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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
› Institutsangaben 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).
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Publikationsverlauf

Received: 22. Februar 2016

Accepted after major revision: 07. September 2016

Publikationsdatum:
09. März 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

 

  • References

  • 1 Popolo A, Adesso S, Pinto A. et al. L-Arginine and its metabolites in kidney and cardiovascular disease. Amino Acids 2014; 46: 2271-2286.
    CrossrefPubMedGoogle Scholar
  • 2 Boger RH. The pharmacodynamics of L-arginine. Altern Ther Health Med 2014; 20: 48-54.
    PubMedGoogle Scholar
  • 3 Lorin J, Zeller M, Guilland JC. et al. Arginine and nitric oxide synthase: regulatory mechanisms and cardiovascular aspects. Mol Nutr Food Res 2014; 58: 101-116.
    CrossrefPubMedGoogle Scholar
  • 4 Luiking YC, Ten Have GA, Wolfe RR. et al. Arginine de novo and nitric oxide production in disease states. Am J Physiol Endocrinol Metab 2012; 303: E1177-1189.
    CrossrefPubMedGoogle Scholar
  • 5 Tousoulis D, Kampoli AM, Tentolouris C. et al. The role of nitric oxide on en-dothelial function. Curr Vasc Pharmacol 2012; 10: 4-18.
    CrossrefPubMedGoogle Scholar
  • 6 Morris Jr. SM. Arginases and arginine deficiency syndromes. Curr Opin Clin Nutr Metab Care 2012; 15: 64-70.
    CrossrefPubMedGoogle Scholar
  • 7 Gokce N. L-arginine and hypertension. J Nutr 2004; 134: 2807S-2811S. discussion 2818S-2819S.
    CrossrefPubMedGoogle Scholar
  • 8 Dong JY, Qin LQ, Zhang Z. et al. Effect of oral L-arginine supplementation on blood pressure: a meta-analysis of randomized, double-blind, placebo-controlled trials. Am Heart J 2011; 162: 959-965.
    CrossrefPubMedGoogle Scholar
  • 9 Luneburg N, Lieb W, Zeller T. et al. Genome-wide association study of L-argi-nine and dimethylarginines reveals novel metabolic pathway for symmetric di-methylarginine. Circ Cardiovasc Genet 2014; 07: 864-872.
    CrossrefPubMedGoogle Scholar
  • 10 Gieger C, Geistlinger L, Altmaier E. et al. Genetics meets metabolomics: a genome-wide association study of metabolite profiles in human serum. PLoS Genet 2008; 04: e1000282.
    CrossrefPubMedGoogle Scholar
  • 11 Illig T, Gieger C, Zhai G. et al. A genome-wide perspective of genetic variation in human metabolism. Nat Genet 2010; 42: 137-141.
    CrossrefPubMedGoogle Scholar
  • 12 Suhre K, Shin SY, Petersen AK. et al. Human metabolic individuality in bio-medical and pharmaceutical research. Nature 2011; 477: 54-60.
    CrossrefPubMedGoogle Scholar
  • 13 Rhee EP, Ho JE, Chen MH. et al. A genome-wide association study of the human metabolome in a community-based cohort. Cell Metab 2013; 18: 130-143.
    CrossrefPubMedGoogle Scholar
  • 14 Yu B, Zheng Y, Alexander D. et al. Genetic determinants influencing human serum metabolome among African Americans. PLoS Genet 2014; 10: e1004212.
    CrossrefPubMedGoogle Scholar
  • 15 Shin SY, Fauman EB, Petersen AK. et al. An atlas of genetic influences on human blood metabolites. Nat Genet 2014; 46: 543-550.
    CrossrefPubMedGoogle Scholar
  • 16 Draisma HH, Pool R, Kobl M. et al. Genome-wide association study identifies novel genetic variants contributing to variation in blood metabolite levels. Nat Commun 2015; 06: 7208.
    CrossrefPubMedGoogle Scholar
  • 17 Chambers JC, Zhang W, Zabaneh D. et al. Common genetic variation near me-latonin receptor MTNR1B contributes to raised plasma glucose and increased risk of type 2 diabetes among Indian Asians and European Caucasians. Diabetes 2009; 58: 2703-2708.
    CrossrefPubMedGoogle Scholar
  • 18 Chambers JC, Elliott P, Zabaneh D. et al. Common genetic variation near MC4R is associated with waist circumference and insulin resistance. Nat Genet 2008; 40: 716-718.
    CrossrefPubMedGoogle Scholar
  • 19 Marchini J, Howie B, Myers S. et al. A new multipoint method for genome-wide association studies by imputation of genotypes. Nat Genet 2007; 39: 906-913.
    CrossrefPubMedGoogle Scholar
  • 20 Howie B, Marchini J, Stephens M. Genotype imputation with thousands of genomes. G3 (Bethesda) 2011; 01: 457-470.
    PubMedGoogle Scholar
  • 21 Day N, Oakes S, Luben R. et al. EPIC-Norfolk: study design and characteristics of the cohort. European Prospective Investigation of Cancer. Br J Cancer 1999; 80 (Suppl. 01) 95-103.
    PubMedGoogle Scholar
  • 22 Kannel WB, Feinleib M, McNamara PM. et al. An investigation of coronary heart disease in families. The Framingham offspring study. Am J Epidemiol 1979; 110: 281-290.
    CrossrefPubMedGoogle Scholar
  • 23 Marchini J, Howie B. Genotype imputation for genome-wide association studies. Nat Rev Genet 2010; 11: 499-511.
    CrossrefPubMedGoogle Scholar
  • 24 Willer CJ, Li Y, Abecasis GR. METAL: fast and efficient meta-analysis of ge-nomewide association scans. Bioinformatics 2010; 26: 2190-2191.
    CrossrefPubMedGoogle Scholar
  • 25 Pruim RJ, Welch RP, Sanna S. et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 2010; 26: 2336-2337.
    CrossrefPubMedGoogle Scholar
  • 26 Han B, Eskin E. Random-effects model aimed at discovering associations in meta-analysis of genome-wide association studies. Am J Hum Genet 2011; 88: 586-598.
    CrossrefPubMedGoogle Scholar
  • 27 Schadt EE, Molony C, Chudin E. et al. Mapping the genetic architecture of gene expression in human liver. PLoS Biol 2008; 06: e107.
    CrossrefPubMedGoogle Scholar
  • 28 Innocenti F, Cooper GM, Stanaway IB. et al. Identification, replication, and functional fine-mapping of expression quantitative trait loci in primary human liver tissue. PLoS Genet 2011; 07: e1002078.
    CrossrefPubMedGoogle Scholar
  • 29 Greenawalt DM, Dobrin R, Chudin E. et al. A survey of the genetics of stomach, liver, and adipose gene expression from a morbidly obese cohort. Genome Res 2011; 21: 1008-1016.
    CrossrefPubMedGoogle Scholar
  • 30 Consortium GT. The Genotype-Tissue Expression (GTEx) project. Nat Genet 2013; 45: 580-585.
    CrossrefPubMedGoogle Scholar
  • 31 Welter D, MacArthur J, Morales J. et al. The NHGRI GWAS Catalog, a curated resource of SNP-trait associations. Nucleic Acids Res 2014; 42: D1001-1006.
    CrossrefPubMedGoogle Scholar
  • 32 Kettunen J, Tukiainen T, Sarin AP. et al. Genome-wide association study identifies multiple loci influencing human serum metabolite levels. Nat Genet 2012; 44: 269-276.
    CrossrefPubMedGoogle Scholar
  • 33 Inouye M, Ripatti S, Kettunen J. et al. Novel Loci for metabolic networks and multi-tissue expression studies reveal genes for atherosclerosis. PLoS Genet 2012; 08: e1002907.
    CrossrefPubMedGoogle Scholar
  • 34 Biswas N, Maihofer AX, Mir SA. et al. Polymorphisms at the F12 and KLKB1 loci have significant trait association with activation of the renin-angiotensin system. BMC Med Genet 2016; 17: 21.
    PubMedGoogle Scholar
  • 35 Verweij N, Mahmud H, Mateo Leach I. et al. Genome-wide association study on plasma levels of midregional-proadrenomedullin and C-terminal-pro-endothe-lin-1. Hypertension 2013; 61: 602-608.
    CrossrefPubMedGoogle Scholar
  • 36 Musani SK, Fox ER, Kraja A. et al. Genome-wide association analysis of plasma B-type natriuretic peptide in blacks: the Jackson Heart Study. Circ Cardiovasc Genet 2015; 08: 122-130.
    CrossrefPubMedGoogle Scholar
  • 37 Williams FM, Carter AM, Hysi PG. et al. Ischemic stroke is associated with the ABO locus: the EuroCLOT study. Ann Neurol 2013; 73: 16-31.
    CrossrefPubMedGoogle Scholar
  • 38 Tang W, Schwienbacher C, Lopez LM. et al. Genetic associations for activated partial thromboplastin time and prothrombin time, their gene expression profiles, and risk of coronary artery disease. Am J Hum Genet 2012; 91: 152-162.
    CrossrefPubMedGoogle Scholar
  • 39 Lieb W, Chen MH, Teumer A. et al. Genome-wide meta-analyses of plasma renin activity and concentration reveal association with the kininogen 1 and prekallikrein genes. Circ Cardiovasc Genet 2015; 08: 131-140.
    CrossrefPubMedGoogle Scholar
  • 40 Katsuda I, Maruyama F, Ezaki K. et al. A new type of plasma prekallikrein deficiency associated with homozygosity for Gly104Arg and Asn124Ser in apple domain 2 of the heavy-chain region. Eur J Haematol 2007; 79: 59-68.
    CrossrefPubMedGoogle Scholar
  • 41 Kanaji T, Okamura T, Osaki K. et al. A common genetic polymorphism (46 C to T substitution) in the 5’-untranslated region of the coagulation factor XII gene is associated with low translation efficiency and decrease in plasma factor XII level. Blood 1998; 91: 2010-2014.
    CrossrefPubMedGoogle Scholar
  • 42 Calafell F, Almasy L, Sabater-Lleal M. et al. Sequence variation and genetic evolution at the human F12 locus: mapping quantitative trait nucleotides that influence FXII plasma levels. Hum Mol Genet 2010; 19: 517-525.
    CrossrefPubMedGoogle Scholar
  • 43 Calvo SE, Pagliarini DJ, Mootha VK. Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans. Proc Natl Acad Sci USA 2009; 106: 7507-7512.
    CrossrefPubMedGoogle Scholar
  • 44 Dendorfer A, Wolfrum S, Wagemann M. et al. Pathways of bradykinin degradation in blood and plasma of normotensive and hypertensive rats. Am J Physiol Heart Circ Physiol 2001; 280: H2182-2188.
    CrossrefPubMedGoogle Scholar
  • 45 Kuoppala A, Lindstedt KA, Saarinen J. et al. Inactivation of bradykinin by an-giotensin-converting enzyme and by carboxypeptidase N in human plasma. Am J Physiol Heart Circ Physiol 2000; 278: H1069-1074.
    CrossrefPubMedGoogle Scholar
  • 46 Sheikh IA, Kaplan AP. Mechanism of digestion of bradykinin and lysylbradykinin (kallidin) in human serum. Role of carboxypeptidase, angiotensin-convert-ing enzyme and determination of final degradation products. Biochem Pharmacol 1989; 38: 993-1000.
    CrossrefPubMedGoogle Scholar
  • 47 Bjorkqvist J, Jamsa A, Renne T. Plasma kallikrein: the bradykinin-producing enzyme. Thromb Haemost 2013; 110: 399-407.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 48 Nikpay M, Goel A, Won HH. et al. A comprehensive 1,000 Genomes-based genome-wide association meta-analysis of coronary artery disease. Nat Genet 2015; 47: 1121-1130.
    CrossrefPubMedGoogle Scholar
  • 49 Olson NC, Butenas S, Lange LA. et al. Coagulation factor XII genetic variation, ex vivo thrombin generation, and stroke risk in the elderly: results from the Cardiovascular Health Study. J Thromb Haemost 2015; 13: 1867-1877.
    CrossrefPubMedGoogle Scholar