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

Weihua Zhang; Fredrik Jernerén; Benjamin C. Lehne; Ming-Huei Chen; Robert N. Luben; Carole Johnston; Amany Elshorbagy; Ruben N. Eppinga; William R. Scott; Elizabeth Adeyeye; James Scott; Rainer H. Böger; Kay-Tee Khaw; Pim van der Harst; Nicholas J. Wareham; Ramachandran S. Vasan; John C. Chambers; Helga Refsum; Jaspal S. Kooner

doi:10.1160/TH16-02-0151

Thrombosis and Haemostasis, Table of Contents

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

Authors

Weihua Zhang

¹Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK

¹Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
Fredrik Jernerén

³Department of Pharmacology, University of Oxford, Oxford, UK
Benjamin C. Lehne

¹Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
Ming-Huei Chen

⁴Population Sciences Branch, National Heart, Lung, Blood Institute, National Institutes of Health, Framingham, Massachusetts, USA
Robert N. Luben

⁵Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
Carole Johnston

³Department of Pharmacology, University of Oxford, Oxford, UK
Amany Elshorbagy

³Department of Pharmacology, University of Oxford, Oxford, UK

⁶Department of Physiology, Faculty of Medicine, University of Alexandria, Alexandria, Egypt
Ruben N. Eppinga

⁷Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands

⁸Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
William R. Scott

¹Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK

⁹National Heart and Lung Institute, Imperial College London, Hammersmith Hospital Campus, London, UK
Elizabeth Adeyeye

²Department of Cardiology, Ealing Hospital NHS Trust, Uxbridge Road, Southall, UK

¹⁰Faculty of Medicine, Imperial College London, South Kensington Campus, London, UK
James Scott

⁹National Heart and Lung Institute, Imperial College London, Hammersmith Hospital Campus, London, UK
Rainer H. Böger

¹¹Department of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Kay-Tee Khaw

⁵Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
Pim van der Harst

⁷Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands

⁸Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
Nicholas J. Wareham

¹²Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge, UK
Ramachandran S. Vasan

¹³Section of Preventive Medicine and Epidemiology and Cardiology, Boston University School of Medicine, Boston, Massachusetts, USA

¹⁴Boston University and National Heart, Lung & Blood Institute’s Framingham Heart Study, Framingham Massachusetts, USA
John C. Chambers

¹Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK

²Department of Cardiology, Ealing Hospital NHS Trust, Uxbridge Road, Southall, UK

¹⁵Imperial College Healthcare NHS Trust, London, UK
Helga Refsum

³Department of Pharmacology, University of Oxford, Oxford, UK

¹⁶Department of Nutrition, Institute of Basic Medical Science, Faculty of Medicine, University of Oslo, Oslo, Norway
Jaspal S. Kooner

²Department of Cardiology, Ealing Hospital NHS Trust, Uxbridge Road, Southall, UK

⁹National Heart and Lung Institute, Imperial College London, Hammersmith Hospital Campus, London, UK

¹⁵Imperial College Healthcare NHS Trust, London, UK

Abstract

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

Full Text

References

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