Several potential limitations should be discussed regarding the current two studies. In genetic association studies, population stratification is often a concern. However, population stratification should be minimized in the NHS and HPFS because both cohorts are predominantly Caucasian, and similar results were observed when restricted to Caucasians only. Additionally, we recognize that the relative socioeconomic homogeneity of the cohorts does not represent random samples of U.S. men and women and may not be generalizeable to other populations. Though the homogeneity is unlikely to influence genetic predisposition, it may be a strength in reducing residual confounding from unmeasured factors related to socioeconomic status. Also, the distribution of cardiovascular risk factors such as smoking status and history of diabetes were different between the men and women, and may have mediated influences through CRP. Finally, chance may be an explanation for the statistically significant findings. Nevertheless, we included a replication study by examining both the NHS and HPFS, and the overall results were identical between the two independent populations.
