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

Accepted version
Peer-reviewed

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Type

Article

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Authors

Zhang, W 
Jernerén, F 
Lehne, BC 
Chen, M-H 
Luben, RN 

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.

Description

Keywords

Serum L-arginine concentration, coagulation, genome-wide association, kallikrein-kinin system

Journal Title

Thrombosis and Haemostasis

Conference Name

Journal ISSN

0340-6245
2567-689X

Volume Title

116

Publisher

Schattauer
Sponsorship
Medical Research Council (MC_UU_12015/1)
MRC (MC_PC_13048)
Department of Health (via National Institute for Health Research (NIHR)) (NF-SI-0512-10135)
Medical Research Council (MR/N003284/1)
Medical Research Council (G1000143)
Medical Research Council (G0401527)
Medical Research Council (MC_U106179471)
Cancer Research Uk (None)
European Commission (279143)
Medical Research Council (G0401527/1)
Medical Research Council (MC_PC_13048)
The British Heart Foundation (SP/04/002), the Medical Research Council (G0601966, G0700931, G0401527, G1000143), the Wellcome Trust (084723/Z/08/Z), the NIHR (RP-PG-0407–10371), European Union FP7 (EpiMigrant, 279143), Action on Hearing Loss (G51), Cancer Research UK (C864/A8257), the Norwegian research Council, and the National Heart, Lung and Blood Institute’s Framingham Heart Study (Contract No. N01-HC-25195) and its contract with Affymetrix Inc. for genotyping services (Contract No. N02-HL-6–4278).