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Genetic screening of candidate genes for a prothrombotic interaction with type I protein C deficiency in a large
B T Scott1, E G Bovill, P W Callas
1Department of Pathology, University of Vermont, Burlington 05405, USA.
Insights
In familial protein C deficiency, thrombosis risk increases with additional hemostatic abnormalities. A study found no evidence implicating 34 candidate genes as the second inherited factor for thrombophilia in the Vermont II kindred.
Area of Science:
- Genetics
- Hematology
- Molecular Biology
Background:
- Familial protein C deficiency exhibits incomplete penetrance for thrombosis, suggesting additional genetic factors contribute to disease.
- The Vermont II kindred, with dominant Type I protein C deficiency, shows a pattern of inherited thrombophilia indicative of a second, independent gene.
- Investigating this second gene is crucial for understanding the complex genetic basis of thrombophilia.
Purpose of the Study:
- To test the hypothesis of a second unidentified gene contributing to thrombophilia in the Vermont II kindred.
- To identify potential candidate genes involved in hemostasis or inflammation that segregate with increased thrombosis risk.
- To analyze linkage between candidate genes and thrombophilia within the kindred.
Main Methods:
- Candidate gene association study utilizing linkage analysis.
- Screening of 34 candidate genes involved in hemostasis and inflammation.
- Employment of highly polymorphic short tandem repeat (STR) markers in an informative subset (n=31) of the kindred.
Main Results:
- Linkage analysis was performed on 34 candidate genes, including fibrinogens, prothrombin, factors V, XI, XII, XIII, von Willebrand factor, and others.
- Despite investigating numerous genes known as independent risk factors for thrombosis, none showed linkage to the increased thrombophilia in this kindred.
- No evidence was found to implicate any of the tested candidate genes as the second inherited factor responsible for thrombophilia.
Conclusions:
- The study failed to identify the second gene responsible for increased thrombophilia in the Vermont II kindred among the 34 candidate genes tested.
- The genetic basis for the incomplete penetrance of thrombosis in familial protein C deficiency remains to be elucidated.
- Further research is needed to identify the unknown genetic factor(s) contributing to thrombophilia in this and similar kindreds.
Abstract:
The incomplete penetrance of thrombosis in familial protein C deficiency suggests disease occurs when this deficit is combined with additional abnormalities in the hemostatic system. The pattern of inherited thrombophilia in the Vermont II kindred, which is affected by a clinically dominant type I protein C deficiency, provides strong evidence for a second unidentified gene that segregates independently of protein C deficiency and increases susceptibility to thrombosis. To test the second gene hypothesis, thirty-four candidate genes for proteins involved in hemostasis or inflammation were tested as the unknown defect, using highly polymorphic short tandem repeat (STR) markers in an informative subset (n = 31) of the kindred. The genes considered are; alpha-fibrinogen, beta-fibrinogen, gamma-fibrinogen, prothrombin, tissue factor, factor V, protein S, complement component 4 binding protein, factor XI, factor XII, factor XIIIa, factor XIIIb, histidine rich glycoprotein, high molecular weight kininogen, kallikrein, von Willebrands factor, platelet factor 4, thrombospondin, antithrombin III, alpha-1-antitrypsin, thrombomodulin, plasminogen, tissue plasminogen activator, urokinase plasminogen activator, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, protein C inhibitor, alpha-2-plasmin inhibitor, kallistatin, lipoprotein a, interleukin 6, interleukin 1, cystathionine-beta-synthase, and methylenetetrahydrofolate reductase. Mutations in many of these genes have been previously established as independent risk factors for thrombosis. However, linkage analysis provided no evidence to implicate any of the candidate genes as the second inherited factor that promotes thrombophilia in this kindred.