Cardiorenal risk varies widely among patients with type 2 diabetes mellitus (T2DM), and genetic susceptibility across biological pathways may contribute to this heterogeneity. A prospective cohort analysis published in Diabetes, Obesity and Metabolism evaluated pathway-specific polygenic risk scores (psPRS) and their associations with cardiorenal outcomes and circulating proteins in a multi-ethnic Asian population.

The study included 2057 individuals with T2DM from the SMART2D cohort. Eight pathway-specific psPRS were constructed using East Asian-specific effect sizes, representing mechanisms such as beta-cell function, lipodystrophy, obesity, and lipid metabolism. Cox regression assessed associations with incident end-stage kidney disease (ESKD) and heart failure (HF), while logistic regression evaluated rapid decline in kidney function (RDKF), and linear regression examined circulating protein levels.

The beta-cell minus proinsulin (−PI) psPRS was associated with lower risk of ESKD (hazard ratio [HR]=0.81; 95% confidence interval [CI]: 0.69–0.95), HF (HR=0.86; 95% CI: 0.74-1.00), and RDKF (odds ratio [OR]=0.81; 95% CI: 0.69-0.94). 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 also showed associations with circulating proteins, including leukocyte immunoglobulin-like receptor A5 (LILRA5), ectodysplasin A2 receptor (EDA2R), and fatty acid binding protein 4 (FABP4).

These findings indicate that pathway-specific genetic susceptibility shows differential associations with cardiorenal outcomes in multi-ethnic Asian populations. Further validation is required to determine clinical applicability.