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

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 A(ROC) 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.