1. Genome scan of clot lysis time and its association with thrombosis in a protein C-deficient kindred.
- Author
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Meltzer ME, Hasstedt SJ, Vossen CY, Callas PW, DE Groot PG, Rosendaal FR, Lisman T, and Bovill EG
- Subjects
- Blood Coagulation Tests, Carboxypeptidase B2 genetics, Chromosomes, Human, Pair 11, Chromosomes, Human, Pair 13, Family, Genetic Linkage, Humans, Mutation, Protein C Deficiency genetics, Prothrombin genetics, Quantitative Trait Loci, Fibrinolysis genetics, Genome, Human physiology, Protein C Deficiency physiopathology, Thrombosis genetics
- Abstract
Background: Previously, we found increased clot-lysis time (CLT), as measured with a plasma-based assay, to increase the risk of venous thrombosis in two population-based case-control studies. The genes influencing CLT are as yet unknown., Patients/methods: We tested CLT as risk factor for venous thrombosis in Kindred Vermont II (n = 346), a pedigree suffering from a high thrombosis risk, partially attributable to a type I protein C deficiency. Furthermore, we tested for quantitative trait loci (QTLs) for CLT, using variance component linkage analysis., Results: Protein C-deficient family members had shorter CLTs than non-deficient members (median CLT 67 min vs. 75 min). One standard deviation increase in CLT increased the risk of venous thrombosis 2.4-fold in non-deficient family members. Protein C deficiency without elevated CLT increased the risk 6.9-fold. Combining both risk factors yielded a 27.8-fold increased risk. The heritability of CLT was 42-52%. We found suggestive evidence of linkage on chromosome 11 (62 cM), partly explained by the prothrombin 20210A mutation, and on chromosome 13 (52 cM). Thrombin-activatable fibrinolysis inhibitor genotypes did not explain the variation in CLT., Conclusion: Hypofibrinolysis appears to increase thrombosis risk in this family, especially in combination with protein C deficiency. Protein C deficiency is associated with short CLT. CLT is partly genetically regulated. Suggestive QTLs were found on chromosomes 11 and 13., (© 2011 International Society on Thrombosis and Haemostasis.)
- Published
- 2011
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