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Coupling and Uncoupling Pleiotropy Between Hypertension and Type 2 Diabetes Contribute to Exploring Potential
Huan Yu1,2, Liuyan Zheng1,2, Jingxian Wu1,2
1Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, China.
Biomedicines
|June 26, 2026
Summary
Genetic pleiotropy between hypertension and type 2 diabetes (T2D) shows distinct cardiovascular risks in East Asians. Understanding these genetic links may enable precision prevention strategies for complex diseases.
Area of Science:
- Genetics
- Cardiovascular Disease Epidemiology
- Metabolic Disorders
Background:
- Hypertension (HTN) and type 2 diabetes (T2D) frequently coexist, sharing underlying genetic factors.
- The specific genetic architecture of this comorbidity and its impact on cardiovascular risk remain incompletely understood, particularly in East Asian populations.
Purpose of the Study:
- To systematically deconstruct the shared genetic architecture of hypertension and type 2 diabetes comorbidity.
- To evaluate how divergent genetic architectures influence differential cardiovascular risk in East Asians.
Main Methods:
- Utilized a two-stage study design with a large East Asian genetic dataset (>300,000 individuals).
- Identified pleiotropic loci using conjunctional false discovery rates, classifying them into coupling and uncoupling types.
- Constructed and validated polygenic risk scores (PRSs) and assessed associations with cardiovascular risk using logistic regression.
Main Results:
- Identified 463 pleiotropic loci (439 coupling, 24 uncoupling) between HTN and T2D.
- Coupling PRS associated with T2D (OR=1.53), while other associations were directionally consistent but not significant.
- Coupling and uncoupling PRSs demonstrated divergent cardiovascular risk profiles and distinct gene-environment interactions.
Conclusions:
- Coupling and uncoupling genetic pleiotropy between HTN and T2D contribute to cardiovascular risk heterogeneity in East Asians.
- Deconstructing genetic pleiotropy provides a framework for precision prevention strategies.
- Findings are exploratory and require validation in larger cohorts.
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