Quantitative trait locus analysis for hemostasis and thrombosis

Abstract

Susceptibility to thrombosis varies in human populations as well as many in inbred mouse strains. The objective of this study was to characterize the genetic control of thrombotic risk on three chromosomes. Previously, utilizing a tail-bleeding/rebleeding assay as a surrogate of hemostasis and thrombosis function, three mouse chromosome substitution strains (CSS) (B6-Chr5 A/J , Chr11 A/J , Chr17 A/J ) were identified (Hmtb1, Hmtb2, Hmtb3). The tailbleeding/rebleeding assay is widely used and distinguishes mice with genetic defects in blood clot formation or dissolution. In the present study, quantitative trait locus (QTL) analysis revealed a significant locus for rebleeding (clot stability) time (time between cessation of initial bleeding and start of the second bleeding) on chromosome 5, suggestive loci for bleeding time (time between start of bleeding and cessation of bleeding) also on chromosomes 5, and two suggestive loci for clot stability on chromosome 17 and one on chromosome 11. The three CSS and the parent A/J had elevated clot stability time. There was no interaction of genes on chromosome 11 with genes on chromosome 5 or chromosome 17. On chromosome 17, twenty-three candidate genes were identified in synteny

Genetic Dissection of Quantitative Trait Loci for Hemostasis and Thrombosis on Mouse Chromosomes 11 and 5 Using Congenic and Subcongenic Strains

“…The only gene known to be related to hemostasis and thrombosis on mouse chromosome 11 is Serpinf2 (α 2 -antiplasmin), an inhibitor of plasmin, the primary enzyme for clot lysis. Serpinf2 is located at 75.2 Mbp and was excluded from the candidates for this trait from our previous study [36]. This conclusion was further confirmed in our current study.…”

“…Our previous study, using F2 progeny from a cross of CSS-11 and B6, identified a QTL for clot stability time in the bleeding/rebleeding assay on mouse distal chromosome 11 that peaked at the genetic marker D11Mit336 [36]. To verify this QTL ( Hmtb6 ), congenic strains were constructed by crossing the CSS-11 mice and B6 mice to produce the congenic strain 6A-4 and the subcongenic strain 6A-2.…”

“…The bleeding time of the 2A-1 was the same as the time in B6 mice suggesting the additional region of 3A-2 harbored the short bleeding time. This narrow region of 3A-2 may be the site for the CSS-5 short bleeding time phenotype (Figure 3A), and the Hmtb 5 locus identified in the QTL mapping [36]. Thus, for the Hmtb 5 locus, the minimum A/J interval on 3A-2 strain, 100.2-108.6 Mbp that did not overlap with 2A-1, there are 78 protein-coding genes (Table S4), and functional annotation analysis revealed 11 relevant genes (Table 2).…”

“…The B6-Chr11 A/J (CSS-11) and B6-Chr5 A/J (CSS-5) had a phenotype similar to A/J mice, long clot stability. We identified the QTLs, Hmtb6 , Hmtb 4, and Hmtb 5, for hemostasis and thrombosis on mouse chromosomes 11 and 5 in an F 2 intercross from CSS-11 X B6 and CSS-5 X B6 [36]. The goal of this study was to fine map the QTLs, Hmtb6 , Hmtb4 , and Hmtb 5, using congenic and subcongenic mouse strains.…”

Contrasting genetic architectures in different mouse reference populations used for studying complex traits

“…2; Shao et al 2010;Yazbek et al 2011;DeSantis et al 2013;Kato et al 2014;Winawer et al 2014;Zhu and Matin 2014). The CSSs and congenic strains derived from CSSs have been used to map QTLs and identify causal genetic variants for traits such as body weight, glucose homeostasis, anxiety, hearing loss, bone morphology, blood clotting, liver fibrosis, energy expenditure, seizure susceptibility, among others (Singer et al 2004;Singer 2005;Winawer et al 2007;Gregorová et al 2008;Sa et al 2008;Shao et al 2008;Boell et al 2011;DeSantis et al 2013;Spiezio et al 2014;Street et al 2014). …”