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

• Published in: Thrombosis and haemostasis Vol. 116; no. 6; p. 1041
• Main Authors: Zhang, Weihua, Jernerén, Fredrik, Lehne, Benjamin C, Chen, Ming-Huei, Luben, Robert N, Johnston, Carole, Elshorbagy, Amany, Eppinga, Ruben N, Scott, William R, Adeyeye, Elizabeth, Scott, James, Böger, Rainer H, Khaw, Kay-Tee, van der Harst, Pim, Wareham, Nicholas J, Vasan, Ramachandran S, Chambers, John C, Refsum, Helga, Kooner, Jaspal S
• Format: Journal Article
• Language: English
• Published: Germany 01.12.2016
• Subjects: 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; kallikrein-kinin system; genome-wide association; coagulation; Serum L-arginine concentration
• ISSN: 2567-689X
• DOI: 10.1160/TH16-02-0151

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 ), 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 ). 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.