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Abstract
Although genetic variation at chromosome 9p21.3 is associated with incident cardiovascular disease, it is unclear whether screening for this polymorphism improves risk prediction. To determine whether knowledge of variation at chromosome 9p21.3 provides predictive information beyond that from other readily available risk factors. Prospective cohort study. United States. 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. Polymorphism at rs10757274 in chromosome 9p21.3 and additional cardiovascular disease risk factors (blood pressure, smoking status, diabetes, blood levels of cholesterol, high-sensitivity C-reactive protein, and family history of premature myocardial infarction). 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). Study participants were all white women. 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.
Highlights
The success of risk prediction models for cardiovascular disease (CVD) reflects an increasing understanding of the molecular basis of atherothrombosis
Polymorphism at rs10757274 was associated with an adjusted hazard ratio for incident CVD of 1.25 for the AG genotype and 1.32 for the GG genotype
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) nor showed improvement of the Net Reclassification Improvement (−0.2%, p=0.59) or the Integrated Discrimination Improvement (0.0, p=0.18)
Summary
The success of risk prediction models for cardiovascular disease (CVD) reflects an increasing understanding of the molecular basis of atherothrombosis. Genetic variation at the chromosome 9p21.3 region is a good candidate for adding additional information to risk prediction. Variation at this locus has consistently been found to have an association with coronary artery disease[3,4,5] as well as diabetes.[6,7,8,9] the risk allele is carried by almost 75% of the Caucasian population, and the lack of correlation between any of the disease-associated 9p21.3 genetic variants and major cardiovascular risk factors suggests novel influences on disease progression. To assess whether knowledge of variation at 9p21.3 improves global risk prediction, we examined the effect of adding genetic information from a single nucleotide polymorphism (SNP) in the 9p21.3 region to previously published prediction models in the Women's Health Study, a large, prospective cohort of initially healthy American women followed over a 10 year period for incident cardiovascular events
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