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Resequencing and clinical associations of the 9p21.3 region: a comprehensive investigation in the Framingham heart study.
Monday,2013-09-30 17:26 America/Los_Angeles — poolea2
| Title | Resequencing and clinical associations of the 9p21.3 region: a comprehensive investigation in the Framingham heart study. |
| Publication Type | Journal Article |
| Year of Publication | 2013 |
| Authors | Johnson, AD, Hwang, S-J, Voorman, A, Morrison, A, Peloso, GM, Hsu, Y-H, Thanassoulis, G, Newton-Cheh, C, Rogers, IS, Hoffmann, U, Freedman, JE, Fox, CS, Psaty, BM, Boerwinkle, E, Cupples, AL, O'Donnell, CJ |
| Journal | Circulation |
| Volume | 127 |
| Issue | 7 |
| Pagination | 799-810 |
| Date Published | 2013 Feb 19 |
| ISSN | 1524-4539 |
| Keywords | Calcinosis, Chromosomes, Human, Pair 9, Coronary Artery Disease, Cyclin-Dependent Kinase Inhibitor p15, Cyclin-Dependent Kinase Inhibitor p16, DNA Copy Number Variations, Female, Follow-Up Studies, Genetic Predisposition to Disease, Genotype, Humans, Longitudinal Studies, Male, Massachusetts, Middle Aged, Myocardial Infarction, Phenotype, Polymorphism, Single Nucleotide, Risk Factors, RNA, Long Noncoding, Sequence Analysis, DNA |
| Abstract | <p><b>BACKGROUND: </b>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).</p><p><b>METHODS AND RESULTS: </b>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.</p><p><b>CONCLUSIONS: </b>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.</p> |
| DOI | 10.1161/CIRCULATIONAHA.112.111559 |
| Alternate Journal | Circulation |
| PubMed ID | 23315372 |
| PubMed Central ID | PMC3686634 |
| Grant List | N01HC55020 / HL / NHLBI NIH HHS / United States N01-HC-25195 / HC / NHLBI NIH HHS / United States RC2 HL102419 / HL / NHLBI NIH HHS / United States UL1TR000124 / TR / NCATS NIH HHS / United States R01-HL-086694 / HL / NHLBI NIH HHS / United States N01HC55018 / HL / NHLBI NIH HHS / United States UL1 RR025005 / RR / NCRR NIH HHS / United States UL1-RR-025005 / RR / NCRR NIH HHS / United States R01 AG015928 / AG / NIA NIH HHS / United States U01 HL080295 / HL / NHLBI NIH HHS / United States N01-HC-55022 / HC / NHLBI NIH HHS / United States T32 HL076136 / HL / NHLBI NIH HHS / United States R01 HL059367 / HL / NHLBI NIH HHS / United States HL105756 / HL / NHLBI NIH HHS / United States R01-HL-087641 / HL / NHLBI NIH HHS / United States N01-HV-48194 / HV / NHLBI NIH HHS / United States N01 HC015103 / HC / NHLBI NIH HHS / United States 1T32HL076136 / HL / NHLBI NIH HHS / United States N01-HC-55016 / HC / NHLBI NIH HHS / United States R56 AG020098 / AG / NIA NIH HHS / United States N01 HC025195 / HC / NHLBI NIH HHS / United States R01 HL086694 / HL / NHLBI NIH HHS / United States U54 HL112311 / HL / NHLBI NIH HHS / United States R01 HL087652 / HL / NHLBI NIH HHS / United States AG-20098 / AG / NIA NIH HHS / United States HHSN268200625226C / / PHS HHS / United States U01 HG004402 / HG / NHGRI NIH HHS / United States N01HC55022 / HL / NHLBI NIH HHS / United States HL087652 / HL / NHLBI NIH HHS / United States UL1 TR000124 / TR / NCATS NIH HHS / United States N01HC55222 / HL / NHLBI NIH HHS / United States N01-HC-55021 / HC / NHLBI NIH HHS / United States N01-HC-85086 / HC / NHLBI NIH HHS / United States N01HC55015 / HL / NHLBI NIH HHS / United States N01HC85086 / HL / NHLBI NIH HHS / United States R01 HL105756 / HL / NHLBI NIH HHS / United States AG-027058 / AG / NIA NIH HHS / United States R01-HL-59367 / HL / NHLBI NIH HHS / United States N01 HC055019 / HC / NHLBI NIH HHS / United States P30 DK063491 / DK / NIDDK NIH HHS / United States N01 HC-55222 / HC / NHLBI NIH HHS / United States N01-HC-55019 / HC / NHLBI NIH HHS / United States HHSN268201200036C / HL / NHLBI NIH HHS / United States N01-HC-55015 / HC / NHLBI NIH HHS / United States N01-HC-75150 / HC / NHLBI NIH HHS / United States N01-HC-55020 / HC / NHLBI NIH HHS / United States N01HC55016 / HL / NHLBI NIH HHS / United States R01 HL080295 / HL / NHLBI NIH HHS / United States R01 AG020098 / AG / NIA NIH HHS / United States N01HC55019 / HL / NHLBI NIH HHS / United States N01HC75150 / HL / NHLBI NIH HHS / United States R21-AR056405 / AR / NIAMS NIH HHS / United States N01HC25195 / HL / NHLBI NIH HHS / United States Z99 HL999999 / / Intramural NIH HHS / United States DK063491 / DK / NIDDK NIH HHS / United States N01-HC-85079 / HC / NHLBI NIH HHS / United States K24 HL113128 / HL / NHLBI NIH HHS / United States HHSN268201200036C / / PHS HHS / United States HL080295 / HL / NHLBI NIH HHS / United States RC2-HL02419 / HL / NHLBI NIH HHS / United States N01-HC-85239 / HC / NHLBI NIH HHS / United States AG-023629 / AG / NIA NIH HHS / United States R21 AR056405 / AR / NIAMS NIH HHS / United States N01HC85079 / HL / NHLBI NIH HHS / United States N01-HC-55018 / HC / NHLBI NIH HHS / United States N01HC55021 / HL / NHLBI NIH HHS / United States R01 AG023629 / AG / NIA NIH HHS / United States R01 HL087641 / HL / NHLBI NIH HHS / United States U01-HG-004402 / HG / NHGRI NIH HHS / United States R01 AG027058 / AG / NIA NIH HHS / United States N01 HC045133 / HC / NHLBI NIH HHS / United States N01 HC035129 / HC / NHLBI NIH HHS / United States R56 AG023629 / AG / NIA NIH HHS / United States N01 HC055016 / HC / NHLBI NIH HHS / United States N01HV48194 / HL / NHLBI NIH HHS / United States |