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.
- animal model cardiovascular disease
- gene expression/regulation
- genetics, rat/mouse
- Received June 21, 2013.
- Revision received August 12, 2013.
- Accepted August 15, 2013.