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lüll Altered expression of Raet1e, a major histocompatibility complex class 1-like molecule, underlies the atherosclerosis modifier locus Ath11 10b Rodriguez JM; Wolfrum S; Robblee M; Chen KY; Gilbert ZN; Choi JH; Teupser D; Breslow JLCirc Res 2013[Oct]; 113 (9): 1054-64RATIONALE: 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. METHODS AND 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.|*Chromosomes, Mammalian[MESH]|*Quantitative Trait Loci[MESH]|Animals[MESH]|Aorta/immunology/metabolism/pathology[MESH]|Aortic Diseases/*genetics/immunology/metabolism/pathology[MESH]|Apolipoproteins E/genetics/metabolism[MESH]|Atherosclerosis/*genetics/immunology/metabolism/pathology[MESH]|Crosses, Genetic[MESH]|Disease Models, Animal[MESH]|Endothelial Cells/immunology/metabolism[MESH]|Female[MESH]|Gene Expression Regulation[MESH]|Genetic Predisposition to Disease[MESH]|Macrophages/immunology/metabolism[MESH]|Male[MESH]|Membrane Proteins/*genetics/metabolism[MESH]|Mice[MESH]|Mice, Inbred BALB C[MESH]|Mice, Inbred C57BL[MESH]|Mice, Knockout[MESH]|Mice, Transgenic[MESH]|Mutation[MESH]|Phenotype[MESH]|Promoter Regions, Genetic[MESH]|Receptors, LDL/genetics/metabolism[MESH]|Species Specificity[MESH] |