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Purpose of ReviewPrevalence of type 2 diabetes (T2D) and progression of complications differ between worldwide populations. While obesity is a major contributing risk factor, variations in physiological manifestations, e.g., developing T2D at lower body mass index in some populations, suggest other contributing factors. Early T2D genetic associations were mostly discovered in European ancestry populations. This review describes the progression of genetic discoveries associated with T2D in individuals of East Asian ancestry in the last 10 years and highlights the shared genetic susceptibility between the population groups and additional insights into genetic contributions to T2D.Recent FindingsThrough increased sample size and power, new genetic associations with T2D were discovered in East Asian ancestry populations, often with higher allele frequencies than European ancestry populations.SummaryAs we continue to generate maps of T2D-associated variants across diverse populations, there will be a critical need to expand and diversify other omics resources to enable integration for clinical translation.

Blood pressure (BP) is a major risk factor for cardiovascular disease and more than 200 genetic loci associated with BP are known. Here, we perform a multi-stage genome-wide association study for BP (max N  = 289,038) principally in East Asians and meta-analysis in East Asians and Europeans. We report 19 new genetic loci and ancestry-specific BP variants, conforming to a common ancestry-specific variant association model. At 10 unique loci, distinct non-rare ancestry-specific variants colocalize within the same linkage disequilibrium block despite the significantly discordant effects for the proxy shared variants between the ethnic groups. The genome-wide transethnic correlation of causal-variant effect-sizes is 0.898 and 0.851 for systolic and diastolic BP, respectively. Some of the ancestry-specific association signals are also influenced by a selective sweep. Our results provide new evidence for the role of common ancestry-specific variants and natural selection in ethnic differences in complex traits such as BP. Blood pressure (BP) is a major risk factor for cardiovascular disease and more than 200 genetic loci associated with BP are known. Here, the authors perform discovery GWAS for BP in East Asians and meta-analysis in East Asians and Europeans and report ancestry-specific BP SNPs and selection signals.

Background It remains unclear what lifestyle behaviors are optimal for controlling postprandial glucose responses under real-world circumstances in persons without diabetes. We aimed to assess associations of diet, physical activity, and sleep with postprandial glucose responses in Asian adults without diabetes under free-living conditions. Methods We conducted an observational study collecting intensive longitudinal data using smartphone-based ecological momentary assessments, accelerometers, and continuous glucose monitors over nine free-living days in Singaporean men and women aged 21–69 years without diabetes. The outcome was the 2-h postprandial glucose incremental area under the curve (mmol/l*min). Associations were estimated using linear mixed-effect models. Results The analyses included 11,333 meals in 789 participants. Greater variations in glucose and lifestyle measures were observed within individuals than between individuals. Higher consumption of carbohydrate-rich and deep-fried foods and lower consumption of protein-rich foods were significantly associated with higher postprandial glucose levels (incremental area under the curve). The strongest association was observed for including refined grains (46.2 [95% CI: 40.3, 52.1]) in meals. Longer postprandial light-intensity physical activity (-24.7 [(-39.5, -9.9] per h) and moderate-to-vigorous-intensity physical activity (-58.0 [-73.8, -42.3]) were associated with substantially lower postprandial glucose levels. Longer daily light-intensity physical activity (-7.5 [-10.7, -4.2]) and sleep duration (-2.7 [-4.4, -1.0]) were also associated with lower postprandial glucose levels. Furthermore, postprandial glucose levels were the lowest in the morning and the highest in the afternoon. The results were largely consistent for males and females and for participants with and without prediabetes. Conclusions Consuming less refined grains and more protein-rich foods, getting more physical activity (particularly during the postprandial period), and having a longer sleep duration were associated with lower postprandial glucose levels in Asian adults without diabetes. Our findings support multi-component lifestyle modifications for postprandial glucose control and highlight the importance of the timing of eating and physical activity.

Norihiro Kato and colleagues perform a meta-analysis of genome-wide association studies to identify common variants associated with blood pressure variation in east Asians. They identify five new genome-wide significant signals and replicate seven loci previously discovered in populations of European ancestry. We conducted a meta-analysis of genome-wide association studies of systolic (SBP) and diastolic (DBP) blood pressure in 19,608 subjects of east Asian ancestry from the AGEN-BP consortium followed up with de novo genotyping ( n = 10,518) and further replication ( n = 20,247) in east Asian samples. We identified genome-wide significant ( P < 5 × 10 −8 ) associations with SBP or DBP, which included variants at four new loci ( ST7L - CAPZA1 , FIGN-GRB14 , ENPEP and NPR3 ) and a newly discovered variant near TBX3 . Among the five newly discovered variants, we obtained significant replication in the independent samples for all of these loci except NPR3 . We also confirmed seven loci previously identified in populations of European descent. Moreover, at 12q24.13 near ALDH2 , we observed strong association signals ( P = 7.9 × 10 −31 and P = 1.3 × 10 −35 for SBP and DBP, respectively) with ethnic specificity. These findings provide new insights into blood pressure regulation and potential targets for intervention.

Despite the dramatic underrepresentation of non-European populations in human genetics studies, researchers continue to exclude participants of non-European ancestry, as well as variants rare in European populations, even when these data are available. This practice perpetuates existing research disparities and can lead to important and large effect size associations being missed. Here, we conducted genome-wide association studies (GWAS) of 31 serum and urine biomarker quantitative traits in African (n = 9354), East Asian (n = 2559), and South Asian (n = 9823) ancestry UK Biobank (UKBB) participants. We adjusted for all known GWAS catalog variants for each trait, as well as novel signals identified in a recent European ancestry-focused analysis of UKBB participants. We identify 7 novel signals in African ancestry and 2 novel signals in South Asian ancestry participants (p < 1.61E−10). Many of these signals are highly plausible, including a cis pQTL for the gene encoding gamma-glutamyl transferase and PIEZO1 and G6PD variants with impacts on HbA1c through likely erythrocytic mechanisms. This work illustrates the importance of using the genetic data we already have in diverse populations, with novel discoveries possible in even modest sample sizes.

Background Eating behaviors are shaped by contextual factors such as where people eat, who they eat with, and their activities and mood during meals. However, data on these determinants of food choice in Asian populations are limited. We examined how eating context is associated with dietary quality, satiety, and postprandial blood glucose levels in an urban Asian population. Methods We analyzed data from up to 1291 Singapore residents aged 21–69 years (20,629 meals) in the Continuous Observations of Behavioral Risk Factors in Asia (COBRA) study. Over nine consecutive days, participants completed smartphone-based ecological momentary assessments six times per day, reporting meal composition, location, companions, concurrent activities, and premeal hunger, tiredness, stress, and happiness. We calculated diet quality scores for each meal (range 0–10). Masked continuous glucose monitors recorded interstitial glucose every 15 min, from which the 2-hour postprandial glucose was derived using incremental area under the curve. We estimated associations using generalized estimating equations, adjusting for sociodemographic, lifestyle, clinical, and other contextual factors. Results Meals were consumed at home (60%), hawker centers (local open-air food courts) (14%), the workplace (11%), other restaurants (9%), fast-food restaurants (2%), or other locations. Compared with home meals, diet quality was significantly lower at all out-of-home locations, particularly at fast-food restaurants (β: -0.70; 95% CI: -0.82, -0.57) and hawker centers (β: -0.56; CI: -0.63, -0.48). Postprandial glucose was higher after meals at hawker centers (β: 30.11 mmol/L*minute; CI: 20.11, 40.11) and the workplace (β: 17.48; CI: 4.34, 30.62) than at home. Eating with friends was associated with lower postprandial glucose than eating alone. Higher premeal happiness was associated with modestly higher diet quality, whereas greater premeal hunger was associated with higher postprandial glucose. Conclusions In this urban Asian setting, eating location was a key determinant of meal quality and postprandial glycemic response. Hawker centers and fast-food restaurants were associated with worse diet quality, and hawker centers and workplace venues with higher postprandial glucose. Interventions that support home-prepared meals and promote healthier food options when eating away from home may improve cardiometabolic health.

While effective risk factor control and medication optimization in early-stage CKD can significantly slow disease progression, a paucity of studies hinders comprehensive understanding. This study aims to identify factors associated with progression of early-stage CKD in primary care. We retrospectively analyzed data of CKD G1-G2 patients with type 2 diabetes or hypertension, recruited from an ongoing cohort between 2017 and 2023 from six polyclinics in Singapore. The outcome of interest was CKD progression, defined as a 25% decline in eGFR from baseline and worsening of CKD stage. Multivariable logistic regression was used to analyze the factors associated with CKD progression among early-stage CKD patients. Among 19,274 patients analyzed, CKD progression occurred in 1,992 patients (10.3%). Patients had a mean age of 62.27 years (SD 9.54), 54.4% were male, 70.4% Chinese, 18.1% Malay, 8.2% Indian, and 3.4% Others. On multivariable analysis, factors associated with CKD progression include Malay ethnicity (OR: 1.52, 95% CI: 1.35, 1.72), A2 (OR: 1.41, 95% CI: 1.18, 1.70) and A3 albuminuria (OR: 4.19, 95% CI: 3.45, 5.10), diabetes (OR: 2.59, 95% CI: 2.18, 3.09), hypertension (OR: 1.69, 95% CI: 1.18, 2.41), increasing systolic BP (OR: 1.005, 95% CI 1.001, 1.008), active smoking (OR: 1.26, 95% CI: 1.09, 1.47), being on maximum doses of ACE inhibitors/ARBs at baseline (OR: 1.28, 95% CI 1.07, 1.53) and having undergone CKD counseling (OR: 1.84, 95% CI 1.59, 2.12). Increasing age (OR: 0.991, 95% CI 0.984, 0.998), higher baseline eGFR (OR: 0.968, 95% CI 0.965, 0.972), higher diastolic BP (OR: 0.989, 95% CI 0.983, 0.995), and BMI (OR: 0.981, 95% CI 0.971, 0.991) significantly reduced odds of CKD progression. This study identified key factors associated with early-stage CKD progression in a multi-ethnic Asian population. Further research is also needed to address benefits of patient counseling and SGLT2i use. Refining risk stratification methods will enable targeted interventions and improve outcomes for high-risk CKD patients.

Prospective data on differences in type two diabetes (T2D) risk between Asian ethnic groups are sparse. We, therefore, compared T2D risk for East (Chinese), South (Indian), and Southeast (Malay) Asians and examined biological factors that may contribute to ethnic differences. We included 7427 adults of Chinese, Malay, and Indian origin participating in the Singapore multi-ethnic cohort. Information on sociodemographic, lifestyle, and biological risk factors (body mass index (BMI), waist circumference, blood lipids, blood pressure, C reactive protein, adiponectin, and homeostasis model assessment for insulin resistance and beta-cell function) were collected using standardized interviews and physical examinations. T2D cases were based on physician diagnoses, a national medical registry, fasting plasma glucose, or glycated hemoglobin A1c. We used multivariable logistic association and mediation analyses. During an average follow-up of 7.2 years (SD 2.2 years), we documented 595 cases of incident diabetes. Ethnic Malays (OR 2.08, 95% CI 1.69 to 2.56) and Indians (OR 2.22, 95% CI 1.80 to 2.74) had an approximately twofold higher risk of T2D compared with ethnic Chinese. Higher BMI explained the higher risk for Malay compared with Chinese ethnicity. Higher BMI, waist circumference, inflammation, and insulin resistance, and lower beta-cell function and high-density lipoprotein-cholesterol significantly contributed to the higher T2D risk for Indian compared with Chinese ethnicity. However, part of the higher T2D risk associated with Indian ethnicity remained unexplained. Despite their lower diabetes risk, Chinese participants had the lowest adiponectin levels. Different Asian ethnic groups have unique biological risk factor profiles related to T2D development that may warrant targeted approaches for prevention and treatment.

Ningli Wang, Tin Aung and colleagues report genome-wide association analyses for primary angle closure glaucoma, a major cause of blindness worldwide. They identify three loci newly associated with this disease. Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study including 1,854 PACG cases and 9,608 controls across 5 sample collections in Asia. Replication experiments were conducted in 1,917 PACG cases and 8,943 controls collected from a further 6 sample collections. We report significant associations at three new loci: rs11024102 in PLEKHA7 (per-allele odds ratio (OR) = 1.22; P = 5.33 × 10 −12 ), rs3753841 in COL11A1 (per-allele OR = 1.20; P = 9.22 × 10 −10 ) and rs1015213 located between PCMTD1 and ST18 on chromosome 8q (per-allele OR = 1.50; P = 3.29 × 10 −9 ). Our findings, accumulated across these independent worldwide collections, suggest possible mechanisms explaining the pathogenesis of PACG.

Structural variants (SVs) are significant contributors to inter-individual genetic variation associated with traits and diseases. Current SV studies using whole-genome sequencing (WGS) have a largely Eurocentric composition, with little known about SV diversity in other ancestries, particularly from Asia. Here, we present a WGS catalogue of 73,035 SVs from 8392 Singaporeans of East Asian, Southeast Asian and South Asian ancestries, of which ~65% (47,770 SVs) are novel. We show that Asian populations can be stratified by their global SV patterns and identified 42,239 novel SVs that are specific to Asian populations. 52% of these novel SVs are restricted to one of the three major ancestry groups studied (Indian, Chinese or Malay). We uncovered SVs affecting major clinically actionable loci. Lastly, by identifying SVs in linkage disequilibrium with single-nucleotide variants, we demonstrate the utility of our SV catalogue in the fine-mapping of Asian GWAS variants and identification of potential causative variants. These results augment our knowledge of structural variation across human populations, thereby reducing current ancestry biases in global references of genetic variation afflicting equity, diversity and inclusion in genetic research. Structural variations (SV) contribute to inter-individual variability. Here, the authors describe a first-generation multi-ancestry Asian SV catalogue containing 73,035 SVs from 8392 Singaporeans to provide insights into Asian SV diversity.