Download PDF
Thromb Haemost 2013; 110(05): 995-1003
DOI: 10.1160/TH13-02-0087
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Gene-centric association signals for haemostasis and thrombosis traits identified with the HumanCVD BeadChip

Tom R. Gaunt   *
1   MRC Centre for Causal Analyses in Translational Epidemiology, School of Social and Community Medicine, University of Bristol, Bristol, UK
,
Delilah Zabaneh   *
2   University College London Genetics Institute, Department of Genetics, Environment and Evolution, London, UK
,
Sonia Shah
2   University College London Genetics Institute, Department of Genetics, Environment and Evolution, London, UK
,
Anna Guyatt
1   MRC Centre for Causal Analyses in Translational Epidemiology, School of Social and Community Medicine, University of Bristol, Bristol, UK
,
Christophe Ladroue
1   MRC Centre for Causal Analyses in Translational Epidemiology, School of Social and Community Medicine, University of Bristol, Bristol, UK
,
Meena Kumari
3   Genetic Epidemiology Group, Department of Epidemiology and Public Health, University College London, London, UK
,
Fotios Drenos
4   Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, UK
,
Tina Shah
3   Genetic Epidemiology Group, Department of Epidemiology and Public Health, University College London, London, UK
,
Philippa J. Talmud
4   Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, UK
,
Juan Pablo Casas
5   Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK
6   Institute of Cardiovascular Science, University College London, London, UK
,
Gordon Lowe
7   Institute of Cardiovascular & Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK
,
Ann Rumley
7   Institute of Cardiovascular & Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK
,
Debbie A. Lawlor
1   MRC Centre for Causal Analyses in Translational Epidemiology, School of Social and Community Medicine, University of Bristol, Bristol, UK
,
Mika Kivimaki
3   Genetic Epidemiology Group, Department of Epidemiology and Public Health, University College London, London, UK
,
John Whittaker
5   Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK
8   Quantitative Sciences, GlaxoSmithKline, Stevenage, UK
,
Aroon D. Hingorani
3   Genetic Epidemiology Group, Department of Epidemiology and Public Health, University College London, London, UK
,
Steve E. Humphries   *
2   University College London Genetics Institute, Department of Genetics, Environment and Evolution, London, UK
4   Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, UK
,
Ian N. Day   *
1   MRC Centre for Causal Analyses in Translational Epidemiology, School of Social and Community Medicine, University of Bristol, Bristol, UK
› Author Affiliations Financial support: BWHHS: The British Women’s Heart and Health Study has been supported by funding from the BHF (PG/07/131/24254) and the Department of Health Policy Research Programme (England). The BWHHS is co-ordinated by Shah Ebrahim (PI), Debbie Lawlor and Juan-Pablo Casas, with cardiochip work funded by the BHF (PG/07/131/24254, PI Tom Gaunt, co-Is Ian Day, Debbie Lawlor, Shah Ebrahim, George Davey Smith, Yoav Ben-Shlomo, Santiago Rodriguez). CL is supported by an MRC project grant (G1000427, PI TRG). WHII: Prof Humphries is a British Heart Foundation (BHF) Chairholder (PG08/008). The UCL Genetics Institute supports DZ, and SS. The work on WH-II was supported by the BHF PG/07/133/24260, RG/08/008, SP/07/007/23671 and a Senior Fellowship to Professor Hingorani (FS/2005/125). Dr Kumari’s and Prof. Kivimaki’s time on this manuscript was partially supported by the National Heart Lung and Blood Institute (NHLBI: HL36310). The WH-II study has been supported by grants from the Medical Research Council; Economic and Social Research Council; British Heart Foundation; Health and Safety Executive; Department of Health; National Institute on Aging (AG13196), US, NIH; Agency for Health Care Policy Research (HS06516); and the John D and Catherine T MacArthur Foundation Research Networks on Successful Midlife Development and Socio-economic Status and Health.
Further Information

Publication History

Received: 01 February 2013

Accepted after major revision: 05 August 2013

Publication Date:
01 December 2017 (online)

Also available at
    Permissions and Reprints

Summary

Coagulation phenotypes show strong intercorrelations, affect cardiovascular disease risk and are influenced by genetic variants. The objective of this study was to search for novel genetic variants influencing the following coagulation phenotypes: factor VII levels, fibrinogen levels, plasma viscosity and platelet count. We genotyped the British Women’s Heart and Health Study (n=3,445) and the Whitehall II study (n=5,059) using the Illumina HumanCVD BeadArray to investigate genetic associations and pleiotropy. In addition to previously reported associations (SH2B3, F7/F10, PROCR, GCKR, FGA/FGB/FGG, IL5), we identified novel associations at GRK5 (rs10128498, p = 1.30×10−6), GCKR (rs1260326, p = 1.63×10−6), ZNF259-APOA5 (rs651821, p = 7.17x10–6) with plasma viscosity; and at CSF1 (rs333948, p = 8.88×10−6) with platelet count. A pleiotropic effect was identified in GCKR which associated with factor VII (p = 2.16×10−7) and plasma viscosity (p = 1.63×10−6), and, to a lesser extent, ZNF259-APOA5 which also associated with factor VII and fibrinogen (p<1.00×10−2) and plasma viscosity (p<1.00×10−5). Triglyceride associated variants were overrepresented in factor VII and plasma viscosity associations. Adjusting for triglyceride levels resulted in attenuation of associations at the GCKR and ZNF259-APOA5 loci. In addition to confirming previously reported associations, we identified four single nucleotide polymorphisms (SNPs) associated with plasma viscosity and platelet count and found evidence of pleiotropic effects with SNPs in GCKR and ZNF259-APOA5. These triglyceride-associated, pleiotropic SNPs suggest a possible causal role for triglycerides in coagulation.

Keywords

Haemostasis - thrombosis - HumanCVD - clotting factors - genetic association

* Equal contribution by these authors.


 

  • References

  • 1 MacCallum PK, Meade TW. Haemostatic function, arterial disease and the prevention of arterial thrombosis. Baillieres Best Pract Res Clin Haematol 1999; 12: 577-599.
    CrossrefPubMedGoogle Scholar
  • 2 Davie EW, Fujikawa K, Kisiel W. The coagulation cascade: initiation, maintenance, and regulation. Biochemistry 1991; 30: 10363-10370.
    CrossrefPubMedGoogle Scholar
  • 3 Smith NL, Chen MH, Dehghan A. et al. Novel Associations of Multiple Genetic Loci With Plasma Levels of Factor VII, Factor VIII, and von Willebrand Factor. Circulation 2010; 121: 1382-1392.
    CrossrefPubMedGoogle Scholar
  • 4 Taylor KC, Lange LA, Zabaneh D. et al. A gene-centric association scan for Coagulation Factor VII levels in European and African Americans: the Candidate Gene Association Resource (CARe) Consortium. Human Molecular Genetics 2011; 20: 3525-3534.
    CrossrefPubMedGoogle Scholar
  • 5 Danik JS, Paré G, Chasman DI. et al. Novel Loci, Including Those Related to Crohn Disease, Psoriasis, and Inflammation, Identified in a Genome-Wide Association Study of Fibrinogen in 17 686 Women / CLINICAL PERSPECTIVE. Circulation: Cardiovascular Genetics 2009; 2: 134-141.
    CrossrefPubMedGoogle Scholar
  • 6 Dehghan A, Yang Q, Peters A. et al. Association of Novel Genetic Loci With Circulating Fibrinogen Levels / CLINICAL PERSPECTIVE. Circulation: Cardiovascular Genetics 2009; 2: 125-133.
    CrossrefPubMedGoogle Scholar
  • 7 Yang Q, Kathiresan S, Lin JP. et al. Genome-wide association and linkage analyses of hemostatic factors and hematological phenotypes in the Framingham Heart Study. BMC Med Genet 2007; 8 (Suppl. 01) S12
    CrossrefPubMedGoogle Scholar
  • 8 Zemunik T, Boban M, Lauc G. et al. Genome-wide association study of biochemical traits in Korcula Island, Croatia. Croat Med J 2009; 50: 23-33.
    CrossrefPubMedGoogle Scholar
  • 9 Kamatani Y, Matsuda K, Okada Y. et al. Genome-wide association study of hematological and biochemical traits in a Japanese population. Nat Genet 2010; 42: 210-215.
    CrossrefPubMedGoogle Scholar
  • 10 Soranzo N, Spector TD, Mangino M. et al. A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium. Nat Genet 2009; 41: 1182-1190.
    CrossrefPubMedGoogle Scholar
  • 11 Soranzo N, Rendon A, Gieger C. et al. A novel variant on chromosome 7q22.3 associated with mean platelet volume, counts, and function. Blood 2009; 113: 3831-3837.
    CrossrefPubMedGoogle Scholar
  • 12 Ferreira MAR, Hottenga JJ, Warrington NM. et al. Sequence Variants in Three Loci Influence Monocyte Counts and Erythrocyte Volume. The American Journal of Human Genetics 2009; 85: 745-749.
    CrossrefPubMedGoogle Scholar
  • 13 Gieger C, Radhakrishnan A, Cvejic A. et al. New gene functions in megakaryopoiesis and platelet formation. Nature 2011; 480: 201-208.
    CrossrefPubMedGoogle Scholar
  • 14 Constantino M, Merskey C, Kudzma DJ. et al. Increased activity of vitamin K-dependent clotting factors in human hyperlipoproteinaemia - association with cholesterol and triglyceride levels. Thromb Haemost 1977; 38: 465-474.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Rosenson RS, Shott S, Tangney CC. Hypertriglyceridemia is associated with an elevated blood viscosity Rosenson: triglycerides and blood viscosity. Atherosclerosis 2002; 161: 433-439.
    CrossrefPubMedGoogle Scholar
  • 16 Keating BJ, Tischfield S, Murray SS. et al. Concept, Design and Implementation of a Cardiovascular Gene-Centric 50 K SNP Array for Large-Scale Genomic Association Studies. PLoS ONE 2008; 3: e3583
    CrossrefPubMedGoogle Scholar
  • 17 Lawlor DA, Bedford C, Taylor M. et al. Aspirin use for the prevention of cardiovascular disease: the British Womens Heart and Health Study. Br J Gen Pract 2001; 51: 743-745.
    PubMedGoogle Scholar
  • 18 Lawlor DL, Ebrahim SE, Davey Smith GDS. The association between components of adult height and Type II diabetes and insulin resistance: British Women's Heart and Health Study. Diabetologia 2002; 45: 1097-1106.
    CrossrefPubMedGoogle Scholar
  • 19 Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Research 1988; 16: 1215
    CrossrefPubMedGoogle Scholar
  • 20 Marmot MG, Stansfeld S, Patel C, North F, Head J, White I. et al. Health inequalities among British civil servants: the Whitehall II study. Lancet 1991; 337: 1387-1393.
    CrossrefPubMedGoogle Scholar
  • 21 Marmot M, Brunner E. Cohort Profile: The Whitehall II study. Int J Epidemiol 2005; 34: 251-256.
    CrossrefPubMedGoogle Scholar
  • 22 Talmud PJ, Drenos F, Shah S. et al. Gene-centric Association Signals for Lipids and Apolipoproteins Identified via the HumanCVD BeadChip. Am J Human Genet 2009; 85: 628-642.
    CrossrefPubMedGoogle Scholar
  • 23 Purcell S, Neale B, Todd-Brown K. et al. PLINK: A Tool Set for Whole-Genome Association and Population-Based Linkage Analyses. Am J Human Genet 2007; 81: 559-575.
    CrossrefPubMedGoogle Scholar
  • 24 Undas A, Brummel-Ziedins KE. et al. Antithrombotic properties of aspirin and resistance to aspirin: beyond strictly antiplatelet actions. Blood 2007; 109: 2285-2292.
    CrossrefPubMedGoogle Scholar
  • 25 Willer CJ, Li Y, Abecasis GR. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 2010; 26: 2190-2191.
    CrossrefPubMedGoogle Scholar
  • 26 Akaike H. New Look at Statistical-Model Identification. Ieee Transactions on Automatic Control 1974; AC19: 716-723.
    CrossrefPubMedGoogle Scholar
  • 27 Hindorff LA, Sethupathy P, Junkins HA. et al. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc Natl Acad Sci USA 2009; 106: 9362-9367.
    CrossrefPubMedGoogle Scholar
  • 28 Teslovich TM, Musunuru K, Smith AV. et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 2010; 466: 707-713.
    CrossrefPubMedGoogle Scholar
  • 29 Arraes SM, Freitas MS, da Silva SV. et al. Impaired neutrophil chemotaxis in sepsis associates with GRK expression and inhibition of actin assembly and tyrosine phosphorylation. Blood 2006; 108: 2906-2913.
    CrossrefPubMedGoogle Scholar
  • 30 Saxena R, Hivert MF, Langenberg C. et al. Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge. Nat Genet 2010; 42: 142-148.
    CrossrefPubMedGoogle Scholar
  • 31 Chambers JC, Zhang W, Sehmi J. et al. Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma. Nat Genet 2011; 43: 1131-1138.
    CrossrefPubMedGoogle Scholar
  • 32 Diabetes Genetics Initiative of Broad Institute of Harvard and MIT LUaNIoBR Saxena R. et al. Genome-Wide Association Analysis Identifies Loci for Type 2 Diabetes and Triglyceride Levels. Science 2007; 316: 1331-1336.
    CrossrefPubMedGoogle Scholar
  • 33 Kathiresan S, Melander O, Guiducci C. et al. Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat Genet 2008; 40: 189-197.
    CrossrefPubMedGoogle Scholar
  • 34 Johansen CT, Wang J, Lanktree MB. et al. Excess of rare variants in genes identified by genome-wide association study of hypertriglyceridemia. Nat Genet 2010; 42: 684-687.
    CrossrefPubMedGoogle Scholar
  • 35 Waterworth DM, Ricketts SL, Song K. et al. Genetic Variants Influencing Circulating Lipid Levels and Risk of Coronary Artery Disease. Arterioscl Thromb Vasc Biol 2010; 30: 2264-2276.
    CrossrefPubMedGoogle Scholar
  • 36 Pollin TI, Damcott CM, Shen H. et al. A Null Mutation in Human APOC3 Confers a Favorable Plasma Lipid Profile and Apparent Cardioprotection. Science 2008; 322: 1702-1705.
    CrossrefPubMedGoogle Scholar
  • 37 Aulchenko YS, Ripatti S, Lindqvist I. et al. Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts. Nat Genet 2008; 41: 47
    PubMedGoogle Scholar
  • 38 Kim WM, Merskey C, Deming QB. et al. Hyperlipidemia, hypercoagulability, and accelerated thrombosis: studies in congenitally hyperlipidemic rats and in rats and monkeys with induced hyperlipidemia. Blood 1976; 47: 275-286.
    PubMedGoogle Scholar
  • 39 Andersen P. Hypercoagulability and reduced fibrinolysis in hyperlipidemia: relationship to the metabolic cardiovascular syndrome. J Cardiovasc Pharmacol 1992; 20 (Suppl. 08) S29-S31.
    PubMedGoogle Scholar
  • 40 Simpson HC, Mann JI, Meade TW. et al. Hypertriglyceridaemia and hypercoagulability. Lancet 1983; 1: 786-790.
    PubMedGoogle Scholar
  • 41 Rosenson RS, Lowe GD. Effects of lipids and lipoproteins on thrombosis and rheology. Atherosclerosis 1998; 140: 271-280.
    CrossrefPubMedGoogle Scholar
  • 42 Tang W, Basu S, Kong X. et al. Genome-wide association study identifies novel loci for plasma levels of protein C: the ARIC study. Blood 2010; 116: 5032-5036.
    CrossrefPubMedGoogle Scholar