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

作者：Rodriguez Jose M; Wolfrum Susanne; Robblee Megan; Chen Kwan Y; Gilbert Zachary N; Choi Jae Hoon; Teupser Daniel; Breslow Jan L^*

来源：Circulation Research, 2013, 113(9): 1054-1064.

DOI：10.1161/CIRCRESAHA.113.302052

• atherosclerosis
• gene expression
• genetic susceptibility
• mice
• mouse model
• quantitative trait loci

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. %26lt;br%26gt;Objective: To identify the causative genetic variation underlying the atherosclerosis modifier locus Ath11 10b. %26lt;br%26gt;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. %26lt;br%26gt;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.

• 出版日期2013-10-12