Cardiovascular Disease Risk Prediction With and Without Knowledge of Genetic Variation at Chromosome 9p21.3

Background: Although genetic variation at chromosome 9p21.3 is associated with incident cardiovascular disease, it is unclear whether screening for this polymorphism improves risk prediction. Objective: To determine whether knowledge of variation at chromosome 9p21.3 provides predictive information beyond that from other readily available risk factors. Design: Prospective cohort study. Setting: United States. Patients: 22 129 female white health professionals participating in the Women's Genome Health Study, initially without any major chronic disease, who were prospectively followed over a median of 10.2 years for incident cardiovascular disease. Measurements: Polymorphism at rs10757274 in chromosome 9p21.3 and additional cardiovascular disease risk factors (blood pressure, smoking status, diabetes, blood levels of cholesterol, highsensitivity C-reactive protein, and family history of premature myocardial infarction). Results: Polymorphism at rs10757274 was associated with an adjusted hazard ratio for incident cardiovascular disease of 1.25 (95% CI, 1.04 to 1.51) for the AG genotype and 1.32 (CI, 1.07 to 1.63) for the GG genotype. However, the addition of the genotype to a prediction model based on traditional risk factors, high-sensitivity C-reactive protein, and family history of premature myocardial infarction had no effect on model discrimination as measured by the c-index (0.807 to 0.809) and did not improve the Net Reclassification Improvement score (-0.2%; P = 0.59) or the Integrated Discrimination Improvement score (0.0; P = 0.18). Limitation: Study participants were all white women. Conclusion: In this large prospective cohort of white women, genetic variation in chromosome 9p21.3 was associated with incident cardiovascular disease but did not improve on the discrimination or classification of predicted risk achieved with traditional risk factors, high-sensitivity C-reactive protein, and family history of premature myocardial infarction.