title: Association of genetic risk variants with expression of proximal genes identifies novel susceptibility genes for cardiovascular disease.
abstract: BACKGROUND
  Population-based genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) associated with cardiovascular disease or its risk factors. Genes in close proximity to these risk-SNPs are often thought to be pathogenetically important based on their location alone. However, the actual connections between SNPs and disease mechanisms remain largely unknown.
  
  
  RESULTS
  To identify novel susceptibility genes, we investigated how 166 SNPs previously found to be associated with increased cardiovascular risk and/or predisposing metabolic traits relate to the expression of nearby genes. Gene expression in 577 samples of aorta, liver, mammary artery, and carotid atherosclerotic plaque was measured using expression arrays. For 47 SNPs, the expression levels of proximal genes (located within 200 kb) were affected (P<0.005). More than 20 of these genes had not previously been identified as candidate genes for cardiovascular or related metabolic traits. SNP-associated gene effects were tissue-specific and the tissue specificity was phenotype-dependent.
  
  
  CONCLUSIONS
  This study demonstrates several instances of association between risk-SNPs and genes immediately adjacent to them. It also demonstrates instances in which the associated gene is not the immediately proximal and obvious candidate gene for disease. This shows the necessity of careful studies of genetic marker data as a first step toward application of genome-wide association studies findings in a clinical setting.
authors.affiliation: Atherosclerosis Research Unit, Experimental Cardiovascular Research Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Lasse
authors.initials: L
authors.lastname: Folkersen
authors.forename: Ferdinand
authors.initials: F
authors.lastname: van't Hooft
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Chernogubova
authors.forename: Hanna E
authors.initials: HE
authors.lastname: Agardh
authors.forename: Göran K
authors.initials: GK
authors.lastname: Hansson
authors.forename: Ulf
authors.initials: U
authors.lastname: Hedin
authors.forename: Jan
authors.initials: J
authors.lastname: Liska
authors.forename: Ann-Christine
authors.initials: AC
authors.lastname: Syvänen
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Paulsson-Berne
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Paulssson-Berne
authors.forename: Anders
authors.initials: A
authors.lastname: Franco-Cereceda
authors.forename: Anders
authors.initials: A
authors.lastname: Hamsten
authors.forename: Anders
authors.initials: A
authors.lastname: Gabrielsen
authors.forename: Per
authors.initials: P
authors.lastname: Eriksson
mesh_terms: D000368:Aged; D002318:Cardiovascular Diseases / Q000235:genetics*; D005260:Female; D005796:Genes; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D012306:Risk