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

TY - JOUR

T1 - Genome-wide association reveals that common genetic variation in the kallikrein-kinin system is associated with serum L-arginine levels

AU - Zhang, Weihua

AU - Jernerén, Fredrik

AU - Lehne, Benjamin C

AU - Chen, Ming-Huei

AU - Luben, Robert N

AU - Johnston, Carole

AU - Elshorbagy, Amany

AU - Eppinga, Ruben N

AU - Scott, William R

AU - Adeyeye, Elizabeth

AU - Scott, James

AU - Böger, Rainer H

AU - Khaw, Kay-Tee

AU - van der Harst, Pim

AU - Wareham, Nicholas J

AU - Vasan, Ramachandran S

AU - Chambers, John C

AU - Refsum, Helga

AU - Kooner, Jaspal S

PY - 2016/11/30

Y1 - 2016/11/30

N2 - 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.

AB - 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.

KW - Adult

KW - Aged

KW - Arginine/blood

KW - Cardiovascular Diseases/genetics

KW - Female

KW - Genome-Wide Association Study

KW - Humans

KW - Kallikrein-Kinin System/genetics

KW - Kallikreins/genetics

KW - Male

KW - Middle Aged

KW - Polymorphism, Single Nucleotide

KW - Risk Factors

U2 - 10.1160/TH16-02-0151

DO - 10.1160/TH16-02-0151

M3 - SCORING: Journal article

C2 - 27656708

VL - 116

SP - 1041

EP - 1049

JO - THROMB HAEMOSTASIS

JF - THROMB HAEMOSTASIS

SN - 0340-6245

IS - 6

ER -