Questions About Genetic Variation in 9p21 as a Predictor of Cardiovascular Risk

IN RESPONSE:

We appreciate the interest in our article and the opportunity to address readers' questions.

Drs. Gulcher and Stefannson bring up the distribution of risk in the study population. Although it is correct that the overall risk in our population is low, other variables have improved prediction in this cohort (1). We do not believe that examining the utility of 9p21 genotype in risk classification of a higher-risk population would necessarily show different results, and we look forward to analyses done in different cohorts. Unfortunately, neither of the studies cited by Drs. Gulcher and Stefannson have examined whether the reclassification was more accurate, which we feel is more important than the total number reclassified. Drs. Gulcher and Steffannson also question the utility of the NRI, given the small number of events in each cell. However, the NRI does not look at each cell individually—instead, it examines whether cases in aggregate are reclassified into higher predicted probability cells more often than into lower cells and whether control participants in aggregate are reclassified into lower cells more often than higher cells. Therefore, we feel the use of the NRI is quite appropriate and not underpowered.

Dr. Kiljanek brings up the concern that the performance of the genetic marker is reduced by the inclusion of CRP and family history of premature myocardial infarction in the prediction score. As shown in Table 3 of our article, the relative hazard for the genetic effect does not change with the addition of CRP and family history. When reclassification is assessed by using the traditional covariates alone, which do not include either CRP or family history, the improvement shown with the genetic variant is modest at best. Because the 9p21 variant is not associated with CRP (as shown in Table 1 of our article), the reduction of the genetic effect from modest to none is largely the result of the inclusion of family history. Our results suggest that, compared with variation at 9p21, a simple question about premature parental myocardial infarction is just as good, if not better, at classifying future risk for cardiovascular disease.

Dr. Schwarzenbach raises the question of an interaction between 9p21 or KIF6 genotype and statin therapy response. We agree that this is an important question and, although we cannot examine it directly in the Women's Genome Health Study, we look forward to additional articles on the subject from other groups.