ArticleDiabetologia2025
Type 2 diabetes pathway-specific polygenic risk scores elucidate heterogeneity in clinical presentation, disease progression and diabetic complications in 18,217 Chinese individuals with type 2 diabetes.
Article in Diabetologia, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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11 citing papers in PubMed.
- Genetic basis of Asian diabetes.Journal of diabetes investigation · 2026Review
- From GWAS Signals to Molecular Mechanisms: Explainable AI for Causal Gene Prioritization and Biomolecular Target Interpretation.Biomolecules · 2026Review
- Maternal and fetal genetic predispositions to insulin deficiency and resistance affect fetal growth through distinct pathways.Diabetologia · 2026Article
- Differential healthcare costs in individuals with type 2 diabetes and incident chronic kidney disease in Hong Kong: a latent class trajectory analysis.Diabetologia · 2026Article
- Phenotypic heterogeneity and polygenic risk scores in a family of maturity-onset diabetes of the young.JCEM case reports · 2026Article
- Redefining Diabetes and Creating Solutions-The Hong Kong Diabetes Register: Kelly West Award Lecture 2025.Diabetes care · 2026Article
- Polygenic risk score and cluster-based analysis suggests links between type 2 diabetes and vascular dementia in the KARE study.Nature communications · 2025Article
- Young-onset type 2 diabetes-Epidemiology, pathophysiology, and management.Journal of diabetes investigation · 2025Review
- Clinical use of polygenic scores in type 2 diabetes: challenges and possibilities.Diabetologia · 2025Review
- Low leg fat mass is associated with low insulin sensitivity, inflammatory markers, and β-cell dysfunction in non-obese Japanese people.Scientific reports · 2025Article
- Immune cell contribution to vascular complications in diabetes.Frontiers in endocrinology · 2025Review
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42 authors.
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Abstract
aims/hypothesisType 2 diabetes is a complex and heterogeneous disease and the aetiological components underlying the heterogeneity remain unclear in the Chinese and East Asian population. Therefore, we aimed to investigate whether specific pathophysiological pathways drive the clinical heterogeneity in type 2 diabetes.
methodsWe employed newly developed type 2 diabetes hard-clustering and soft-clustering pathway-specific polygenic risk scores (psPRSs) to characterise individual genetic susceptibility to pathophysiological pathways implicated in type 2 diabetes in 18,217 Chinese patients from Hong Kong. The 'total' type 2 diabetes polygenic risk score (PRS) was summed by genome-wide significant type 2 diabetes signals (n=1289). We examined the associations between psPRSs and cardiometabolic profile, age of onset, two glycaemic deterioration outcomes (clinical requirement of insulin treatment, defined by two consecutive HbA
resultsAlthough most psPRSs and total type 2 diabetes PRS were associated with an earlier and younger onset of type 2 diabetes, the psPRSs showed distinct associations with clinical outcomes. In particular, individuals with normal weight showed higher psPRSs for beta cell dysfunction and lipodystrophy than those who were overweight. The psPRSs for obesity were associated with faster progression to clinical requirement of insulin treatment (adjusted HR [95% CI] 1.09 [1.05, 1.13], p<0.0001), end-stage renal disease (1.10 [1.04, 1.16], p=0.0007) and CVD (1.10 [1.05, 1.16], p<0.0001) while the psPRSs for beta cell dysfunction were associated with reduced incident end-stage renal disease (0.90 [0.85, 0.95], p=0.0001) and heart failure (0.83 [0.73, 0.93], p=0.0011). Major findings remained significant after adjusting for a set of clinical variables. CONCLUSIONS/
interpretationBeta cell dysfunction and lipodystrophy could be the driving pathological pathways in type 2 diabetes in individuals with normal weight. Genetic risks of beta cell dysfunction and obesity represent two major genetic drivers of type 2 diabetes heterogeneity in disease progression and diabetic complications, which are shared across ancestry groups. Type 2 diabetes psPRSs may help inform patient stratification according to aetiology and guide precision diabetes care.
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