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

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

7 Citations (Scopus)

Abstract

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; and at 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.

Original languageEnglish
Pages (from-to)995-1003
Number of pages9
JournalThrombosis & Haemostasis
Volume110
Issue number5
DOIs
Publication statusPublished - Nov 2013

Keywords

  • Adaptor Proteins, Signal Transducing
  • Apolipoproteins A
  • Blood Platelets
  • Blood Viscosity
  • Carrier Proteins
  • Cell Count
  • DNA Mutational Analysis
  • Factor VII
  • Fibrinogen
  • G-Protein-Coupled Receptor Kinase 5
  • Genetic Association Studies
  • Hemostasis
  • Humans
  • Macrophage Colony-Stimulating Factor
  • Microarray Analysis
  • Microspheres
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Quantitative Trait, Heritable
  • Thrombosis
  • HumanCVD
  • clotting factors
  • GENOME-WIDE ASSOCIATION
  • BRITISH WOMENS HEART
  • TRIGLYCERIDE LEVELS
  • BIOCHEMICAL TRAITS
  • LINKAGE ANALYSES
  • PLASMA-LEVELS
  • WHITEHALL-II
  • LIPID-LEVELS
  • LOCI

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