Altered expression of Raet1e, a major histocompatibility complex class 1-like molecule, underlies the atherosclerosis modifier locus Ath11 10b.
BACKGROUND
Quantitative trait locus mapping of an intercross between C57.Apoe⁻/⁻ and FVB.Apoe⁻/⁻ mice revealed an atherosclerosis locus controlling aortic root lesion area on proximal chromosome 10, Ath11. In a previous work, subcongenic analysis showed Ath11 to be complex with proximal (10a) and distal (10b) regions.


OBJECTIVE
To identify the causative genetic variation underlying the atherosclerosis modifier locus Ath11 10b.


RESULTS
We now report subcongenic J, which narrows the 10b region to 5 genes, Myb, Hbs1L, Aldh8a1, Sgk1, and Raet1e. Sequence analysis of these genes revealed no amino acid coding differences between the parental strains. However, comparing aortic expression of these genes between F1.Apoe⁻/⁻ Chr10SubJ((B/F)) and F1.Apoe⁻/⁻ Chr10SubJ((F/F)) uncovered a consistent difference only for Raet1e, with decreased, virtually background, expression associated with increased atherosclerosis in the latter. The key role of Raet1e was confirmed by showing that transgene-induced aortic overexpression of Raet1e in F1.Apoe⁻/⁻ Chr10SubJ((F/F)) mice decreased atherosclerosis. Promoter reporter constructs comparing C57 and FVB sequences identified an FVB mutation in the core of the major aortic transcription start site abrogating activity.


CONCLUSIONS
This nonbiased approach has revealed Raet1e, a major histocompatibility complex class 1-like molecule expressed in lesional aortic endothelial cells and macrophage-rich regions, as a novel atherosclerosis gene and represents one of the few successes of the quantitative trait locus strategy in complex diseases.
From the Laboratory of Biochemical Genetics and Metabolism.
José M
JM
Rodríguez
Susanne
S
Wolfrum
Megan
M
Robblee
Kwan Y
KY
Chen
Zachary N
ZN
Gilbert
Jae-Hoon
JH
Choi
Daniel
D
Teupser
Jan L
JL
Breslow
D000818:Animals; D001011:Aorta / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001018:Aortic Diseases / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D033481:Chromosomes, Mammalian; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D010641:Phenotype; D011401:Promoter Regions, Genetic; D040641:Quantitative Trait Loci; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D013045:Species Specificity
D001057:Apolipoproteins E; D008565:Membrane Proteins; C584972:Raet1e protein, mouse; D011973:Receptors, LDL
atherosclerosis; gene expression; genetic susceptibility; mice; mouse model; quantitative trait loci