Key result
Multi-omics profiling identifies East Asian-specific molecular markers for T2D including ALDH2 effects on 2-hydroxyisovalerate.
Why the study?
Type 2 diabetes in East Asians exhibits distinct clinical characteristics, yet East Asian-specific molecular mechanisms remain understudied.
Cohort (n=5,438)
Yes
Multi-omics integration in a Korean cohort identified East Asian-specific genetic and proteometabolic markers for Type 2 Diabetes, highlighting regulatory mechanisms absent in European populations.
Should not alter T2D care yet; extends multi-omics to East Asian-specific markers.
Introduction and Objective: Type 2 diabetes (T2D) in East Asians (EA) exhibits distinct clinical characteristics, yet EA-specific molecular mechanisms remain understudied. To address this gap, we established a Korean T2D-focused biobank integrating multi-omics with longitudinal electronic health records. Methods: A multicenter hospital-based cohort of 5,438 Koreans (93.2% T2D; mean follow-up 2.87 years) was integrated with genomics (N=2,742; WES and GWAS), proteomics (N=1,310; 5,416 proteins), and metabolomics (N=4,712; 392 metabolites). We identified proteometabolic signatures for T2D traits and medication use, performed Mendelian randomization (MR), and mapped protein quantitative trait loci (pQTLs) and metabolite QTLs (metabQTLs) for colocalization with EA T2D GWAS loci. Results: Participants had a mean age of 62.1 years, and 60.9% were male. We identified 1,031 robust (Bonferroni-adjusted) proteometabolic signatures for BMI, HbA1c, and T2D duration, along with medication use (e.g., metformin-GDF15 and statin-PCOLCE/PCSK9). We detected approximately 50,000 significant protein-metabolite associations, a subset of which showed evidence of causality by MR. Genetic analysis identified 2,106 pQTL loci and 208 mQTL loci, including 138 EA-specific signals absent in European pQTL data from UK Biobank, such as cis-pQTLs at REG1A and TIMP3. We found at least 23 protein colocalizations with EA T2D GWAS signals (e.g., ALDH2, ABO, and FGFR4) and 47 significant protein-metabolite colocalizations. Notably, an EA-specific T2D GWAS signal colocalized with an ALDH2 cis-pQTL and the metabolite 2-hydroxyisovalerate. MR supported a causal effect of ALDH2 protein levels on 2-hydroxyisovalerate (P=2.75×10-6), a branched-chain amino acid metabolite linked to insulin resistance. Conclusion: This multi-omics integration defines the EA-specific genetic and proteometabolic architecture of T2D. These findings highlight regulatory mechanisms absent in Europeans, establishing a foundation for population-specific precision medicine.
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Kho et al. (2026) conducted a cohort in Type 2 diabetes (n=5,438). Multi-omics profiling (genomics, proteomics, metabolomics) was evaluated on Identification of proteometabolic signatures, pQTLs, mQTLs, and colocalizations with East Asian T2D GWAS loci. Multi-omics profiling in 5,438 Korean individuals identified East Asian-specific molecular markers for type 2 diabetes, including a causal effect of ALDH2 on 2-hydroxyisovalerate (P=2.75x10-6).
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