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Thromb Haemost 2016; 116(06): 1041-1049
DOI: 10.1160/TH16-02-0151
Coagulation and Fibrinolysis
Schattauer Publishers Schattauer

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

Weihua Zhang
1   Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
1   Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
,
Fredrik Jernerén
3   Department of Pharmacology, University of Oxford, Oxford, UK
,
Benjamin C. Lehne
1   Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
,
Ming-Huei Chen
4   Population Sciences Branch, National Heart, Lung, Blood Institute, National Institutes of Health, Framingham, Massachusetts, USA
,
Robert N. Luben
5   Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
,
Carole Johnston
3   Department of Pharmacology, University of Oxford, Oxford, UK
,
Amany Elshorbagy
3   Department of Pharmacology, University of Oxford, Oxford, UK
6   Department of Physiology, Faculty of Medicine, University of Alexandria, Alexandria, Egypt
,
Ruben N. Eppinga
7   Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
8   Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
,
William R. Scott
1   Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
9   National Heart and Lung Institute, Imperial College London, Hammersmith Hospital Campus, London, UK
,
Elizabeth Adeyeye
2   Department of Cardiology, Ealing Hospital NHS Trust, Uxbridge Road, Southall, UK
10   Faculty of Medicine, Imperial College London, South Kensington Campus, London, UK
,
James Scott
9   National Heart and Lung Institute, Imperial College London, Hammersmith Hospital Campus, London, UK
,
Rainer H. Böger
11   Department of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
,
Kay-Tee Khaw
5   Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
,
Pim van der Harst
7   Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
8   Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
,
Nicholas J. Wareham
12   Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge, UK
,
Ramachandran S. Vasan
13   Section of Preventive Medicine and Epidemiology and Cardiology, Boston University School of Medicine, Boston, Massachusetts, USA
14   Boston University and National Heart, Lung & Blood Institute’s Framingham Heart Study, Framingham Massachusetts, USA
,
John C. Chambers
1   Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
2   Department of Cardiology, Ealing Hospital NHS Trust, Uxbridge Road, Southall, UK
15   Imperial College Healthcare NHS Trust, London, UK
,
Helga Refsum
3   Department of Pharmacology, University of Oxford, Oxford, UK
16   Department of Nutrition, Institute of Basic Medical Science, Faculty of Medicine, University of Oslo, Oslo, Norway
,
Jaspal S. Kooner
2   Department of Cardiology, Ealing Hospital NHS Trust, Uxbridge Road, Southall, UK
9   National Heart and Lung Institute, Imperial College London, Hammersmith Hospital Campus, London, UK
15   Imperial College Healthcare NHS Trust, London, UK
› Author Affiliations Financial support: 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#x2013;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).
Further Information

Publication History

Received: 22 February 2016

Accepted after major revision: 07 September 2016

Publication Date:
09 March 2018 (online)

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Summary

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.

Supplementary Material to this article is available online at www.thrombosis-online.com.

Keywords

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

 

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