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

Title
Altered Expression of Raet1e, a Major Histocompatibility Complex Class 1-Like Molecule, Underlies the Atherosclerosis Modifier Locus Ath11 10b
Author
최재훈
Keywords
atherosclerosis; gene expression; genetic susceptibility; mice; mouse model; quantitative trait loci; GENOME-WIDE ASSOCIATION; CORONARY-ARTERY-DISEASE; QUANTITATIVE TRAIT LOCI; NKG2D LIGAND EXPRESSION; SUSCEPTIBILITY LOCUS; CELL-PROLIFERATION; LABORATORY MOUSE; NATURAL-KILLER; DEFICIENT MICE; T-CELLS
Issue Date
2013-10
Publisher
LIPPINCOTT WILLIAMS & WILKINS, 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA
Citation
CIRCULATION RESEARCH, 2013, 113(9), P.1054-1064
Abstract
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.
URI
http://circres.ahajournals.org/content/113/9/1054http://hdl.handle.net/20.500.11754/44869
ISSN
0009-7330; 1524-4571
DOI
10.1161/CIRCRESAHA.113.302052
Appears in Collections:
COLLEGE OF NATURAL SCIENCES[S](자연과학대학) > LIFE SCIENCE(생명과학과) > Articles
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