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Lipids, Lipoproteins, and Cardiovascular Risk Factors |
1 Centre for Cardiovascular Genetics, Department of Medicine, University College London, London;2 HUGO Gene Nomenclature Committee (HGNC), Department of Biology, University College London, London;3 Centre for Clinical Pharmacology, Department of Medicine, University College London, London, UK.
aAddress correspondence to this author at Centre for Cardiovascular Genetics, Department of Medicine, Rayne Building, University College London, 5 University St., London WC1E 6JF, UK. Fax 0107 679 6212; e-mail rmhaseh{at}ucl.ac.uk.
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 (AROC) 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 AROC improvements to the FRS prediction (P = 0.01), whereas further variants had smaller incremental effects (final AROC = 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.
The following articles in journals at HighWire Press have cited this article:
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  A. Brautbar, C. M. Ballantyne, K. Lawson, V. Nambi, L. Chambless, A. R. Folsom, J. T. Willerson, and E. Boerwinkle Impact of Adding a Single Allele in the 9p21 Locus to Traditional Risk Factors on Reclassification of Coronary Heart Disease Risk and Implications for Lipid-Modifying Therapy in the Atherosclerosis Risk in Communities Study Circ Cardiovasc Genet, June 1, 2009; 2(3): 279 - 285. [Abstract] [Full Text] [PDF]
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 J. Gulcher and K. Stefansson Questions About Genetic Variation in 9p21 as a Predictor of Cardiovascular Risk Ann Intern Med, May 19, 2009; 150(10): 736 - 736. [Full Text] [PDF]
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J. P.A. Ioannidis Prediction of Cardiovascular Disease Outcomes and Established Cardiovascular Risk Factors by Genome-Wide Association Markers Circ Cardiovasc Genet, February 1, 2009; 2(1): 7 - 15. [Abstract] [Full Text] [PDF]
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N. P. Paynter, D. I. Chasman, J. E. Buring, D. Shiffman, N. R. Cook, and P. M. Ridker Cardiovascular Disease Risk Prediction With and Without Knowledge of Genetic Variation at Chromosome 9p21.3 Ann Intern Med, January 20, 2009; 150(2): 65 - 72. [Abstract] [Full Text] [PDF]
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 J. Emmerich and P. M Ridker Can Fishing for New Genes Catch Patients at Risk of Coronary Artery Disease? Clin. Chem., March 1, 2008; 54(3): 453 - 455. [Full Text] [PDF]
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