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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)

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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.


 

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