title: Genome-wide association reveals that common genetic variation in the kallikrein-kinin system is associated with serum L-arginine levels.
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.
authors.affiliation: Weihua Zhang, PhD, Department of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine, Imperial College London, Norfolk Place, London W2 1PG, UK, Tel.: +44 20 8242 5926, Fax: +44 20 8967 5007, E-mail: weihua.zhang@imperial.ac.uk.
authors.forename: Weihua
authors.initials: W
authors.lastname: Zhang
authors.forename: Fredrik
authors.initials: F
authors.lastname: Jernerén
authors.forename: Benjamin C
authors.initials: BC
authors.lastname: Lehne
authors.forename: Ming-Huei
authors.initials: MH
authors.lastname: Chen
authors.forename: Robert N
authors.initials: RN
authors.lastname: Luben
authors.forename: Carole
authors.initials: C
authors.lastname: Johnston
authors.forename: Amany
authors.initials: A
authors.lastname: Elshorbagy
authors.forename: Ruben N
authors.initials: RN
authors.lastname: Eppinga
authors.forename: William R
authors.initials: WR
authors.lastname: Scott
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Adeyeye
authors.forename: James
authors.initials: J
authors.lastname: Scott
authors.forename: Rainer H
authors.initials: RH
authors.lastname: Böger
authors.forename: Kay-Tee
authors.initials: KT
authors.lastname: Khaw
authors.forename: Pim
authors.initials: P
authors.lastname: van der Harst
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Wareham
authors.forename: Ramachandran S
authors.initials: RS
authors.lastname: Vasan
authors.forename: John C
authors.initials: JC
authors.lastname: Chambers
authors.forename: Helga
authors.initials: H
authors.lastname: Refsum
authors.forename: Jaspal S
authors.initials: JS
authors.lastname: Kooner
mesh_terms: D000328:Adult; D000368:Aged; D001120:Arginine / Q000097:blood*; D002318:Cardiovascular Diseases / Q000235:genetics; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D016234:Kallikrein-Kinin System / Q000235:genetics*; D007610:Kallikreins / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
chemical_list: D001120:Arginine; D007610:Kallikreins
keywords: Serum L-arginine concentration; coagulation; genome-wide association; kallikrein-kinin system