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

Abstract

SummaryDeficiencies 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 = 1AE19 · 10) 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.

SASH1, a new potential link between smoking and atherosclerosis

“…The MARTHA study is a collection of 1,542 patients with venous thrombosis (VT) recruited from the Thrombophilia centre of La Timone hospital (Marseille, France) 169,170,171,172 . All subjects had a documented history of VT, were free of chronic diseases, and were free of inherited thrombophilia including: anti-thrombin, protein C and protein S deficiencies and homozygosity for the Factor V Leiden and Factor II G20210A mutations.…”

A meta-analysis of genome-wide association studies identifies ORM1 as a novel gene controlling thrombin generation potential

“…The MARTHA study has already been extensively described. 32,33 It is composed of 1542 patients with venous thrombosis (VT) recruited from the thrombophilia center of La Timone hospital (Marseille, France). All subjects, with a documented history of VT, were free of any chronic conditions and free of any thrombophilia including anti-thrombin, protein C and protein S deficiencies, and homozygosity for factor V Leiden and factor II G20210A mutations.…”

Age-specific onset and distribution of the natural anticoagulant deficiency in pediatric thromboembolism

“…In this setting, the concordant mutation rate by the independent studies would warrant the utility of plasma activities for genetic screening in Japanese children. No mutation in >30% of patients raises the possibility of large gene deletions, polymorphisms, and the other genetic variations or certain modifiers affecting the activity and antigen concentration (22). The present measures studied polymorphisms including the promoter regions but not deletions.…”