Altered Expression of Raet1e, an MHC Class 1-Like Molecule, Underlies the Atherosclerosis Modifier Locus Ath11 10b

Rationale: QTL 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 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 five 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 transgene-induced aortic over-expression 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 non-biased approach has revealed Raet1e , an MHC 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 QTL strategy in complex diseases.