Altered Expression of Raet1e , a Major Histocompatibility Complex Class 1–Like Molecule, Underlies the Atherosclerosis Modifier Locus Ath11 10b

Rationale : 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.