Genome scan of venous thrombosis in a pedigree with protein C deficiency

Abstract

See also Almasy L. The complex hunt for genes influencing complex disease. This issue, pp 866-7.Summary. Kindred Vermont II has a high frequency of venous thrombosis, occurring primarily in pedigree members with type I protein C deficiency due to a 3363 inserted (Ins) C mutation in exon 6 of the protein C gene. However, only a subset of 3363 InsC carriers have suffered thrombotic episodes, suggesting that the increased risk of thrombosis results upon the co-occurrence of 3363 InsC with a second, unknown, thrombophilic mutation that segregates independently within the pedigree. To test this hypothesis and to localize the co-occurring gene, we performed a genome scan of venous thrombosis in Kindred Vermont II. Non-parametric linkage statistics identified three potential gene locations, on chromosomes 11q23 (nominal P < 0.0001), 18p11.2-q11.2 (P < 0.0007), and 10p12 (P < 0.0003), supporting the presence of at least one additional thrombophilic mutation in the pedigree. Identification of the unknown mutation(s) promises to reveal a new genetic risk factor for thrombophilia, contribute to our understanding of the blood clotting mechanism, and expand our knowledge of the diversity of oligogenic disease.

Age- and Gender-Specific Familial Risks for Venous Thromboembolism

“…Genome scanning of large thrombophilic families may be an important option for identifying such risk factors. 38 The low incidence rate in children aged Ͻ10 years in our study was similar to those in previous reports. 39 The lack of familial cases among children aged Ͻ10 years could be due to the small number of cases, but it could also reflect the fact that the risk is very low even among familial cases and that in most children aged Ͻ10 years, 1 or more acquired risk factors, such as cancer, infection, congenital heart disease, and a central venous catheter, are necessary to provoke VTE.…”

Inherited Thrombophilia: Past, Present, and Future Research

“…The second main genome wide linkage analysis was performed in the Kindred Vermont II study, which includes a single large pedigree with a high rate of VTE, partly due to type I protein C deficiency resulting from a single mutation in the protein C gene. Only a subset of the carriers of this mutation experienced a VTE and therefore a genome scan was performed including 375 microsatellite markers to investigate the presence of a second thrombophilic mutation in this pedigree (Hasstedt et al, 2004). Three potential gene loci were found and 109 genes within these loci were re-sequenced.…”

Cell adhesion molecule 1: a novel risk factor for venous thrombosis

“…A total of 109 genes from the linkage regions on chromosomes 11q23, 18p11.2-q11.2, and 10p12 18 were selected as potential thrombophilia candidates or to fill gaps between candidates. We classified as potential candidates genes involved in hemostasis, inflammation, or the regulation of either pathway.…”

“…16,17 Further evidence that additional thrombophilia genes segregate in the kindred comes from an autosomal genome-wide linkage analysis that implicated chromosome 11q23 as well as potentially chromosomes 18p11.2-q11.2 and 10p12. 18 We previously tested and rejected PAFAH1B2 as the chromosome 11q23 thrombophilia gene. 19 Herein, we evaluate variants identified through resequencing of 109 genes within the linkage regions on chromosomes 10, 11, and 18 as candidates for thrombophilia genes that interact with PC deficiency in Kindred Vermont II.…”