Athsq1 is an atherosclerosis modifier locus with dramatic effects on lesion area and prominent accumulation of versican.
OBJECTIVE
Susceptibility to atherosclerosis is genetically complex, and modifier genes that do not operate via traditional risk factors are largely unknown. A mouse genetics approach can simplify the genetic analysis and provide tools for mechanistic studies.


RESULTS
We previously identified atherosclerosis susceptibility QTL (Athsq1) on chromosome 4 acting independently of systemic risk factors. We now report confirmation of this locus in congenic strains carrying the MOLF-derived susceptibility allele in the C57BL/6J-Ldlr(-/-) genetic background. Homozygous congenic mice exhibited up to 4.5-fold greater lesion area compared to noncongenic littermates (P<0.0001). Analysis of extracellular matrix composition revealed prominent accumulation of versican, a presumed proatherogenic matrix component abundant in human lesions but almost absent in the widely-used C57BL/6 murine atherosclerosis model. The results of a bone marrow transplantation experiment suggested that both accelerated lesion development and versican accumulation are mediated, at least in part, by macrophages. Interestingly, comparative mapping revealed that the Athsq1 congenic interval contains the mouse region homologous to a widely-replicated CHD locus on human chromosome 9p21.


CONCLUSIONS
These studies confirm the proatherogenic activity of a novel gene(s) in the MOLF-derived Athsq1 locus and provide in vivo evidence for a causative role of versican in lesion development.
Seidelmann
Sara Bretschger
SB
Department of Medicine, Columbia University, New York, NY 10032, USA.
Kuo
Chaoling
C
Pleskac
Nick
N
Molina
Jennifer
J
Sayers
Scott
S
Li
Rong
R
Zhou
Jing
J
Johnson
Pamela
P
Braun
Kathleen
K
Chan
Christina
C
Teupser
Daniel
D
Breslow
Jan L
JL
Wight
Thomas N
TN
Tall
Alan R
AR
Welch
Carrie L
CL
D000818:Animals; D050197:Atherosclerosis / Q000209:etiology / Q000235:genetics* / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D004195:Disease Models, Animal; D005260:Female; D020022:Genetic Predisposition to Disease; D006720:Homozygote; D006801:Humans; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D040641:Quantitative Trait Loci; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D013045:Species Specificity; D053675:Versicans / Q000235:genetics / Q000378:metabolism*
D012333:RNA, Messenger; D011973:Receptors, LDL; C508323:Vcan protein, mouse; D053675:Versicans