Genome-wide association reveals that common genetic variation in the kallikrein-kinin system is associated with serum L-arginine levels

Weihua Zhang, Fredrik Jernerén, Benjamin C Lehne, Ming-Huei Chen, Robert N Luben, Carole Johnston, Amany Elshorbagy, Ruben N Eppinga, William R Scott, Elizabeth Adeyeye, James Scott, Rainer H Böger, Kay-Tee Khaw, Pim van der Harst, Nicholas J Wareham, Ramachandran S Vasan, John C Chambers, Helga Refsum, Jaspal S Kooner

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

L-arginine is the essential precursor of nitric oxide, and is involved in multiple key physiological processes, including vascular and immune function. The genetic regulation of blood L-arginine levels is largely unknown. We performed a genome-wide association study (GWAS) to identify genetic factors determining serum L-arginine levels, amongst 901 Europeans and 1,394 Indian Asians. We show that common genetic variations at the KLKB1 and F12 loci are strongly associated with serum L-arginine levels. The G allele of single nucleotide polymorphism (SNP) rs71640036 (T/G) in KLKB1 is associated with lower serum L-arginine concentrations (10 µmol/l per allele copy, p=1×10-24), while allele T of rs2545801 (T/C) near the F12 gene is associated with lower serum L-arginine levels (7 µmol/l per allele copy, p=7×10-12). Together these two loci explain 7 % of the total variance in serum L-arginine concentrations. The associations at both loci were replicated in independent cohorts with plasma L-arginine measurements (p<0.004). The two sentinel SNPs are in nearly complete LD with the nonsynonymous SNP rs3733402 at KLKB1 and the 5'-UTR SNP rs1801020 at F12, respectively. SNPs at both loci are associated with blood pressure. Our findings provide new insight into the genetic regulation of L-arginine and its potential relationship with cardiovascular risk.

Original languageEnglish
Pages (from-to)1041-1049
Number of pages9
JournalThrombosis and Haemostasis
Volume116
Issue number6
DOIs
Publication statusPublished - 30 Nov 2016
Externally publishedYes

Keywords

  • Adult
  • Aged
  • Arginine/blood
  • Cardiovascular Diseases/genetics
  • Female
  • Genome-Wide Association Study
  • Humans
  • Kallikrein-Kinin System/genetics
  • Kallikreins/genetics
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Risk Factors

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