361 results found
Chambers J, 2023, Smokeless and combustible tobacco use among 148,944 South Asian adults: a cross-sectional study of South Asia Biobank, BMC Public Health, ISSN: 1471-2458
Xie W, Rani Paul R, Goon I, et al., 2023, Enhancing care quality and accessibility through digital technology-supported decentralization of hypertension and diabetes management: a proof-of-concept study in rural Bangladesh, BMJ Open, ISSN: 2044-6055
Objective: The critical shortage of healthcare workers, particularly in rural areas, is a major barrier to quality care for noncommunicable disease (NCD) in low- and middle-income countries. In this proof-of-concept study, we aimed to test a decentralized model for integrated diabetes and hypertension management in rural Bangladesh to improve accessibility and quality of care. Design and setting: The study is a single cohort proof-of-concept study. The key interventions comprised shifting screening, routine monitoring, and dispensing of medication refill from a doctor-managed subdistrict NCD clinic to non-physician health worker managed village level community clinics; a digital care coordination platform was developed for electronic health record, point-of-care support, referral, and routine patient follow-up. The study was conducted in Parbatipur subdistrict, Rangpur Division, Bangladesh.Participants: A total of 624 participants were enrolled in the study (mean[sd] age, 59.5 [12.0]; 65.1% female). Outcomes: Changes in blood pressure and blood glucose control, patient retention, and patient-visit volume at the NCD clinic and community clinics. Results: The proportion of patients with uncontrolled blood pressure reduced from 60% at baseline to 26% at the third month of follow-up, a 56% (IRR 0.44; 95% CI 0.33, 0.57) reduction after adjustment for covariates. The proportion of patients with uncontrolled blood glucose decreased from 74% to 43% at the third month of follow-up. Attrition rates immediately after baseline and during the entire study period were 29.1% and 36.2%, respectively. Conclusion: The proof-of-concept study highlights the potential for involving lower-level primary care facilities and non-physician health workers to rapidly expand much needed services to the patients with hypertension and diabetes in Bangladesh, and in similar global settings. Further investigations are needed to evaluate the effectiveness of decentralized hypertension and diabetes c
Seah JYH, Yao J, Hong Y, et al., 2023, Risk prediction models for type 2 diabetes using either fasting plasma glucose or HbA1c in Chinese, Malay, and Indians: Results from three multi-ethnic Singapore cohorts, DIABETES RESEARCH AND CLINICAL PRACTICE, Vol: 203, ISSN: 0168-8227
van de Vegte Y, Eppinga RP, van der Ende MY, et al., 2023, Genetic insights into resting heart rate and its role in cardiovascular disease, Nature Communications, Vol: 14, ISSN: 2041-1723
Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.
Yew YW, Mina T, Ng HK, et al., 2023, Investigating causal relationships between obesity and skin barrier function in a multi-ethnic Asian general population cohort, International Journal of Obesity, Vol: 47, Pages: 963-969, ISSN: 0307-0565
BACKGROUND: Skin diseases impact significantly on the quality of life and psychology of patients. Obesity has been observed as a risk factor for skin diseases. Skin epidermal barrier dysfunctions are typical manifestations across several dermatological disturbances. OBJECTIVES: We aim to establish the association between obesity and skin physiology measurements and investigate whether obesity may play a possible causal role on skin barrier dysfunction. METHODS: We investigated the relationship of obesity with skin physiology measurements, namely transepidermal water loss (TEWL), skin surface moisture and skin pH in an Asian population cohort (n = 9990). To assess for a possible causal association between body mass index (BMI) and skin physiology measurements, we performed Mendelian Randomization (MR), along with subsequent additional analyses to assess the potential causal impact of known socioeconomic and comorbidities of obesity on TEWL. RESULTS: Every 1 kg/m2 increase in BMI was associated with a 0.221% (95%CI: 0.144-0.298) increase in TEWL (P = 2.82E-08), a 0.336% (95%CI: 0.148-0.524) decrease in skin moisture (P = 4.66E-04) and a 0.184% (95%CI: 0.144-0.224) decrease in pH (P = 1.36E-19), adjusting for age, gender, and ethnicity. Relationships for both TEWL and pH with BMI remained strong (Beta 0.354; 95%CI: 0.189-0.520 and Beta -0.170; 95%CI: -0.253 to -0.087, respectively) even after adjusting for known confounders, with MR experiments further supporting BMI's possible causal relationship with TEWL. Based on additional MR performed, none of the socioeconomic and comorbidities of obesity investigated are likely to have possible causal relationships with TEWL. CONCLUSION: We establish strong association of BMI with TEWL and skin pH, with MR results suggestive of a possible causal relationship of obesity with TEWL. It emphasizes the potential impact of obesity on skin barrier function and therefore op
Li JH, Brenner LN, Kaur V, et al., 2023, Genome-wide association analysis identifies ancestry-specific genetic variation associated with acute response to metformin and glipizide in SUGAR-MGH., Diabetologia, Vol: 66, Pages: 1260-1272
AIMS/HYPOTHESIS: Characterisation of genetic variation that influences the response to glucose-lowering medications is instrumental to precision medicine for treatment of type 2 diabetes. The Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH) examined the acute response to metformin and glipizide in order to identify new pharmacogenetic associations for the response to common glucose-lowering medications in individuals at risk of type 2 diabetes. METHODS: One thousand participants at risk for type 2 diabetes from diverse ancestries underwent sequential glipizide and metformin challenges. A genome-wide association study was performed using the Illumina Multi-Ethnic Genotyping Array. Imputation was performed with the TOPMed reference panel. Multiple linear regression using an additive model tested for association between genetic variants and primary endpoints of drug response. In a more focused analysis, we evaluated the influence of 804 unique type 2 diabetes- and glycaemic trait-associated variants on SUGAR-MGH outcomes and performed colocalisation analyses to identify shared genetic signals. RESULTS: Five genome-wide significant variants were associated with metformin or glipizide response. The strongest association was between an African ancestry-specific variant (minor allele frequency [MAFAfr]=0.0283) at rs149403252 and lower fasting glucose at Visit 2 following metformin (p=1.9×10-9); carriers were found to have a 0.94 mmol/l larger decrease in fasting glucose. rs111770298, another African ancestry-specific variant (MAFAfr=0.0536), was associated with a reduced response to metformin (p=2.4×10-8), where carriers had a 0.29 mmol/l increase in fasting glucose compared with non-carriers, who experienced a 0.15 mmol/l decrease. This finding was validated in the Diabetes Prevention Program, where rs111770298 was associated with a worse glycaemic response to metformin: heterozygous carriers had an increa
Graham SE, Clarke SL, Wu K-HH, et al., 2023, Author Correction: The power of genetic diversity in genome-wide association studies of lipids, Nature, Vol: 618, Pages: E19-E20, ISSN: 0028-0836
McAllan L, Baranasic D, Villicaña S, et al., 2023, Integrative genomic analyses in adipocytes implicate DNA methylation in human obesity and diabetes, Nature Communications, Vol: 14, Pages: 1-20, ISSN: 2041-1723
DNA methylation variations are prevalent in human obesity but evidence of a causative role in disease pathogenesis is limited. Here, we combine epigenome-wide association and integrative genomics to investigate the impact of adipocyte DNA methylation variations in human obesity. We discover extensive DNA methylation changes that are robustly associated with obesity (N = 190 samples, 691 loci in subcutaneous and 173 loci in visceral adipocytes, P < 1 × 10-7). We connect obesity-associated methylation variations to transcriptomic changes at >500 target genes, and identify putative methylation-transcription factor interactions. Through Mendelian Randomisation, we infer causal effects of methylation on obesity and obesity-induced metabolic disturbances at 59 independent loci. Targeted methylation sequencing, CRISPR-activation and gene silencing in adipocytes, further identifies regional methylation variations, underlying regulatory elements and novel cellular metabolic effects. Our results indicate DNA methylation is an important determinant of human obesity and its metabolic complications, and reveal mechanisms through which altered methylation may impact adipocyte functions.
Shih CC, Chen J, Lee AS, et al., 2023, A five-safes approach to a secure and scalable genomics data repository, ISCIENCE, Vol: 26
Costanzo MC, von Grotthuss M, Massung J, et al., 2023, The Type 2 Diabetes Knowledge Portal: an open access genetic resource dedicated to type 2 diabetes and related traits, Cell Metabolism, Vol: 35, Pages: 695-710.e6, ISSN: 1550-4131
Associations between human genetic variation and clinical phenotypes have become a foundation of biomedical research. Most repositories of these data seek to be disease-agnostic and therefore lack disease-focused views. The Type 2 Diabetes Knowledge Portal (T2DKP) is a public resource of genetic datasets and genomic annotations dedicated to type 2 diabetes (T2D) and related traits. Here, we seek to make the T2DKP more accessible to prospective users and more useful to existing users. First, we evaluate the T2DKP's comprehensiveness by comparing its datasets with those of other repositories. Second, we describe how researchers unfamiliar with human genetic data can begin using and correctly interpreting them via the T2DKP. Third, we describe how existing users can extend their current workflows to use the full suite of tools offered by the T2DKP. We finally discuss the lessons offered by the T2DKP toward the goal of democratizing access to complex disease genetic results.
Mina T, Yew YW, Ng HK, et al., 2023, Adiposity impacts cognitive function in Asian populations: an epidemiological and Mendelian Randomization study., The Lancet Regional Health. Western Pacific, Vol: 33, Pages: 1-11, ISSN: 2666-6065
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 vari
Suzuki K, Hatzikotoulas K, Southam L, et al., 2023, Multi-ancestry genome-wide study in >2.5 million individuals reveals heterogeneity in mechanistic pathways of type 2 diabetes and complications., medRxiv
Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes. To characterise the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study (GWAS) data from 2,535,601 individuals (39.7% non-European ancestry), including 428,452 T2D cases. We identify 1,289 independent association signals at genome-wide significance (P<5×10-8) that map to 611 loci, of which 145 loci are previously unreported. We define eight non-overlapping clusters of T2D signals characterised by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial, and enteroendocrine cells. We build cluster-specific partitioned genetic risk scores (GRS) in an additional 137,559 individuals of diverse ancestry, including 10,159 T2D cases, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned GRS are more strongly associated with coronary artery disease and end-stage diabetic nephropathy than an overall T2D GRS across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings demonstrate the value of integrating multi-ancestry GWAS with single-cell epigenomics to disentangle the aetiological heterogeneity driving the development and progression of T2D, which may offer a route to optimise global access to genetically-informed diabetes care.
Wong E, Bertin N, Hebrard M, et al., 2023, The Singapore National Precision Medicine Strategy, NATURE GENETICS, Vol: 55, Pages: 178-+, ISSN: 1061-4036
Raveendiran AG, Pradeepa R, Ulagamathesan V, et al., 2023, Prevalence of and Risk Factors for Diabesity in Urban Chennai, JOURNAL OF DIABETOLOGY, Vol: 14, Pages: 34-40, ISSN: 2543-3288
Loh M, Chambers JC, 2023, Polygenic risk scores for complex diseases: Where are we now?, Singapore Med J, Vol: 64, Pages: 88-89
Kanoni S, Graham SE, Wang Y, et al., 2022, Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis, GENOME BIOLOGY, Vol: 23, ISSN: 1474-760X
Leong W-Y, Gupta A, Hasan M, et al., 2022, Reference equations for evaluation of spirometry function tests in South Asia, and amongst South Asians living in other countries, European Respiratory Journal, Vol: 60, ISSN: 0903-1936
Background:There is little data to accurate interpretation of spirometry data in SouthAsia, a major global region with high reported burden for chronicrespiratory disease.Method:We measured lung function in 7,453 healthy men and women aged over18 years, from Bangladesh, North India, South India, Pakistan and SriLanka, as part of the South Asia Biobank study. We first assessed theaccuracy of existing equations for predicting normal forced vital capacity(FVC), forced expiratory volume in 1s (FEV1), and FEV1/FVC ratio. Wethen used our data to derive (N=5,589) and internally validate(N=1,864) new prediction equations amongst South Asians, with furtherexternal validation amongst 339 healthy South Asians living inSingapore.Results:GLI2012 and NHANESIII consistently overestimated expiratory volumes(best fit GLI-SEA, mean [sd] z-score: FEV1 -1.29 [1.04]; FVC -1.12[1.12]). Age, height and weight were strong predictors of lung functionin our participants (P<0.001), and sex specific reference equations usingthese three variables were highly accurate in both internal validation (z-scores: FEV1 0.03 [0.99]; FVC 0.04 [0.97]; FEV1/FVC -0.03 [0.99]) andexternal validation (z-scores: FEV1 0.31 [0.99]; FVC 0.24 [0.97];FEV1/FVC 0.16 [0.91]). Further adjustment for study regions improvesthe model fit, with highest accuracy for estimation of region specific lungfunction in South Asia.Conclusion:We present improved equations for predicting lung function in SouthAsians. These offer the opportunity to enhance diagnosis andmanagement of acute and chronic lung diseases in this major globalpopulation.
Hawe JS, Saha A, Waldenberger M, et al., 2022, Network reconstruction for trans acting genetic loci using multi-omics data and prior information., Genome Med, Vol: 14
BACKGROUND: Molecular measurements of the genome, the transcriptome, and the epigenome, often termed multi-omics data, provide an in-depth view on biological systems and their integration is crucial for gaining insights in complex regulatory processes. These data can be used to explain disease related genetic variants by linking them to intermediate molecular traits (quantitative trait loci, QTL). Molecular networks regulating cellular processes leave footprints in QTL results as so-called trans-QTL hotspots. Reconstructing these networks is a complex endeavor and use of biological prior information can improve network inference. However, previous efforts were limited in the types of priors used or have only been applied to model systems. In this study, we reconstruct the regulatory networks underlying trans-QTL hotspots using human cohort data and data-driven prior information. METHODS: We devised a new strategy to integrate QTL with human population scale multi-omics data. State-of-the art network inference methods including BDgraph and glasso were applied to these data. Comprehensive prior information to guide network inference was manually curated from large-scale biological databases. The inference approach was extensively benchmarked using simulated data and cross-cohort replication analyses. Best performing methods were subsequently applied to real-world human cohort data. RESULTS: Our benchmarks showed that prior-based strategies outperform methods without prior information in simulated data and show better replication across datasets. Application of our approach to human cohort data highlighted two novel regulatory networks related to schizophrenia and lean body mass for which we generated novel functional hypotheses. CONCLUSIONS: We demonstrate that existing biological knowledge can improve the integrative analysis of networks underlying trans associations and generate novel hypotheses about regulatory mechanisms.
Chan SH, Bylstra Y, Teo JX, et al., 2022, Analysis of clinically relevant variants from ancestrally diverse Asian genomes, Nature Communications, Vol: 13, ISSN: 2041-1723
Asian populations are under-represented in human genomics research. Here, we characterize clinically significant genetic variation in 9051 genomes representing East Asian, South Asian, and severely under-represented Austronesian-speaking Southeast Asian ancestries. We observe disparate genetic risk burden attributable to ancestry-specific recurrent variants and identify individuals with variants specific to ancestries discordant to their self-reported ethnicity, mostly due to cryptic admixture. About 27% of severe recessive disorder genes with appreciable carrier frequencies in Asians are missed by carrier screening panels, and we estimate 0.5% Asian couples at-risk of having an affected child. Prevalence of medically-actionable variant carriers is 3.4% and a further 1.6% harbour variants with potential for pathogenic classification upon additional clinical/experimental evidence. We profile 23 pharmacogenes with high-confidence gene-drug associations and find 22.4% of Asians at-risk of Centers for Disease Control and Prevention Tier 1 genetic conditions concurrently harbour pharmacogenetic variants with actionable phenotypes, highlighting the benefits of pre-emptive pharmacogenomics. Our findings illuminate the diversity in genetic disease epidemiology and opportunities for precision medicine for a large, diverse Asian population.
Yengo L, Vedantam S, Marouli E, et al., 2022, A saturated map of common genetic variants associated with human height, NATURE, Vol: 610, Pages: 704-+, ISSN: 0028-0836
Muilwijk M, Loh M, Mahmood S, et al., 2022, The iHealth-T2D study: a cluster randomised trial for the prevention of type 2 diabetes amongst South Asians with central obesity and prediabetes-a statistical analysis plan, TRIALS, Vol: 23
Dixon PH, Levine AP, Cebola I, et al., 2022, GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements, Nature Communications, Vol: 13, ISSN: 2041-1723
Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder affecting 0.5–2% of pregnancies. The majority of cases present in the third trimester with pruritus, elevated serum bile acids and abnormal serum liver tests. ICP is associated with an increased risk of adverse outcomes, including spontaneous preterm birth and stillbirth. Whilst rare mutations affecting hepatobiliary transporters contribute to the aetiology of ICP, the role of common genetic variation in ICP has not been systematically characterised to date. Here, we perform genome-wide association studies (GWAS) and meta-analyses for ICP across three studies including 1,138 cases and 153,642 controls. Eleven loci achieve genome-wide significance and have been further investigated and fine-mapped using functional genomics approaches. Our results pinpoint common sequence variation in liver-enriched genes and liver-specific cis-regulatory elements as contributing mechanisms to ICP susceptibility.
Ramdas S, Judd J, Graham SE, et al., 2022, A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids, AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 109, Pages: 1366-1387, ISSN: 0002-9297
Winkler TW, Rasheed H, Teumer A, et al., 2022, Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals, Communications Biology, Vol: 5, ISSN: 2399-3642
Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (nDM = 178,691, nnoDM = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM.
Loh M, Zhang W, Ng HK, et al., 2022, Identification of genetic effects underlying type 2 diabetes in South Asian and European populations (vol 5, 329, 2022), COMMUNICATIONS BIOLOGY, Vol: 5
Jarvelin M-R, Wielscher M, Mandaviya PR, et al., 2022, DNA methylation signature of chronic low-gradeinflammation and its role in cardio-respiratorydiseases, Nature Communications, Vol: 13, ISSN: 2041-1723
We performed a multi-ethnic Epigenome Wide Association study on 22,774 individuals to describe the DNA methylation signature of chronic low-grade inflammation as measured by C-Reactive protein (CRP). We find 1,511 independent differentially methylated loci associated with CRP. These CpG sites show correlation structures across chromosomes, and are primarily situated in euchromatin, depleted in CpG islands. These genomic loci are predominantly situated in transcription factor binding sites and genomic enhancer regions. Mendelian randomization analysis suggests altered CpG methylation is a consequence of increased blood CRP levels. Mediation analysis reveals obesity and smoking as important underlying driving factors for changed CpG methylation. Finally, we find that an activated CpG signature significantly increases the risk for cardiometabolic diseases and COPD.
Mahajan A, Spracklen CN, Zhang W, et al., 2022, Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation, NATURE GENETICS, Vol: 54, Pages: 560-+, ISSN: 1061-4036
Fraszczyk E, Spijkerman AMW, Zhang Y, et al., 2022, Epigenome-wide association study of incident type 2 diabetes: a meta-analysis of five prospective European cohorts, DIABETOLOGIA, Vol: 65, Pages: 763-776, ISSN: 0012-186X
Ranjani H, Avari P, Nitika S, et al., 2022, ACCEPTABILITY OF TWO NOVEL MHEALTH APPLICATIONS FOR DIABETES PREVENTION IN URBAN AND RURAL INDIA, Publisher: MARY ANN LIEBERT, INC, Pages: A186-A187, ISSN: 1520-9156
Ranjani H, Anjana RM, Valabhji J, et al., 2022, USING MHEALTH FOR TYPE 2 DIABETES RISK REDUCTION IN URBAN AND RURAL INDIA - A PILOT STUDY, Publisher: MARY ANN LIEBERT, INC, Pages: A186-A186, ISSN: 1520-9156
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