title: The cis and trans effects of the risk variants of coronary artery disease in the Chr9p21 region.
abstract: BACKGROUND
  Recent genome-wide association studies (GWAS) have shown that single nucleotide polymorphisms (SNPs) in the Chr9p21 region are associated with coronary artery disease (CAD). Most of the SNPs identified in this region are non-coding SNPs, suggesting that they may influence gene expression by cis or trans mechanisms to affect disease susceptibility. Since all cells from an individual have the same DNA sequence variations, levels of gene expression in immortalized cell lines can reflect the functional effects of DNA sequence variations that influence or regulate gene expression. The objective of this study is to evaluate the functional consequences of the risk variants in the Chr9p21 region on gene expression.
  
  
  METHODS
  We examined the association between the variants in the Chr9p21 region and the transcript-level mRNA expression of the adjacent genes (cis) as well as all other genes across the whole genome (trans) from transformed beta-lymphocytes in 801 non-Hispanic white participants from The Genetic Epidemiology Network of Arteriopathy (GENOA) study.
  
  
  RESULTS
  We found that the CAD risk variants in the Chr9p21 region were significantly associated with the mRNA expression of the ANRIL transcript ENST00000428597 (p = 8.58e-06). Importantly, a few distant transcripts were also found to be associated with the variants in this region, including the well-known CAD risk gene ABCA1 (p = 1.01e-05). Gene enrichment testing suggests that retinol metabolism, N-Glycan biosynthesis, and TGF signaling pathways may be involved.
  
  
  CONCLUSIONS
  These results suggest that the effect of risk variants in the Chr9p21 region on susceptibility to CAD is likely to be mediated through both cis and trans mechanisms.
authors.affiliation: Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA. zhaowei@umich.edu.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA. smjenn@umich.edu.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Smith
authors.affiliation: Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA. maogm@umich.edu.
authors.forename: Guangmei
authors.initials: G
authors.lastname: Mao
authors.affiliation: Institute of Molecular Medicine and Human Genetics Center, University of Texas Health Science Center, Houston, TX, USA. Myriam.Fornage@uth.tmc.edu.
authors.forename: Myriam
authors.initials: M
authors.lastname: Fornage
authors.affiliation: Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA. ppeyser@umich.edu.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Peyser
authors.affiliation: Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA. yan.v.sun@emory.edu.
authors.forename: Yan V
authors.initials: YV
authors.lastname: Sun
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN, USA. sturner@mayo.edu.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Turner
authors.affiliation: Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA. skardia@umich.edu.
authors.forename: Sharon L R
authors.initials: SL
authors.lastname: Kardia
mesh_terms: D000368:Aged; D002899:Chromosomes, Human, Pair 9 / Q000648:ultrastructure*; D003324:Coronary Artery Disease / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006801:Humans; D008214:Lymphocytes / Q000166:cytology; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D011786:Quality Control; D012333:RNA, Messenger / Q000378:metabolism; D017422:Sequence Analysis, DNA
chemical_list: D012333:RNA, Messenger