Pathway‐Specific Polygenic Risk Scores and Cardiorenal Complications in Asians With Type 2 Diabetes

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AIM: Risk of cardiorenal complications varies among patients with type 2 diabetes (T2D). T2D pathway-specific polygenic risk scores (psPRS) capture genetic susceptibility related to distinct intermediate biological processes associated with T2D and cardiorenal outcomes, predominantly in European populations. Their relevance in multi-ethnic Asian populations remains unclear. We explored associations between T2D-derived psPRS and cardiorenal outcomes and circulating proteins linked to cardiorenal complications. METHODS: We included 2057 multi-ethnic individuals with T2D from the prospective SMART2D cohort. Eight T2D pathway-related psPRS (Beta-cell +Proinsulin [PI], Beta-cell -PI, residual glycaemia, body fat, metabolic syndrome, obesity, lipodystrophy, liver and lipid metabolism) were constructed using East Asian-specific effect sizes. Cox regression was used to assess associations with incident end-stage kidney disease (ESKD) and heart failure (HF), logistic regression for rapid decline in kidney function (RDKF) and linear regression for circulating proteins. RESULTS: The Beta-cell -PI psPRS was inversely associated with ESKD (HR = 0.81; 95% CI: 0.69-0.95), RDKF (OR = 0.81; 95% CI: 0.69-0.94) and HF (HR = 0.86; 95% CI: 0.74-1.00). In contrast, the lipodystrophy psPRS was associated with higher odds of RDKF (OR = 1.21; 95% CI: 1.04-1.41). The Beta-cell -PI psPRS was also associated with circulating levels of LILRA5, EDA2R and FABP4. CONCLUSION: In a multi-ethnic Asian population, pathway-specific genetic susceptibility was differentially associated with cardiorenal outcomes and related circulating proteins. These findings suggest the potential relevance of biologically informed genetic pathways in diverse populations and warrant validation in independent cohorts.

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