title: Genetic analysis of atherosclerosis identifies a major susceptibility locus in the major histocompatibility complex of mice.
abstract: Recent genome-wide association studies (GWAS) have identified over 50 significant loci containing common variants associated with coronary artery disease. However, these variants explain only 26% of the genetic heritability of the disease, suggesting that many more variants remain to be discovered. Here, we examined the genetic basis underlying the marked difference between SM/J-Apoe-/-and BALB/cJ-Apoe-/-mice in atherosclerotic lesion formation.
  
  
  
  206 female F2mice generated from an intercross between the two Apoe-/-strains were fed 12 weeks of western diet. Atherosclerotic lesion sizes in the aortic root were measured and 149 genetic markers genotyped across the entire genome.
  
  
  
  A significant locus, named Ath49 (LOD score: 4.18), for atherosclerosis was mapped to the H2 complex [mouse major histocompatibility complex (MHC)] on chromosome 17. Bioinformatic analysis identified 12 probable candidate genes, including Tnfrsf21, Adgrf1, Adgrf5, Mep1a, and Pla2g7. Corresponding human genomic regions of Ath49 showed significant association with coronary heart disease. Five suggestive loci on chromosomes 1, 4, 5, and 8 for atherosclerosis were also identified. Atherosclerotic lesion sizes were significantly correlated with HDL but not with non-HDL cholesterol, triglyceride or glucose levels in the F2cohort.
  
  
  
  We have identified the MHC as a major genetic determinant of atherosclerosis, highlighting the importance of inflammation in atherogenesis.
authors.affiliation: Department of Biochemistry & Molecular Genetics, University of Virginia, Charlottesville, VA, USA.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Grainger
authors.affiliation: Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA, USA.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Jones
authors.affiliation: Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA, USA.
authors.forename: Mei-Hua
authors.initials: MH
authors.lastname: Chen
authors.affiliation: Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
authors.forename: Ani
authors.initials: A
authors.lastname: Manichaikul
authors.affiliation: Department of Biochemistry & Molecular Genetics, University of Virginia, Charlottesville, VA, USA; Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA, USA. Electronic address: ws4v@virginia.edu.
authors.forename: Weibin
authors.initials: W
authors.lastname: Shi
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000175:diagnosis / Q000235:genetics*; D001786:Blood Glucose / Q000032:analysis; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D003433:Crosses, Genetic; D005260:Female; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D016678:Genome; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007249:Inflammation; D008055:Lipids / Q000097:blood; D008126:Lod Score; D008285:Major Histocompatibility Complex / Q000235:genetics*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D000074085:Mice, Knockout, ApoE
chemical_list: D001786:Blood Glucose; D008055:Lipids
keywords: Atherosclerosis; Major histocompatibility complex; Mice; Quantitative trait locus