Journal of the American Heart Association · Oct 23, 2026

Integrative Genomic Analyses Identify Collagen Type XXI Alpha 1 Chain and ENPEP-Fibroblast Growth Factor 5 Regulatory Pathways for Blood Pressure Variation in East Asian People

By Lau ZC, Chang X, Sim KS et al.

BACKGROUND: Hypertension and diabetes are common cardiometabolic disorders that may share genetic and environmental risk factors. However, the regulatory genes and tissue-specific mechanisms underlying blood pressure variations remain incompletely understood. METHODS: Leveraging a well-characterized prospective population-based cohort comprised of 27 308 participants from the SCHS (Singapore Chinese Health Study), we evaluated genome-wide genetic associations for 5 blood pressure traits: hypertension status, systolic blood pressure, diastolic blood pressure, mean arterial pressure and pulse pressure. Additionally, we conducted a transcriptome-wide association study, integrating gene expression data from 49 tissues, followed by colocalization and fine-mapping to prioritize regulatory genes. Association of identified variants with incident diabetes was additionally evaluated in the longitudinal data. RESULTS: We validated 10 blood pressure loci (P between 1.64×10⁻²⁰-4.10×10⁻⁸) and identified an East Asian-specific splice donor variant at the COL21A1 gene associated with pulse pressure (rs149344559, P=6.78×10⁻¹⁰). Integrative analyses prioritized FGF5 in kidney cortex and ENPEP in pituitary tissue as candidate regulatory genes. The blood pressure-lowering allele at ENPEP (T allele, rs1879056) was associated with reduced risk of incident diabetes. Mediation analysis demonstrated that ∼20.1% of the genetic association with diabetes was mediated through mean arterial pressure (Pindirect-effect<0.001). CONCLUSIONS: This study refines genetic predispositions for blood pressure among East Asian individuals. We further delineate tissue-specific regulatory pathways underlying blood pressure variations and identify ENPEP-mediated dysfunctions linking blood pressure genetics to diabetes risk, underscoring integrated disease mechanisms.

doi.org/10.1161/jaha.126.052309 Open access PubMed 42924838 Mechanisms