Coupling and Uncoupling Pleiotropy Between Hypertension and Type 2 Diabetes Contribute to Exploring Potential Heterogeneity in Cardiovascular Risk in East Asian Population

Background/Objectives: This study aims to systematically deconstruct the shared genetic architecture underlying the comorbidity of hypertension (HTN) and type 2 diabetes (T2D) and evaluate how these divergent genetic architectures are associated with differential cardiovascular risk in East Asian population. Methods: This two-stage study first leveraged the largest genetic dataset from >300,000 East Asian individuals to identify pleiotropic loci between hypertension and type 2 diabetes using conjunctional false discovery rates, classifying them into coupling and uncoupling types based on effect directions. Corresponding polygenic risk scores (PRSs) were then constructed and validated in an independent family-based cohort. A logistic regression model was used to examine the associations between different genetic architectures and cardiovascular risk, including comorbidity onset and cardiovascular outcomes. Results: A total of 463 pleiotropic loci were identified, including 439 coupling loci and 24 uncoupling loci. The coupling PRS showed a significant association with single T2D (OR = 1.53; 95% CI: 1.08–2.18; p = 0.017), whereas the other associations were not significant, although the effect estimates were directionally consistent with our hypothesis. Crucially, coupling and uncoupling PRSs showed divergent cardiovascular risk profiles and exhibited distinct gene–environment interactions. Conclusions: Our findings suggest that coupling and uncoupling pleiotropy between hypertension and type 2 diabetes may contribute to the heterogeneity of cardiovascular risk in East Asians. Deconstructing genetic pleiotropy offers a potential framework for precision prevention strategies, although these findings are exploratory and warrant further validation in larger cohorts.