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

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 ( P indirect‐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.