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

Abstract

Background While genetic variation at chromosome 9p21.3 is associated with incident cardiovascular disease (CVD), 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 Caucasian health professionals participating in the Women's Genome Health Study, initially free of any major chronic disease, who were prospectively followed over a median of 10.2 years for incident CVD. Measurements Polymorphism at rs10757274 in chromosome 9p21.3 and additional CVD risk factors (blood pressure, smoking status, diabetes, blood levels of cholesterol, high-sensitivity C-reactive protein, and family history of premature myocardial infarction). Results Polymorphism at rs10757274 was associated with an adjusted hazard ratio for incident CVD of 1.25 (95% CI 1.04 − 1.51) for the AG genotype and 1.32 (95% CI 1.07 − 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) nor showed improvement of the Net Reclassification Improvement (−0.2%, p=0.59) or the Integrated Discrimination Improvement (0.0, p=0.18). Limitations Results are limited to Caucasian women. Conclusions In this large prospective cohort of Caucasian women, genetic variation in chromosome 9p21.3 was associated with incident CVD 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.

Genetic profiling and individualized prognosis of fracture

“…(41) Empirically, it has been shown that the incorporation of genes did not result in an appreciable increase in the accuracy of the prognosis of type 2 diabetes (42) and cardiovascular diseases, (39,40) which suggests that common genetic variants have a minimal effect on the prognosis of these diseases. However, the mentioned work assessed the incremental prognostic value based on the AUC rather than the reclassification analysis as in our work.…”

The family history: the first genetic test, and still useful after all those years?

“…Naturally, the question was then posed as to the relative importance of this one marker in clinical risk prediction. In both a prospective cohort study of white women 49 and a meta-analysis of possible clinical utility, 50 knowledge of the 9p21 genotype added little or nothing to traditional risk factor assessment. The Evaluation of Genomic Applications in Practice and Prevention Working Group recently evaluated 9p21 and 57 other genetic variants linked by GWAS to coronary artery disease and "… found that the magnitude of net health benefit from use of any of these tests alone or in combination is negligible. "…”

The genetics of cardiovascular disease: new insights from emerging approaches

“…The association of the 9p21.3 locus with conditions such as dementia [33] and stroke [34] may indicate a role in a common mechanism of disease, rather than specifically CAD. Incorporation of 9p21.3 and other risk-conferring alleles into a CAD prediction algorithm still performs worse than current models, based on clinical parameters [35], or provide no additional benefit [36], despite the availability of 9p21.3 genotyping via the internet. The 9p21.3 locus, although undoubtedly hugely exciting, remains therefore to be substantiated in terms of its true importance.…”