributed by a panel of genetic variants present throughout the genome. The concept of integrating information from these multiple genetic variants into a single metric of genetic risk was initially proposed in the shape of genetic risk scores, which generally limited the score to include single-nucleotide polymorphisms (SNPs) that were common and reached genome-wide significance in the initial GWASs. In contrast, PRS incorporates information from a much larger set of genetic variants, typically hundreds of thousands, including SNPs below the threshold for genome-wide statistical significance, and often with much more modest effect sizes. Indeed, recent findings have pointed to how polygenic background could also increase the accuracy of risk estimation for individuals with monogenic risk variant in conditions such as familial hypercholesterolaemia, hereditary breast and ovarian cancer, and Lynch syndrome. Published version

ObjectiveTo ascertain the accuracy of 2 upper-arm blood pressure monitors, GE Carescape V100 Vital Signs and Omron HEM-9210T, used in a large, South-East Asian epidemiological cohort by the AAMI/ESH/ISO 81060-2:2018.Methods149 participants were recruited from the ongoing Health for Life in Singapore (HELIOS) Study in multi-ethnic Singapore.Results110 datasets were analysed. For criterion 1, the mean ± SD of differences for GE Carescape V100 was -3.5 ± 7.4/ -3.5 ± 7.4 mmHg (systolic/diastolic), and -4.2 ± 6.9/ -4.2 ± 6.9 mmHg (systolic/diastolic) for Omron HEM-9210T. For criterion 2, GE Carescape V100was -3.5 ± 5.6 / -3.5 ± 5.6 mmHg (systolic/diastolic), and -4.2 ± 4.5 / - 4.2 ± 4.6 mmHg (systolic/diastolic) for Omron HEM-9210T.ConclusionBoth GE Carescape V100 Vital Signs and Omron HEM-9210T monitor passed the AAMI/ESH/ISO 81060-2:2018 validation standard.

Human blood is conventionally considered sterile. Recent studies have challenged this, suggesting the presence of a blood microbiome in healthy humans. We present the largest investigation to date of microbes in blood, based on shotgun sequencing libraries from 9,770 healthy subjects. Leveraging the availability of data from multiple cohorts, we stringently filtered for laboratory contaminants to identify 117 microbial species detected in the blood of sampled individuals, some of which had signatures of DNA replication. These primarily comprise of commensals associated with human body sites such as the gut (n=40), mouth (n=32), and genitourinary tract (n=18), which are species that are distinct from common pathogens detected in clinical blood cultures based on more than a decade of records from a tertiary hospital. Contrary to the expectations of a shared blood microbiome, no species were detected in 84% of individuals, while only a median of one microbial species per individual was detected in the remaining 16%. Futhermore, microbes of the same species were detected in

Metabolic-bariatric surgery delivers substantial weight loss and can induce remission or improvement of obesity-related risks and complications. However, more robust estimates of its effect on long-term mortality and life expectancy-especially stratified by pre-existing diabetes status-are needed to guide policy and facilitate patient counselling. We compared long-term survival outcomes of severely obese patients who received metabolic-bariatric surgery versus usual care.We did a prespecified one-stage meta-analysis using patient-level survival data reconstructed from prospective controlled trials and high-quality matched cohort studies. We searched PubMed, Scopus, and MEDLINE (via Ovid) for randomised trials, prospective controlled studies, and matched cohort studies comparing all-cause mortality after metabolic-bariatric surgery versus non-surgical management of obesity published between inception and Feb 3, 2021. We also searched grey literature by reviewing bibliographies of included studies as well as review articles. Shared-frailty (ie, random-effects) and stratified Cox models were fitted to compare all-cause mortality of adults with obesity who underwent metabolic-bariatric surgery compared with matched controls who received usual care, taking into account clustering of participants at the study level. We also computed numbers needed to treat, and extrapolated life expectancy using Gompertz proportional-hazards modelling. The study protocol is prospectively registered on PROSPERO, number CRD42020218472.Among 1470 articles identified, 16 matched cohort studies and one prospective controlled trial were included in the analysis. 7712 deaths occurred during 1·2 million patient-years. In the overall population consisting 174 772 participants, metabolic-bariatric surgery was associated with a reduction in hazard rate of death of 49·2% (95% CI 46·3-51·9, p0·0001) and median life expectancy was 6·1 years (95% CI 5·2-6·9) longer than usual care. In subgroup analyses, both individuals with (hazard ratio 0·409, 95% CI 0·370-0·453, p0·0001) or without (0·704, 0·588-0·843, p0·0001) baseline diabetes who underwent metabolic-bariatric surgery had lower rates of all-cause mortality, but the treatment effect was considerably greater for those with diabetes (between-subgroup IAmong adults with obesity, metabolic-bariatric surgery is associated with substantially lower all-cause mortality rates and longer life expectancy than usual obesity management. Survival benefits are much more pronounced for people with pre-existing diabetes than those without.None.

Aims/hypothesis Type 2 diabetes is a complex metabolic disease with increasing prevalence worldwide. Improving the prediction of incident type 2 diabetes using epigenetic markers could help tailor prevention efforts to those at the highest risk. The aim of this study was to identify predictive methylation markers for incident type 2 diabetes by combining epigenome-wide association study (EWAS) results from five prospective European cohorts. Methods We conducted a meta-analysis of EWASs in blood collected 7–10 years prior to type 2 diabetes diagnosis. DNA methylation was measured with Illumina Infinium Methylation arrays. A total of 1250 cases and 1950 controls from five longitudinal cohorts were included: Doetinchem, ESTHER, KORA1, KORA2 and EPIC-Norfolk. Associations between DNA methylation and incident type 2 diabetes were examined using robust linear regression with adjustment for potential confounders. Inverse-variance fixed-effects meta-analysis of cohort-level individual CpG EWAS estimates was performed using METAL. The methylGSA R package was used for gene set enrichment analysis. Confirmation of genome-wide significant CpG sites was performed in a cohort of Indian Asians (LOLIPOP, UK). Results The meta-analysis identified 76 CpG sites that were differentially methylated in individuals with incident type 2 diabetes compared with control individuals (p values −7). Sixty-four out of 76 (84.2%) CpG sites were confirmed by directionally consistent effects and p values 1c) showed no improvement (AUC 0.757 vs 0.753). Gene set enrichment analysis of the full epigenome-wide results clearly showed enrichment of processes linked to insulin signalling, lipid homeostasis and inflammation. Conclusions/interpretation By combining results from five European cohorts, and thus significantly increasing study sample size, we identified 76 CpG sites associated with incident type 2 diabetes. Replication of 64 CpGs in an independent cohort of Indian Asians suggests that the association between DNA methylation levels and incident type 2 diabetes is robust and independent of ethnicity. Our data also indicate that BMI partly explains the association between DNA methylation and incident type 2 diabetes. Further studies are required to elucidate the underlying biological mechanisms and to determine potential causal roles of the differentially methylated CpG sites in type 2 diabetes development. Graphical abstract

We determined the relationships between DNA sequence variation and DNA methylation using blood samples from 3,799 Europeans and 3,195 South Asians. We identify 11,165,559 SNP-CpG associations (methylation quantitative trait loci (meQTL), P

BackgroundThere are few data to support accurate interpretation of spirometry data in South Asia, a major global region with a high reported burden of chronic respiratory disease.MethodWe measured lung function in 7453 healthy men and women aged ≥18 years, from Bangladesh, North India, South India, Pakistan and Sri Lanka, as part of the South Asia Biobank study. First, we assessed the accuracy of existing equations for predicting normal forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) and FEV1/FVC ratio. Then, we used our data to derive (n=5589) and internally validate (n=1864) new prediction equations among South Asians, with further external validation among 339 healthy South Asians living in Singapore.ResultsThe Global Lung Initiative (GLI) and National Health and Nutrition Examination Survey consistently overestimated expiratory volumes (best fit GLI-African American, mean±sdz-score: FEV1−0.94±1.05, FVC −0.91±1.10; n=7453). Age, height and weight were strong predictors of lung function in our participants (p10.03±0.99, FVC 0.04±0.97, FEV1/FVC −0.03±0.99) and external validation (z-scores: FEV10.31±0.99, FVC 0.24±0.97, FEV1/FVC 0.16±0.91). Further adjustment for study regions improves the model fit, with highest accuracy for estimation of region-specific lung function in South Asia.ConclusionWe present improved equations for predicting lung function in South Asians. These offer the opportunity to enhance diagnosis and management of acute and chronic lung diseases in this major global population.

IntroductionSouth Asians are at high risk of type 2 diabetes (T2D). We assessed whether intensive family-based lifestyle intervention leads to significant weight loss, improved glycaemia and blood pressure in adults at elevated risk for T2D.MethodsThis cluster randomised controlled trial (iHealth-T2D) was conducted at 120 locations across India, Pakistan, Sri Lanka and the UK. We included 3684 South Asian men and women, aged 40–70 years, without T2D but with raised haemoglobin A1c (HbA1c) and/or waist circumference. Participants were randomly allocated either to the family-based lifestyle intervention or control group by location clusters. Participants in the intervention received 9 visits and 13 telephone contacts by community health workers over 1-year period, and the control group received usual care. Reductions in weight (aim >7% reduction), waist circumference (aim ≥5 cm reduction), blood pressure and HbA1C at 12 months of follow-up were assessed. Our linear mixed-effects regression analysis was based on intention-to-treat principle and adjusted for age, sex and baseline values.ResultsThere were 1846 participants in the control and 1838 in the intervention group. Between baseline and 12 months, mean weight of participants in the intervention group reduced by 1.8 kg compared with 0.4 kg in the control group (adjusted mean difference −1.10 kg (95% CI −1.70 to −1.06), pConclusionAn intensive family-based lifestyle intervention adopting low-resource strategies led to effective reduction in weight and waist circumference at 12 months, which has potential long-term benefits for preventing T2D. A higher number of attended sessions increased the effect on waist circumference, blood pressure and HbA1c.Trial registration numberEudraCT: 2016-001350-18; ClinicalTrials.gov: NCT02949739.

Background Ethnic Asians are known to exhibit worse metabolic phenotypes as compared to Caucasians despite lower body mass index1, 2. Ethnic South-Asians and Malays were also found to display greater insulin resistance than Chinese3. One potential biological mechanism for this phenomenon is the inter-ethnic differences in the visceral adiposity deposition4. Here we hypothesised that visceral adiposity contributes to ethnic differences in metabolic phenotype more than subcutaneous adiposity. Methods We quantified total, subcutaneous and visceral adipose deposition (BMI, waist circumferences, Dual-energy X-ray absorptiometry [DEXA]) and metabolic phenotypes (blood pressure, fasting glucose and lipid profile, HbA1c) in 3403 participants. Analyses were adjusted for age, and sex. Results Participants were 40.6% male, mean age 49.7±11.4 years, Chinese: Malays: South-Asians in 72:9:19 ratio. Ethnic Malays and South-Asians had raised blood pressure, fasting glucose, triglycerides, HbA1c, reduced HDL, and higher total and visceral fat than Chinese (P Conclusions Visceral adiposity contributes to poorer metabolic phenotype in ethnic Malays and South Asians as compared to Chinese. Key messages Visceral adiposity expansion is an important determinant of metabolic health in Asian populations.

Background Obesity and type 2 diabetes (T2D) are major public health issues worldwide, and put a significant burden on the healthcare system. Genetic variants, along with traditional risk factors such as diet and physical activity, could account for up to approximately a quarter of disease risk. Epigenetic factors have demonstrated potential in accounting for additional phenotypic variation, along with providing insights into the causal relationship linking genetic variants to phenotypes. Scope of review In this review article, we discuss the epidemiological and functional insights into epigenetic disturbances in obesity and diabetes, along with future research directions and approaches, with a focus on DNA methylation. Major conclusions Epigenetic mechanisms have been shown to contribute to obesity and T2D disease development, as well as potential differences in disease risks between ethnic populations. Technology to investigate epigenetic profiles in diseased individuals and tissues has advanced significantly in the last years, and suggests potential in application of epigenetic factors in clinical monitoring and as therapeutic options., Highlights • Aberrance in epigenetics associated with metabolic disturbances. • Whole-genome bisulfite sequencing provides improved coverage at lower precision relative to arrays. • Demethylating therapies could play a role in future obesity and diabetes treatment.

© The Author(s) 2019. A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-Alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2- degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10?6) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 × 10?8 using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models. National Heart, Lung, and Blood Institute; American Heart Association Grant

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P-8), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.A trans-ancestry meta-analysis of GWAS of glycemic traits in up to 281,416 individuals identifies 99 novel loci, of which one quarter was found due to the multi-ancestry approach, which also improves fine-mapping of credible variant sets.

Background South Asia has become a major epicentre of the COVID-19 pandemic. Understanding South Asians’ awareness, attitudes and experiences of early measures for the prevention of COVID-19 is key to improving the effectiveness and mitigating the social and economic impacts of pandemic responses at a critical time for the Region. Methods We assessed the knowledge, behaviours, health and socio-economic circumstances of 29,809 adult men and women, at 93 locations across four South Asian countries. Data were collected during the national lockdowns implemented from March to July 2020, and compared with data collected prior to the pandemic as part of an ongoing prospective surveillance initiative. Results Participants were 61% female, mean age 45.1 years. Almost half had one or more chronic disease, including diabetes (16%), hypertension (23%) or obesity (16%). Knowledge of the primary COVID-19 symptoms and transmission routes was high, but access to hygiene and personal protection resources was low (running water 63%, hand sanitisers 53%, paper tissues 48%). Key preventive measures were not widely adopted. Knowledge, access to, and uptake of COVID-19 prevention measures were low amongst people from disadvantaged socio-economic groups. Fifteen percent of people receiving treatment for chronic diseases reported loss of access to long-term medications; 40% reported symptoms suggestive of anxiety or depression. The prevalence of unemployment rose from 9.3% to 39.4% (P, Highlights • South Asia has become a major epicentre of the COVID-19 pandemic and faces multiple challenges (health, economic, social). • Our findings identified important knowledge, access and uptake barriers to the prevention of COVID-19 in the region. • We demonstrated adverse impacts on chronic disease treatment, mental health, health behaviours, employment, finances. • There is a need for immediate large-scale action to close gaps in knowledge and access to essential resources for prevention. • Along with measures to safeguard economic production and mitigate socio-economic impacts on the young and the poor.

Funder: Singapore Ministry of Health's National Medical Research Council, Funder: National Institute for Health Research, Funder: Wellcome Trust or the Department of Health, Funder: NIHR Biomedical Research Centre Cambridge: Nutrition, Diet, and Lifestyle Research Theme; Grant(s): IS-BRC-1215-20014

Background The prevalence of obesity and its related chronic diseases have been increasing especially in Asian countries. Obesity-related genetic variants have been identified, but these explain little of the variation in BMI. Recent studies reported associations between DNA methylation and obesity, mostly in non-Asian populations. Methods We performed an epigenome-wide association study (EWAS) on general adiposity (body mass index, BMI) and abdominal adiposity (waist circumference, WC) in 409 multi-ethnic Asian individuals and replicated BMI and waist-associated DNA methylation CpGs identified in other populations. The cross-lagged panel model and Mendelian randomization were used to assess the temporal relationship between methylation and BMI. The temporal relationship between the identified CpGs and inflammation and metabolic markers was also examined. Results EWAS identified 116 DNA methylation CpGs independently associated with BMI and eight independently associated with WC at false discovery rate PFDR Conclusion Our study provides evidence of an association between obesity and DNA methylation in multi-ethnic Asians and suggests that obesity can drive methylation change. The results also suggested possible causal influence that obesity-related methylation changes might have on inflammation and lipoprotein levels.

We conducted a randomized controlled trial to examine choral singing's effect on cognitive decline in aging. Older Singaporeans who were at high risk of future dementia were recruited: 47 were assigned to choral singing intervention (CSI) and 46 were assigned to health education program (HEP). Participants attended weekly one-hour choral singing or weekly one-hour health education for two years. Change in cognitive function was measured by a composite cognitive test score (CCTS) derived from raw scores of neuropsychological tests; biomarkers included brain magnetic resonance imaging, oxidative damage and immunosenescence. The average age of the participants were 70 years and 73/93 (78.5%) were female. The change of CCTS from baseline to 24 months was 0.05 among participants in the CSI group and -0.1 among participants in the HEP group. The between-group difference (0.15, p=0.042) became smaller (0.12, p=0.09) after adjusting for baseline CCTS. No between-group differences on biomarkers were observed. Our data support the role of choral singing in improving cognitive health in aging. The beneficial effect is at least comparable than that of health education in preventing cognitive decline in a community of elderly people. Biological mechanisms underlying the observed efficacy should be further studied. Ministry of Health (MOH) Published version This work is supported by the National Innovation Challenge on Active and Confident Ageing Programme, Ministry of Health of Singapore (Award No.: MOH/NIC/COG06/2017) and the National University of Singapore Society (NUSS) Choir Dementia Research Fund. The funders played no role in the study design, data acquisition, analysis, or manuscript preparation. The views expressed are those of the authors and are not an official view of the institutions or funders.

BackgroundSouth Asians are at high risk of type 2 diabetes (T2D). Lifestyle modification is effective at preventing T2D amongst South Asians, but the approaches to screening and intervention are limited by high-costs, poor scalability and thus low impact on T2D burden. An intensive family-based lifestyle modification programme for prevention of T2D was developed. The aim of the iHealth-T2D trial is to compare the effectiveness of this programme with usual care.MethodsThe iHealth-T2D trial is designed as a cluster randomised controlled trial (RCT) conducted at 120 locations across India, Pakistan, Sri Lanka and the UK. A total of 3,682 South Asian men and women with age between 40-70 years without T2D but at elevated risk for T2D [defined by central obesity (waist circumference ≥95cm in Sri Lanka, or ≥100cm in India, Pakistan and UK) and/or prediabetes (HbA1c ≥6.0%)] were included in the trial. Here we describe in detail the statistical analysis plan (SAP), which was finalised before outcomes were available to the investigators. The primary outcome will be evaluated after three years of follow-up after enrolment to the study, and is defined as T2D incidence in the intervention arm compared to usual care. Secondary outcomes are evaluated both after one and three years of follow-up and include biochemical measurements, anthropometric measurements, behavioural components and treatment compliance.DiscussionThe iHealth-T2D trial will provide evidence whether an intensive family-based lifestyle modification programme in South Asians who are at high risk for T2D is effective in the prevention of T2D. The data from the trial will be analysed according to this pre-specified SAP.Ethics and disseminationThe trial was approved by the international review board of each participating study site. Study findings will be disseminated through peer-reviewed publications and in conference presentations.Trial registrationEudraCT 2016-001350-18. Registered 14 April 2016 https://www.hra.nhs.uk/planning-and-improving-research/application-summaries/research-summaries/ihealth-t2d/; ClinicalTrials.govNCT02949739. Registered 31 October 2016, https://clinicaltrials.gov/ct2/show/NCT02949739, First posted 31/10/2016.

BackgroundPeople from South Asia are at increased risk of type 2 diabetes (T2D). There is an urgent need to develop approaches for prevention of T2D in South Asians, that are cost-effective, generalisable and scalable across settings.HypothesisCompared to usual care, risk of T2D can be reduced amongst South Asians with central obesity or raised HbA1c, through a 12 month lifestyle modification programme delivered by community health workers.DesignCluster randomised clinical trial (1:1 allocation to Intervention or Usual care), carried out in India, Pakistan, Sri Lanka, and UK, with 30 sites per country (120 sites total). Target recruitment 3,600 (30 participants per site) with annual follow-up for three years.Entry criteriaSouth Asian, men or women, age 40-70 years with i. Central obesity (waist circumference ≥100cm in India and Pakistan; ≥90cm in Sri Lanka) and / or ii. Prediabetes (HbA1c 6.0-6.4% inclusive). Exclusion criteria: known type 1 or 2 diabetes, normal or underweight (body mass indexEndpointsThe primary end point is new onset T2D at 3 years, defined as: i. HbA1c≥6.5% or ii. Physician diagnosis and on treatment for T2D. Secondary endpoints at 1 and 3 years are: i. Physical measures: waist circumference, weight and blood pressure; ii. Lifestyle measures: smoking status, alcohol intake, physical activity, dietary intake; iii. Biochemical measures: Fasting glucose, insulin and lipids (total and HDL cholesterol, triglycerides); and iv. Treatment compliance.InterventionLifestyle intervention (60 sites) or Usual care (60 sites). Lifestyle intervention was delivered by a trained community health worker over 12 months (5 one-one session, 4 group sessions, 13 telephone sessions) with the goal of the participants achieving e a 7% reduction in body mass index and a 10 cm reduction in waist circumference through i. improved diet and ii. increased physical activity. Usual care comprised a single 30 minute session of lifestyle modification advice from the community health worker.ResultsWe screened 33,212 people for inclusion into the study. We identified 10,930 people who met study entry criteria, amongst whom, 3,682 agreed to take part in the intervention. Study participants are 49.2% female and aged 52.8 (SD 8.2) years. Clinical characteristics are well balanced between Intervention and Usual care sites. More than 90% of follow-up visits are scheduled to be complete December 2020. Based on follow-up to end 2019, the observed incidence of T2D in the study population is in line with expectations (6.1% per annum).ConclusionThe iHealth-T2D study will advance understanding of strategies for prevention of diabetes amongst South Asians, use approaches for screening and intervention that are adapted for low-resource settings. Our study will thus inform the implementation of strategies for improving the health and well-being of this major global ethnic group.IRB approval16/WM/0171Trial registrationEudraCT 2016-001350-18. Registered 14 April 2016 https://www.hra.nhs.uk/planning-and-improving-research/application-summaries/research-summaries/ihealth-t2d/ ; ClinicalTrials.gov NCT02949739. Registered 31 October 2016, https://clinicaltrials.gov/ct2/show/NCT02949739, First posted 31/10/2016.FunderEuropean Commission (award 643774) and National Institute for Health Research (award 16/136/68)

We assembled an ancestrally diverse collection of genome-wide association studies of type 2 diabetes (T2D) in 180,834 cases and 1,159,055 controls (48.9% non-European descent). We identified 277 loci at genome-wide significance (p-8), including 237 attaining a more stringent trans-ancestry threshold (p-9), which were delineated to 338 distinct association signals. Trans-ancestry meta-regression offered substantial enhancements to fine-mapping, with 58.6% of associations more precisely localised due to population diversity, and 54.4% of signals resolved to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying foundations for functional investigations. Trans-ancestry genetic risk scores enhanced transferability across diverse populations, providing a step towards more effective clinical translation to improve global health.