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. 2007 Feb;5(2):329-35.
doi: 10.1111/j.1538-7836.2007.02325.x. Epub 2006 Nov 28.

Genetic Regulation of Plasma Von Willebrand Factor Levels: Quantitative Trait Loci Analysis in a Mouse Model

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Free PMC article

Genetic Regulation of Plasma Von Willebrand Factor Levels: Quantitative Trait Loci Analysis in a Mouse Model

H L Lemmerhirt et al. J Thromb Haemost. .
Free PMC article

Abstract

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 approximately 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 approximately 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.

Conflict of interest statement

Disclosure of Conflict of Interests: The authors state that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Original distribution of plasma von Willebrand factor (VWF) levels in 200 (A/J × CASA/RkJ) F2 mice. VWF levels were calculated as a percentage of the CASA/RkJ parental strain. The latter is arbitrarily defined as 100%. F2 values are summarized by the bar graph. Averages for the parental and F1 populations (± SD) are shown: A/J (open diamond), CASA/RkJ (black diamond) and F1 (gray diamond). This figure is adapted from Figure 1 of Lemmerhirt et al. (Blood 2006; 108: 3061).
Fig. 2
Fig. 2
Logarithm of odds (LOD) curves from a single quantitative trait locus analysis. (A) Inclusion of sex as an additive covariate. (B) Inclusion of both sex and the genotype at D6Mit12 as additive covariates. The dashed horizontal lines indicate the 95% LOD thresholds.
Fig. 3
Fig. 3
Genotype and phenotype correlation at three candidate additive von Willebrand factor (VWF) modifier loci. Individual VWF levels and marker genotypes, partitioned by sex, at three candidate murine modifier loci identified via a single quantitative trait locus model. VWF levels are represented as a percentage of CASA/RkJ parental values. Error bars represent 95% confidence intervals.
Fig. 4
Fig. 4
Logarithm of odds (LOD) scores, partitioned by D6Mit12 genotype. LOD scores obtained by single quantitative trait locus analyses, performed separately in the three groups defined by the genotype at D6Mit12, with sex included as an additive covariate. The dashed horizontal lines indicate the 95% LOD thresholds.
Fig. 5
Fig. 5
Phenotype vs. genotype in a two-locus model of epistasis with D6Mit12. Individual von Willebrand factor (VWF) levels for individuals partitioned by their two-locus marker genotypes, for markers showing evidence for an epistatic interaction with D6Mit12. VWF levels are represented as a percentage of CASA/RkJ parental values. Error bars represent 95% confidence intervals.
Fig. 6
Fig. 6
1.5-Logarithm of odds (LOD) support intervals for regions of significant linkage and relevant human homology of synteny. The 1.5-LOD support intervals are shown to the left of the chromosomes. Shown to the right (patterned boxes) are relevant regions of human homology of synteny containing quantitative trait loci associated with von Willebrand factor (VWF) level variation in the Genetic Analysis of Idiopathic Thrombophilia (GAIT) study, as reported by Souto et al. (Thromb Haemost 2003; 89: 468). Additionally, the LOD support interval on murine chromosome 6 shares homology of synteny with the VWF locus on human chromosome 12.

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