A phenotype-sensitizing Apoe-deficient genetic background reveals novel atherosclerosis predisposition loci in the mouse.
Therapeutic intervention for atherosclerosis has predominantly concentrated on regulating cholesterol levels; however, these therapeutics are not efficacious for all patients, suggesting that other factors are involved. This study was initiated to identify mechanisms that regulate atherosclerosis predisposition in mice other than cholesterol level regulation. To do so we performed quantitative trait locus analysis using two inbred strains that each carry the atherosclerosis phenotype-sensitizing Apoe deficiency and that have been shown to have widely disparate predilection to atherosclerotic lesion formation. One highly significant locus on chromosome 10 (LOD = 7.8) accounted for 19% of the variance in lesion area independent of cholesterol. Two additional suggestive loci were identified on chromosomes 14 (LOD = 3.2) and 19 (LOD = 3.2), each accounting for 7-8% of the lesion variance. In all, five statistically significant and suggestive loci affecting lesion size but not lipoprotein levels were identified. Many of these were recapitulated in an independent confirmatory cross. In summary, two independently performed crosses between C57BL/6 and FVB/N Apoe-deficient mice have revealed several previously unreported atherosclerosis susceptibility loci that are distinct from loci linked to lipoprotein levels.
Dansky
Hayes M
HM
Laboratory of Biochemical Genetics and Metabolism, The Rockefeller University, New York, New York 10021, USA.
Shu
Pei
P
Donavan
M
M
Montagno
Jill
J
Nagle
Deborah L
DL
Smutko
John S
JS
Roy
Natalie
N
Whiteing
S
S
Barrios
Judith
J
McBride
T J
TJ
Smith
Jonathan D
JD
Duyk
Geoffrey
G
Breslow
Jan L
JL
Moore
Karen J
KJ
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001161:Arteriosclerosis / Q000235:genetics*; D002784:Cholesterol / Q000097:blood; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D019655:Quantitative Trait, Heritable
D001057:Apolipoproteins E; D008055:Lipids; D002784:Cholesterol