The overall objective of the Genetic Analysis of Idiopathic Thrombosis (GAIT) project is to identify genetic influences on susceptibility to thrombosis through genetic analyses of quantitative risk factors related to disease, including plasma levels of components of the hemostatic and fibrinolytic pathways as well as functional measures of protein activity and blood clotting efficiency. The GAIT sample includes 396 individuals in 21 multigenerational Spanish families for whom quantitative and diagnostic phenotypes are available as well as genotypes for a 10 cM genome scan. Analyses in the GAIT sample have previously documented the strong heritabiliites of many of these quantitative measures of hemostasis and fibrinolysis, identified which of these risk factors share pleiotropic genetic influences with liability to thrombosis, and localized quantitative trait loci (QTLs) influencing some of these traits. In the current grant period, we have followed up three of the most promising linkage results from the genome scan using standard fine-mapping techniques to narrow a linkage region on chromosome 10 for clotting factor XII levels and using a newly developed method, called Bayesian quantitative trait nucleotide (BQTN) analysis, to evaluate positional candidate genes within two regions of linkage, specifically the F12 gene under a linkage peak for factor XII levels and the TFPI gene under a linkage peak for tissue factor pathway inhibitor (TFPI) levels. In this renewal application, we propose to build on the results of these analyses through functional studies of variants identified in BQTN analyses, to extend our quantitative trait nucleotide studies to two new linkage signals with obvious positional candidate genes, and to replicate some of these findings in an independent data set.
The specific aims of the proposed research are:1) to follow-up three regions with strong linkage signals but no obvious candidate genes, including the factor XII linkage on chromosome 10, by assessing association with a gene-centric panel of SNPs; 2) to determine whether CPB2 is the previously detected QTL on chromosome 13 influencing levels of thrombin-activatable fibrinolysis inhibitor (TAFI); 3) to determine whether NNMT is the previously detected QTL on chromosome 11 influencing levels of homocysteine; and 4) to use in vitro functional studies to investigate potential mechanisms of action of polymorphisms identified as having a high posterior probability of effect in the quantitative trait nucleotide analyses.
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