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

Journal: Thrombosis and Haemostasis
ISSN: 0340-6245
Topic:

Theme Issue
Platelets: basic mechanisms and translational implications

DOI: http://dx.doi.org/10.1160/TH13-02-0087
Issue: 2013: 110/5 (Nov) pp. 857-1085
Pages: 995-1003

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

Online Supplementary Material

T. R. Gaunt (1), D. Zabaneh (2), S. Shah (2), A. Guyatt (1), C. Ladroue (1), M. Kumari (3), F. Drenos (4), T. Shah (3), P. J. Talmud (4), J. P. Casas (5, 6), G. Lowe (7), A. Rumley (7), D. A. Lawlor (1), M. Kivimaki (3), J. Whittaker (5, 8), A. D. Hingorani (3), S. E. Humphries (2, 4), I. N. Day (1)

(1) MRC Centre for Causal Analyses in Translational Epidemiology, School of Social and Community Medicine, University of Bristol, Bristol, UK; (2) University College London Genetics Institute, Department of Genetics, Environment and Evolution, London, UK; (3) Genetic Epidemiology Group, Department of Epidemiology and Public Health, University College London, London, UK; (4) Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, UK; (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; (7) Institute of Cardiovascular & Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK; (8) Quantitative Sciences, GlaxoSmithKline, Stevenage, UK

Keywords

thrombosis, Haemostasis, HumanCVD, clotting factors, genetic association

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=1.30x10⁻⁶), GCKR (rs1260326, p=1.63x10⁻⁶), ZNF259-APOA5 (rs651821, p=7.17x10⁻⁶) with plasma viscosity; andat CSF1 (rs333948, p=8.88x10⁻⁶) with platelet count. A pleiotropic effect was identified in GCKR which associated with factor VII (p=2.16x10⁻⁷) and plasma viscosity (p=1.63x10⁻⁶), and, to a lesser extent, ZNF259-APOA5 which also associated with factor VII and fibrinogen (p<1.00x10⁻²) and plasma viscosity (p<1.00x10⁻⁵). 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.

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