title: Locating Ath8, a locus for murine atherosclerosis susceptibility and testing several of its candidate genes in mice and humans.
abstract: A previous study revealed that the difference in susceptibility to atherosclerotic lesions between inbred mouse strains SM/J and NZB/BlNJ was determined by one major locus (Ath8). In this study a (SM/J x NZB/BlNJ) F(1) x SM/J backcross localized Ath8 by quantitative trait locus mapping to chromosome 4 with a suggestive LOD score of 2.7. This quantitative trait locus (QTL) was confirmed using an (SM/J x NZB/BlNJ) intercross; Ath8 mapped to a 23cM region with a significant LOD score of 3.6. The genes for toll-like receptor 4 (T1r4), arachidonic acid epoxygenase (Cyp2j5), and angiopoietin-like protein 3 (Angptl3) map to this region. These candidate genes were analyzed for expression and sequence differences in the mouse and for associations with cardiovascular traits in human. Sequence analysis of Angptl3 shows a base pair substitution in SM, the susceptible strain, giving rise to an amino acid change in the fibrinogen homology domain of the protein. We found a significant association between ANGPTL3 and atherosclerotic lesions (P < 0.05) in human. These results suggest that Angptl3 is involved in atherosclerosis susceptibility in both mouse and human.
authors.affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA.
authors.forename: Ron
authors.initials: R
authors.lastname: Korstanje
authors.forename: Per
authors.initials: P
authors.lastname: Eriksson
authors.forename: Ann
authors.initials: A
authors.lastname: Samnegård
authors.forename: Per G
authors.initials: PG
authors.lastname: Olsson
authors.forename: Kristina
authors.initials: K
authors.lastname: Forsman-Semb
authors.forename: Saunak
authors.initials: S
authors.lastname: Sen
authors.forename: Gary A
authors.initials: GA
authors.lastname: Churchill
authors.forename: Jarod
authors.initials: J
authors.lastname: Rollins
authors.forename: Stephen
authors.initials: S
authors.lastname: Harris
authors.forename: Anders
authors.initials: A
authors.lastname: Hamsten
authors.forename: Beverly
authors.initials: B
authors.lastname: Paigen
mesh_terms: D000818:Animals; D001161:Arteriosclerosis / Q000235:genetics*; D002874:Chromosome Mapping; D033481:Chromosomes, Mammalian; D020022:Genetic Predisposition to Disease; D006801:Humans; D008126:Lod Score; D051379:Mice; D008815:Mice, Inbred Strains; D040641:Quantitative Trait Loci