title: Characterization of Ath29, a major mouse atherosclerosis susceptibility locus, and identification of Rcn2 as a novel regulator of cytokine expression.
abstract: Ath29 is an atherosclerosis susceptibility locus on chromosome 9 identified in an intercross between C57BL/6 (B6) and C3H/HeJ (C3H) apolipoprotein E-deficient (apoE(-/-)) mice. This locus was subsequently replicated in two separate intercrosses that developed early or advanced atherosclerotic lesions. The objective of this study was to characterize Ath29 through construction and analysis of a congenic strain and identify underlying candidate genes. A congenic line was constructed by introgressing the chromosomal segment harboring Ath29 from C3H.apoE(-/-) into B6.apoE(-/-) mice. Congenic mice developed significantly smaller early and advance atherosclerotic lesions than B6.apoE(-/-) mice. Microarray analysis revealed 317 genes to be differentially expressed in the aorta of congenic mice compared with B6.apoE(-/-) mice. Pathway analysis of these genes suggested the Ca(2+) signaling pathway to be implicated in regulating atherosclerosis susceptibility. Rcn2 is located underneath the linkage peak of Ath29 and involved in Ca(2+) signaling. Multiple single-nucleotide polymorphisms between B6 and C3H mice were detected within and surrounding Rcn2 with one single-nucleotide polymorphism falling within an upstream cAMP response element. Immunostaining demonstrated its expression in atherosclerotic lesions. Knockdown of Rcn2 with small interfering RNAs resulted in significant reductions in both baseline and oxidized phospholipid-induced VCAM-1 and monocyte chemoattractant protein-1 expression by endothelial cells. Ath29 is confirmed to be a major atherosclerosis susceptibility locus affecting both early and advanced lesion formation in mice, and Rcn2 is identified as a novel regulator of cytokine expression.
authors.affiliation: Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia 22908, USA.
authors.forename: Ani
authors.initials: A
authors.lastname: Manichaikul
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.forename: Yu Lena
authors.initials: YL
authors.lastname: Shi
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Zhang
authors.forename: Norbert
authors.initials: N
authors.lastname: Leitinger
authors.forename: Weibin
authors.initials: W
authors.lastname: Shi
mesh_terms: D000818:Animals; D001018:Aortic Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism*; D020869:Gene Expression Profiling / Q000379:methods; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D051379:Mice; D020297:Mice, Congenic; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D010084:Oxidation-Reduction; D010641:Phenotype; D010743:Phospholipids / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D034622:RNA Interference; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D002135:Calcium-Binding Proteins; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D010743:Phospholipids; C562051:Rcn2 protein, mouse; D019010:Vascular Cell Adhesion Molecule-1