Received on July 27, 2007
Accepted on November 5, 2007

Molecular Diagnostics and Genetics

Chromosome 9p21.3 Coronary Heart Disease Locus Genotype and Prospective Risk of CHD in Healthy Middle-Aged Men

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

^* To whom correspondence should be addressed. 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 (range 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 A_ROC for CRFs alone [0.62 (0.58–0.66)] did not increase significantly (P = 0.14) when rs10757274 A>G genotype was added [0.64 (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.