Bruce T. Scott

Heritability of plasma concentrations of clotting factors and measures of a prethrombotic state in a protein C-deficient family

Summary.  Background: Earlier studies found strong support for a genetic basis for regulation of coagulation factor levels and measures of a prethrombotic state (d‐dimer, prothrombin fragment 1.2). Objectives: Estimation of how much of the variation in the levels of coagulation factors and measures of a prethrombotic state, including measures of protein C activation and inactivation, could be attributed to heritability and household effect. Patients and methods: Blood samples were collected from 330 members of a large kindred of French‐Canadian origin with type I protein C deficiency. Heritability and common household effect were estimated for plasma concentrations of prothrombin, factor (F)V, factor VIII, factor (F)IX, fibrinogen, von Willebrand factor (VWF), antithrombin, protein C, protein S, protein Z, protein Z‐dependent protease inhibitor (ZPI), fibrinopeptide A (FPA), protein C activation peptide (PCP), activated protein C–protein C inhibitor complex (APC–PCI), activated protein C–α1‐antitrypsin complex (APC–α1AT), prothrombin fragment 1.2 (F1.2) and d‐dimer, using the variance component method in sequential oligo‐genic linkage analysis routines (SOLAR). Results: The highest heritability was found for measures of thrombin activity (PCP and FPA). High estimates were also found for prothrombin, FV, FIX, protein C, protein Z, ZPI, APC–PCI and APC–α1AT. An important influence of shared household effect on phenotypic variation was found for VWF, antithrombin, protein S and F1.2. Conclusions: We found strong evidence for the heritability of single coagulation factors and measures of a prethrombotic state. Hemostatic markers with statistically significant heritability constitute potential targets for the identification of novel genes involved in the control of quantitative trait loci.

Exclusion of the α2 subunit of platelet-activating factor acetylhydrolase 1b (PAFAH1B2) as a prothrombotic gene in a protein C-deficient kindred and population-based case-control sample

Protein C deficiency increases the risk of venous thromboembolic disease among members of Kindred Vermont II, but fails to fully account for the inheritance pattern. A genome scan of the pedigree supported the presence of a prothrombotic gene on chromosome 11q23 (107-119 Mb, nominal P < 0.0001), with weaker support on chromosomes 10p12 (11-25 Mb, P < 0.0003) and 18p11.2-q11 (12-24 Mb, P < 0.0007). The 11q23 region contains the alpha(2) subunit (gene name PAFAH1B2) of platelet-activating factor acetylhydrolase 1b, a candidate prothrombotic gene. Re-sequencing of the PAFAH1B2 regulatory region in 137 pedigree members, including 25 thrombosis cases, revealed 12 variants; eight were present in only 0-2 affected individuals; the other four assorted into three haplotypes and included three variants predicted to destroy transcription factor-binding sites. More extensive re-sequencing of the PAFAH1B2 gene in 11 affected and five unaffected pedigree members revealed an additional 13 variants that assorted into the same three haplotypes. We rejected as thrombosis risk factors each of the three presumed destructive variants as well as each of the three haplotypes. We also rejected (odds ratio = 1.31 CI: 0.91-1.88) one of the three variants in 469 cases and 472 controls from the Leiden Thrombophilia Study (LETS). Therefore, PAFAH1B2 is not the gene responsible for the linkage evidence on chromosome 11q23.

A genome search for genetic determinants of markers of protein C activation

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