Locating Ath8, a locus for murine atherosclerosis susceptibility and testing several of its candidate genes in mice and humans.
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.
Korstanje
Ron
R
The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA.
Eriksson
Per
P
Samnegård
Ann
A
Olsson
Per G
PG
Forsman-Semb
Kristina
K
Sen
Saunak
S
Churchill
Gary A
GA
Rollins
Jarod
J
Harris
Stephen
S
Hamsten
Anders
A
Paigen
Beverly
B
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