Journal
THROMBOSIS AND HAEMOSTASIS
Volume 116, Issue 6, Pages 1041-1049Publisher
GEORG THIEME VERLAG KG
DOI: 10.1160/TH16-02-0151
Keywords
Serum L-arginine concentration; genome-wide association; coagulation; kallikrein-kinin system
Categories
Funding
- British Heart Foundation [SP/04/002]
- Medical Research Council [G0601966, G0700931, G0401527, G1000143]
- Wellcome Trust [084723/Z/08/Z]
- NIHR [RP-PG-0407-10371]
- European Union FP7 (EpiMigrant) [279143]
- Action on Hearing Loss [G51]
- Cancer Research UK [C864/A8257]
- Norwegian research Council
- National Heart, Lung and Blood Institute's Framingham Heart Study [N01-HC-25195]
- Affymetrix Inc. [N02-HL-6-4278]
- Medical Research Council [G1000143, MC_U106179471, MR/K002414/1, MR/N003284/1, MC_UU_12015/1, G0700931, MC_PC_13048, G0401527, G0601966] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0512-10114, ACF-2009-18-005] Funding Source: researchfish
- MRC [G0601966, MR/N003284/1, MC_UU_12015/1, G0700931, MR/K002414/1] Funding Source: UKRI
- Wellcome Trust [084723/Z/08/Z] Funding Source: Wellcome Trust
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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 mu mol/l per allele copy, p=1x10(-24)), while allele T of rs2545801 (T/C) near the F12 gene is associated with lower serum L-arginine levels (7 mu mol/l per allele copy, p=7x10(-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.
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