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Peer-reviewedCC BY-NC-NDJournal of the American Heart Association

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

  • Zhi Chng Lau1,2
  • Xuling Chang2,3,4
  • Kar Seng Sim1
  • Hao Wu1
  • Arshia Naaz1
  • Umamaheswari Muniasamy2
  • Chiea Chuen Khor1,5
  • Woon‐Puay Koh2,6
  • Vitaly A. Sorokin2,7
  • Rajkumar Dorajoo1,2
7 affiliations
  1. 1Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR)
  2. 2National University of Singapore
  3. 3National University Health System
  4. 4The University of Melbourne, The Peter Doherty Institute for Infection and Immunity
  5. 5Singapore National Eye Centre
  6. 6Institute for Human Development and Potential (IHDP), Agency for Science, Technology and Research (A*STAR)
  7. 7National University Hospital, National University Health System
Open at sourceDOICite

Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{lau2026integrative,
  title = {{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}},
  author = {Zhi Chng Lau and Xuling Chang and Kar Seng Sim and Hao Wu and Arshia Naaz and Umamaheswari Muniasamy and Chiea Chuen Khor and Woon‐Puay Koh and Vitaly A. Sorokin and Rajkumar Dorajoo},
  journal = {Journal of the American Heart Association},
  year = {2026},
  month = oct,
  doi = {10.1161/jaha.126.052309},
  url = {https://www.ahajournals.org/doi/10.1161/JAHA.126.052309},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - 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
AU  - Zhi Chng Lau
AU  - Xuling Chang
AU  - Kar Seng Sim
AU  - Hao Wu
AU  - Arshia Naaz
AU  - Umamaheswari Muniasamy
AU  - Chiea Chuen Khor
AU  - Woon‐Puay Koh
AU  - Vitaly A. Sorokin
AU  - Rajkumar Dorajoo
PY  - 2026
DA  - 2026/10/23
JO  - Journal of the American Heart Association
DO  - 10.1161/jaha.126.052309
UR  - https://www.ahajournals.org/doi/10.1161/JAHA.126.052309
AB  - 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.
SN  - 2047-9980
ER  -