title: Quantitative trait loci affecting atherosclerosis at the aortic root identified in an intercross between DBA2J and 129S6 apolipoprotein E-null mice.
abstract: Apolipoprotein E-null mice on a DBA/2J genetic background (DBA-apoE) are highly susceptible to atherosclerosis in the aortic root area compared with those on a 129S6 background (129-apoE). To explore atherosclerosis-responsible genetic regions, we performed a quantitative trait locus (QTL) analysis using 172 male and 137 female F2 derived from an intercross between DBA-apoE and 129-apoE mice. A genome-wide scan identified two significant QTL for the size of lesions at the root: one is Ath44 on Chromosome (Chr) 1 at 158 Mb, and the other Ath45 on Chr 2 at 162 Mb. Ath44 co-localizes with but appears to be independent of a previously reported QTL, Ath1, while Ath45 is a novel QTL. DBA alleles of both Ath44 and Ath45 confer atherosclerosis-susceptibility. In addition, a QTL on Chr 14 at 73 Mb was found significant only in males, and 129 allele conferring susceptibility. Further analysis detected female-specific interactions between a second QTL on Chr 1 at 73 Mb and a QTL on Chr 3 at 21 Mb, and between Chr 7 at 84 Mb and Chr 12 at 77 Mb. These loci for the root atherosclerosis were independent of QTLs for plasma total cholesterol and QTLs for triglycerides, but a QTL for HDL (Chr 1 at 126 Mb) overlapped with the Ath44. Notably, haplotype analysis among 129S6, DBA/2J and C57BL/6 genomes and their gene expression data narrowed the candidate regions for Ath44 and Ath45 to less than 5 Mb intervals where multiple genome wide associations with cardiovascular phenotypes have also been reported in humans. SNPs in or near Fmo3, Sele and Selp for Ath44, and Lbp and Pkig for Ath45 were suggested for further investigation as potential candidates underlying the atherosclerosis susceptibility.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Yukako
authors.initials: Y
authors.lastname: Kayashima
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Tomita
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Zhilicheva
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Shinja
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Hyung-Suk
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Bennett
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Nobuyo
authors.initials: N
authors.lastname: Maeda
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001011:Aorta / Q000473:pathology*; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000235:genetics* / Q000473:pathology; D002874:Chromosome Mapping; D003433:Crosses, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D046228:Microarray Analysis; D018895:Microsatellite Repeats / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics*; D012737:Sex Factors
chemical_list: D001057:Apolipoproteins E