03716nas a2200577 4500008004100000022001400041245012600055210006900181260001600250300001200266490000800278520196800286653001502254653003102269653002802300653004202328653004202370653003102412653001102443653002202454653003802476653001302514653001102527653002502538653000902563653001802572653001602590653002602606653001402632653003602646653001702682653002402699653002702723100002302750700002002773700001902793700002102812700002002833700001902853700002502872700002902897700001902926700001802945700002202963700002102985700002003006700002103026700002503047700003003072856003603102 2013 eng d a1524-453900aResequencing and clinical associations of the 9p21.3 region: a comprehensive investigation in the Framingham heart study.0 aResequencing and clinical associations of the 9p213 region a com c2013 Feb 19 a799-8100 v1273 a
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).
METHODS AND 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.
10aCalcinosis10aChromosomes, Human, Pair 910aCoronary Artery Disease10aCyclin-Dependent Kinase Inhibitor p1510aCyclin-Dependent Kinase Inhibitor p1610aDNA Copy Number Variations10aFemale10aFollow-Up Studies10aGenetic Predisposition to Disease10aGenotype10aHumans10aLongitudinal Studies10aMale10aMassachusetts10aMiddle Aged10aMyocardial Infarction10aPhenotype10aPolymorphism, Single Nucleotide10aRisk Factors10aRNA, Long Noncoding10aSequence Analysis, DNA1 aJohnson, Andrew, D1 aHwang, Shih-Jen1 aVoorman, Arend1 aMorrison, Alanna1 aPeloso, Gina, M1 aHsu, Yi-Hsiang1 aThanassoulis, George1 aNewton-Cheh, Christopher1 aRogers, Ian, S1 aHoffmann, Udo1 aFreedman, Jane, E1 aFox, Caroline, S1 aPsaty, Bruce, M1 aBoerwinkle, Eric1 aCupples, Adrienne, L1 aO'Donnell, Christopher, J uhttps://chs-nhlbi.org/node/6074