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 journalArticlepeer-review

5 Scopus citations


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 (US)
Pages (from-to)1041-1049
Number of pages9
JournalThrombosis and Haemostasis
Issue number6
StatePublished - Dec 2016
Externally publishedYes


  • Coagulation
  • Genome-wide association
  • Kallikrein-kinin system
  • Serum L-arginine concentration

ASJC Scopus subject areas

  • Hematology


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