An Unknown Genetic Defect Increases Venous Thrombosis Risk, through Interaction with Protein C Deficiency

University of Utah, Department of Human Genetics, Salt Lake City, UT 84112-5330, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 09/1998; 63(2):569-76. DOI: 10.1086/301947
Source: PubMed


We used two-locus segregation analysis to test whether an unknown genetic defect interacts with protein C deficiency to increase susceptibility to venous thromboembolic disease in a single large pedigree. Sixty-seven pedigree members carry a His107Pro mutation in the protein C gene, which reduces protein C levels to a mean of 46% of normal. Twenty-one carriers of the mutation and five other pedigree members had verified thromboembolic disease. We inferred the presence in this pedigree of a thrombosis-susceptibility gene interacting with protein C deficiency, by rejecting the hypothesis that the cases of thromboembolic disease resulted from protein C deficiency alone and by not rejecting Mendelian transmission of the interacting gene. When coinherited with protein C deficiency, the interacting gene conferred a probability of a thrombotic episode of approximately 79% for men and approximately 99% for women, before age 60 years.

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Available from: Peter Callas, Jun 03, 2014
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    • "A recent study by Christiansen et al. [53] showed that approximately half of the thrombotic recurrences in women were provoked and were mainly related to oral contraceptive use. In earlier research on this family, we found that PC deficiency increased risk of thrombosis in female family members when taking oral contraceptives and during pregnancy [15], [52] Because of those studies, women in the family who are PC deficient were strongly advised against use of oral contraceptives and are almost always given prophylactic heparin during pregnancy. Further studies regarding plasma compositional differences to elucidate the mechanism behind the increased thrombin generation in women and the effect from additional thrombotic risk factors are warranted in this family. "
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    ABSTRACT: The underlying cause of thrombosis in a large protein C (PC) deficient Vermont kindred appears to be multicausal and not explained by PC deficiency alone. We evaluated the contribution of coagulation factors to thrombin generation in this population utilizing a mathematical model that incorporates a mechanistic description of the PC pathway. Thrombin generation profiles for each individual were generated with and without the contribution of the PC pathway. Parameters that describe thrombin generation: maximum level (MaxL) and rate (MaxR), their respective times (TMaxL, TMaxR), area under the curve (AUC) and clotting time (CT) were examined in individuals ±PC mutation, ±prothrombin G20210A polymorphism and ±thrombosis history (DVT or PE). This family (n = 364) is shifted towards greater thrombin generation relative to the mean physiologic control. When this family was analyzed with the PC pathway, our results showed that: carriers of the PC mutation (n = 81) had higher MaxL and MaxR and greater AUC (all p<0.001) than non-carriers (n = 283); and individuals with a DVT and/or PE history (n = 13) had higher MaxL (p = 0.005) and greater AUC (p<0.001) than individuals without a thrombosis history (n = 351). These differences were further stratified by gender, with women in all categories generating more thrombin than males. These results show that all individuals within this family with or without PC deficiency have an increased baseline procoagulant potential reflective of increased thrombin generation. In addition, variations within the plasma composition of each individual can further segregate out increased procoagulant phenotypes, with gender-associated plasma compositional differences playing a large role.
    PLoS ONE 09/2012; 7(9):e44378. DOI:10.1371/journal.pone.0044378 · 3.23 Impact Factor
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    • "In contrast, the F1 mice from a cross of B6-Chr5 × B6-Chr17 restored the prolonged clot stability to the elevated consomic values (Hoover-Plow et al. 2006). Likewise, other studies (Shavit et al. 2009) have reported several loci that modify the von Willibrand factor that is required for platelet aggregation, and Hasstedt et al. (1998) suggested that there was a modifier gene for protein C that increases thromboembolism risk. "
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    ABSTRACT: Two overlapping quantitative trait loci (QTLs) for clot stability, Hmtb8 and Hmtb9, were identified on mouse chromosome 17 in an F2 intercross derived from C57BL/6J (B6) and B6-Chr17A/J (B6-Chr17) mouse strains. The intervals were in synteny with a QTL for thrombotic susceptibility on chromosome 18 in a human study, and there were 23 homologs between mouse and human. The objective of this study was to determine whether any of these genes in the syntenic region are likely candidates as modifiers for clot stability. Seven genes, Twsg1, Zfp161, Dlgap1, Ralbp1, Myom1, Rab31, and Emilin2, of the 23 genes with single nucleotide polymorphisms (SNPs) in the mRNA-UTR had differential expression in B6 and A/J mice. Dlgap1, Ralbp1, Myom1, and Emilin2 also had nonsynonymous SNPs. In addition, two other genes had nonsynonymous SNPs, Lama1 and Ndc80. Of these nine candidate genes, Emilin2 was selected for further analysis since other EMILIN (Elastin Microfibril Interface Located Protein) proteins have known functions in vascular structure and coagulation. Differences were found between B6 and A/J mice in vessel wall architecture and EMILIN2 protein in plasma, carotid vessel wall, and thrombi formed after ferric chloride injury. In B6-Chr17A/J mice both clot stability and Emilin2 mRNA expression were higher compared to those in B6 and A/J mice, suggesting the exposure of epistatic interactions. Although other homologous genes in the QTL region cannot be ruled out as causative genes, further investigation of Emilin2 as a candidate gene for thrombosis susceptibility is warranted. Electronic supplementary material The online version of this article (doi:10.1007/s00335-010-9274-6) contains supplementary material, which is available to authorized users.
    Mammalian Genome 08/2010; 21(7-8):337-49. DOI:10.1007/s00335-010-9274-6 · 3.07 Impact Factor
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    • "A QTL on human chromosome 18 was reported to influence protein C resistance and thrombotic risk (Hasstedt et al. 1998; Soria et al. 2003). This human QTL region (18p11.32-11.23) "
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    ABSTRACT: Susceptibility to thrombosis varies in human populations as well as many in inbred mouse strains. The objective of this study was to characterize the genetic control of thrombotic risk on three chromosomes. Previously, utilizing a tail-bleeding/rebleeding assay as a surrogate of hemostasis and thrombosis function, three mouse chromosome substitution strains (CSS) (B6-Chr5(A/J), Chr11(A/J), Chr17(A/J)) were identified (Hmtb1, Hmtb2, Hmtb3). The tail-bleeding/rebleeding assay is widely used and distinguishes mice with genetic defects in blood clot formation or dissolution. In the present study, quantitative trait locus (QTL) analysis revealed a significant locus for rebleeding (clot stability) time (time between cessation of initial bleeding and start of the second bleeding) on chromosome 5, suggestive loci for bleeding time (time between start of bleeding and cessation of bleeding) also on chromosomes 5, and two suggestive loci for clot stability on chromosome 17 and one on chromosome 11. The three CSS and the parent A/J had elevated clot stability time. There was no interaction of genes on chromosome 11 with genes on chromosome 5 or chromosome 17. On chromosome 17, twenty-three candidate genes were identified in synteny with previously identified loci for thrombotic risk on human chromosome 18. Thus, we have identified new QTLs and candidate genes not previously known to influence thrombotic risk.
    Mammalian Genome 10/2008; 19(6):406-12. DOI:10.1007/s00335-008-9122-0 · 3.07 Impact Factor
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