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Genetic regulation of plasma von Willebrand factor levels: quantitative trait loci analysis in a mouse model
Author(s) -
LEMMERHIRT H. L.,
BROMAN K. W.,
SHAVIT J. A.,
GINSBURG D.
Publication year - 2007
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/j.1538-7836.2007.02325.x
Subject(s) - quantitative trait locus , biology , genetics , von willebrand disease , von willebrand factor , genetic linkage , allele , candidate gene , chromosome 4 , genetic variation , gene , chromosome , immunology , platelet
Summary. Background: The genetic factors responsible for the wide variation in plasma von Willebrand factor (VWF) levels observed among individuals are largely unknown, although these genes are also likely to contribute to variability in the severity of von Willebrand disease (VWD) and other bleeding and thrombotic disorders. We have previously mapped two genes contributing to the regulation of plasma VWF levels in mice ( Mvwf1 on chromosome 11 and Mvwf2 on chromosome 6). Objective: To identify additional quantitative trait loci (QTL) contributing to the genetic regulation of murine plasma VWF levels. Methods: To map genetic loci contributing to the > 7‐fold difference in plasma VWF levels between two mouse strains (A/J and CASA/RkJ), high‐density individual genotyping and R/qtl analyses were applied to a previously generated set of ∼200 F2 mice obtained from an intercross of these two inbred lines. Results: Genomic loci for two additional candidate VWF modifier genes were identified: Mvwf3 on chromosome 4 and Mvwf4 on chromosome 13. These loci demonstrate primarily epistatic effects when co‐inherited with two CASA/RkJ Vwf alleles, although Mvwf4 may also exert a small, independent, additive effect. Conclusions: Mvwf3 and Mvwf4 , combined with the effect of Mvwf2 , explain ∼45% of the genetic variation in plasma VWF level among the A/J and CASA/RkJ strains. Mvwf3 and Mvwf4 exhibit homology of synteny to three human chromosomal segments (on chromosomes 1, 5 and 6) previously reported by the Genetic Analysis of Idiopathic Thrombophilia (GAIT) study, suggesting that orthologs of Mvwf3 and Mvwf4 may also encode important VWF modifier genes in humans.