In our genetic substudy of DREAM, we observed an increase in edema among individuals who received rosiglitazone (n = 390 [22.3%]) versus placebo (n = 256 [14.5%]). Among the Europeans, 253 (26.2%) individuals receiving rosiglitazone experienced edema compared with 154 (16.1%) receiving placebo (P = 8.63 × 10−7) (supplementary Table 1). The clinical characteristics of the Europeans were not significantly different between the rosiglitazone and placebo arms (supplementary Table 2).
We tested 32,088 SNPs against edema in the Europeans receiving rosiglitazone. One SNP, rs6123045, in the nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 2 (NFATC2) gene was significantly associated with edema (odds ratio [OR] 1.89 [95% CI 1.47–2.42]; P = 5.32 × 10−7, corrected P = 0.017) (A). The distribution of the observed versus the expected P values is shown in supplementary Fig. 1. We detected a significant interaction between rs6123045 and rosiglitazone treatment for edema in Europeans (P = 7.68 × 10−3). The effect of rs6123045, although in the same direction, was not significantly associated with edema in the placebo group (OR 1.16, P = 0.29) (B).
Figure 1 A: Results of the association analysis between SNPs and TZD-induced peripheral edema at the NFATC2 locus. The −log of the P values are plotted against SNP location. P values were calculated from a logistic regression analysis adjusted for age, (more ...)
A Cox proportional hazards analysis revealed that individuals homozygous for the risk allele had a decrease in the time to the first report of edema in comparison with individuals heterozygous or homozygous for the protective allele (HR 1.76, P = 3.43 × 10−5 and HR 2.89, P = 4.22 × 10−4, respectively) (B). The effect appears to be additive because heterozygous individuals had an increased rate of edema compared with homozygous individuals (HR 1.64, P = 0.11).
Among Europeans receiving rosiglitazone, rs6123045 was not significantly associated with diabetes or death or with cardiovascular end points, including CHF, myocardial infarction, stroke, angina, or a composite of these outcomes (data not shown).
rs6123045 was not significantly associated with TZD-induced edema in Latin Americans. However, six SNPs in NFATC2 were significant in both Europeans and Latin Americans (A). A haplotype defined by these SNPs is significant in both populations (OR 0.45 [95% CI 0.30–0.66]; P = 2.26 × 10−5 and OR 0.34 [95% CI 0.13–0.90]; P = 1.47 × 10−2 in Europeans and Latin Americans, respectively) (data not shown). All significantly associated SNPs were in Hardy-Weinberg equilibrium (P > 0.05).