Genome wide association study for plasma levels of natural anticoagulant inhibitors and protein C anticoagulant pathway: the MARTHA project

Br J Haematol. 2012 Apr;157(2):230-9. doi: 10.1111/j.1365-2141.2011.09025.x. Epub 2012 Jan 16.


Deficiencies of antithrombin (AT), protein C (PC) and protein S (PS) or an impaired PC anticoagulant pathway increase the risk of venous thrombosis (VT). By conducting a genome-wide association study (GWAS) on two independent samples of VT patients totalling 951 subjects typed for 472 173 single nucleotide polymorphisms (SNPs), we observed that common SNPs explain 21% and 27% of the genetic variance of plasma AT and PS levels, even though no SNP reached genome-wide significance. For PC, we showed that two PROCR SNPs, rs867186 (Ser219Gly) and rs6060278, additionally explained c. 20% (P = 1·19 × 10(-31)) of the variance of plasma PC levels. We also observed that c. 40% of the remaining genetic variance of PC levels could be due to yet unidentified common SNPs. The PROCR locus was also found to explain c. 8% (P < 10(-10)) of agkistrodon contortrix venom (ACV) (exploring the PC pathway) variability which was under the main control of the F5 and F2 loci that further explained about 40% and 10%, respectively. We presented here the first GWAS for plasma AT and free-PS levels and ACV in Caucasian samples. We identified three independent loci associated with ACV (F2, F5 and PROCR) and replicated two independent effects on plasma PC levels at the PROCR locus.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antigens, CD / genetics
  • Antithrombin Proteins* / genetics
  • Antithrombin Proteins* / metabolism
  • Blood Coagulation / drug effects
  • Blood Coagulation / genetics
  • Crotalid Venoms / pharmacology
  • Endothelial Protein C Receptor
  • Female
  • Genetic Loci
  • Genome-Wide Association Study*
  • Humans
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide*
  • Protein C* / genetics
  • Protein C* / metabolism
  • Protein S* / genetics
  • Protein S* / metabolism
  • Receptors, Cell Surface / genetics
  • Retrospective Studies
  • Risk Factors
  • Venous Thrombosis* / blood
  • Venous Thrombosis* / genetics


  • Agkistrodon venoms
  • Antigens, CD
  • Antithrombin Proteins
  • Crotalid Venoms
  • Endothelial Protein C Receptor
  • PROCR protein, human
  • Protein C
  • Protein S
  • Receptors, Cell Surface