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Chromosome 9p21.3 coronary heart disease locus genotype and prospective risk of CHD in healthy middle-aged men

Talmud, PJ; Cooper, JA; Palmen, J; Lovering, R; Drenos, F; Hingorani, AD; Humphries, SE; (2008) Chromosome 9p21.3 coronary heart disease locus genotype and prospective risk of CHD in healthy middle-aged men. Clinical Chemistry , 54 (3) pp. 467-474. 10.1373/clinchem.2007.095489.

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Abstract

BACKGROUND: We investigated whether chromosome 9p21.3 single-nucleotide polymorphisms (SNPs), identified in coronary heart disease (CHD) genome-wide association scans, added significantly to the predictive utility for CHD of conventional risk factors (CRF) in the Framingham risk score (FRS) algorithm. METHODS: In the Northwick Park Heart Study II of 2742 men (270 CHD events occurring during a 15-year prospective study), rs10757274 A > G [mean frequency G = 0.48 (95% CI 0.47-0.50)] was genotyped. Using the area under the ROC curve (A ROC ) and the likelihood ratio (LR) statistic, we assessed the discriminatory performance of the FRS based on CRFs with and without genotype. RESULTS: rs10757274 A > G was associated with incident CHD, with an effect size as reported previously [hazard ratio in GG vs AA men of 1.60 (95% CI 1.12-2.28)], independent of CRFs and family history of CHD. Although the AROC for CRFs alone [0.62 (95% CI 0.58-0.66)] did not increase significantly (P = 0.14) when rs10757274 A > G genotype was added [0.64 (95% CI 0.60-0.68)], including genotype gave better fit (LR P = 0.01) and including rs10757274 moved 369 men (13.5% of the total) into more accurate risk categories. To model polygenic effects, 10 hypothetical, randomly assigned gene variants, with similar effect size and frequencies were added. Two variants made significant A ROC improvements to the FRS prediction (P = 0.01), whereas further variants had smaller incremental effects (final A ROC = 0.71, P < 0.001 vs CRFs; LR vs CRFs P < 0.0001). CONCLUSIONS: Although overall, rs10757274 did not add substantially to the usefulness of the FRS for predicting future events, it did improve reclassification of CHD risk, and thus may have clinical utility. © 2008 American Association for Clinical Chemistry.

Type: Article
Title: Chromosome 9p21.3 coronary heart disease locus genotype and prospective risk of CHD in healthy middle-aged men
DOI: 10.1373/clinchem.2007.095489
URI: http://discovery.ucl.ac.uk/id/eprint/83265
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