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

Tom R. Gaunt; Delilah Zabaneh; Sonia Shah; Anna Guyatt; Christophe Ladroue; Meena Kumari; Fotios Drenos; Tina Shah; Philippa J. Talmud; Juan Pablo Casas; Gordon Lowe; Ann Rumley; Debbie A. Lawlor; Mika Kivimaki; John Whittaker; Aroon D. Hingorani; Steve E. Humphries; Ian N. Day

doi:10.1160/TH13-02-0087

Thrombosis and Haemostasis, Table of Contents

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^*

¹MRC Centre for Causal Analyses in Translational Epidemiology, School of Social and Community Medicine, University of Bristol, Bristol, UK

,

Delilah Zabaneh^*

²University College London Genetics Institute, Department of Genetics, Environment and Evolution, London, UK

,

Sonia Shah

²University College London Genetics Institute, Department of Genetics, Environment and Evolution, London, UK

,

Anna Guyatt

¹MRC Centre for Causal Analyses in Translational Epidemiology, School of Social and Community Medicine, University of Bristol, Bristol, UK

,

Christophe Ladroue

¹MRC Centre for Causal Analyses in Translational Epidemiology, School of Social and Community Medicine, University of Bristol, Bristol, UK

,

Meena Kumari

³Genetic Epidemiology Group, Department of Epidemiology and Public Health, University College London, London, UK

,

Fotios Drenos

⁴Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, UK

,

Tina Shah

³Genetic Epidemiology Group, Department of Epidemiology and Public Health, University College London, London, UK

,

Philippa J. Talmud

⁴Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, UK

,

Juan Pablo Casas

⁵Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK

⁶Institute of Cardiovascular Science, University College London, London, UK

,

Gordon Lowe

⁷Institute of Cardiovascular & Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK

,

Ann Rumley

⁷Institute of Cardiovascular & Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK

,

Debbie A. Lawlor

¹MRC Centre for Causal Analyses in Translational Epidemiology, School of Social and Community Medicine, University of Bristol, Bristol, UK

,

Mika Kivimaki

³Genetic Epidemiology Group, Department of Epidemiology and Public Health, University College London, London, UK

,

John Whittaker

⁵Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK

⁸Quantitative Sciences, GlaxoSmithKline, Stevenage, UK

,

Aroon D. Hingorani

³Genetic Epidemiology Group, Department of Epidemiology and Public Health, University College London, London, UK

,

Steve E. Humphries^*

²University College London Genetics Institute, Department of Genetics, Environment and Evolution, London, UK

⁴Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, UK

,

Ian N. Day^*

¹MRC Centre for Causal Analyses in Translational Epidemiology, School of Social and Community Medicine, University of Bristol, Bristol, UK

› Author Affiliations

Abstract

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

Full Text

References

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