title: Resequencing and clinical associations of the 9p21.3 region: a comprehensive investigation in the Framingham heart study.
abstract: BACKGROUND
  9p21.3 is among the most strongly replicated regions for cardiovascular disease. There are few reports of sequencing the associated 9p21.3 interval. We set out to sequence the 9p21.3 region followed by a comprehensive study of genetic associations with clinical and subclinical cardiovascular disease and its risk factors, as well as with copy number variation and gene expression, in the Framingham Heart Study (FHS).
  
  
  RESULTS
  We sequenced 281 individuals (94 with myocardial infarction, 94 with high coronary artery calcium levels, and 93 control subjects free of elevated coronary artery calcium or myocardial infarction), followed by genotyping and association in >7000 additional FHS individuals. We assessed genetic associations with clinical and subclinical cardiovascular disease, risk factor phenotypes, and gene expression levels of the protein-coding genes CDKN2A and CDKN2B and the noncoding gene ANRIL in freshly harvested leukocytes and platelets. Within this large sample, we found strong associations of 9p21.3 variants with increased risk for myocardial infarction, higher coronary artery calcium levels, and larger abdominal aorta diameters and no evidence for association with traditional cardiovascular disease risk factors. No common protein-coding variation, variants in splice donor or acceptor sites, or copy number variation events were observed. By contrast, strong associations were observed between genetic variants and gene expression, particularly for a short isoform of ANRIL and for CDKN2B.
  
  
  CONCLUSIONS
  Our thorough genomic characterization of 9p21.3 suggests common variants likely account for observed disease associations and provides further support for the hypothesis that complex regulatory variation affecting ANRIL and CDKN2B gene expression may contribute to increased risk for clinically apparent and subclinical coronary artery disease and aortic disease.
authors: National Institutes of Health/National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham, MA, USA.
authors: Andrew D
authors: AD
authors: Johnson
authors: Shih-Jen
authors: SJ
authors: Hwang
authors: Arend
authors: A
authors: Voorman
authors: Alanna
authors: A
authors: Morrison
authors: Gina M
authors: GM
authors: Peloso
authors: Yi-Hsiang
authors: YH
authors: Hsu
authors: George
authors: G
authors: Thanassoulis
authors: Christopher
authors: C
authors: Newton-Cheh
authors: Ian S
authors: IS
authors: Rogers
authors: Udo
authors: U
authors: Hoffmann
authors: Jane E
authors: JE
authors: Freedman
authors: Caroline S
authors: CS
authors: Fox
authors: Bruce M
authors: BM
authors: Psaty
authors: Eric
authors: E
authors: Boerwinkle
authors: L Adrienne
authors: LA
authors: Cupples
authors: Christopher J
authors: CJ
authors: O'Donnell
mesh_terms: D002114:Calcinosis / Q000235:genetics; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D003324:Coronary Artery Disease / Q000453:epidemiology / Q000235:genetics*; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D056915:DNA Copy Number Variations; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D005838:Genotype; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008404:Massachusetts / Q000453:epidemiology; D008875:Middle Aged; D009203:Myocardial Infarction / Q000453:epidemiology / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D062085:RNA, Long Noncoding / Q000235:genetics*; D012307:Risk Factors; D017422:Sequence Analysis, DNA
chemical_list: C561518:CDKN2B antisense RNA, human; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D062085:RNA, Long Noncoding