Variation at the NFATC2 Locus Increases the Risk of Thiazolidinedione-Induced Edema in the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) Study

OBJECTIVE: Thiazolidinediones are used to treat type 2 diabetes. Their use has been associated with peripheral edema and congestive heart failure-outcomes that may have a genetic etiology. RESEARCH DESIGN AND METHODS: We genotyped 4,197 participants of the multiethnic DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) trial with a 50k single nucleotide polymorphisms (SNP) array, which captures ∼2000 cardiovascular, inflammatory, and metabolic genes. We tested 32,088 SNPs for an association with edema among Europeans who received rosiglitazone (n = 965). RESULTS: One SNP, rs6123045, in NFATC2 was significantly associated with edema (odds ratio 1.89 [95% CI 1.47-2.42]; P = 5.32 × 10(-7), corrected P = 0.017). Homozygous individuals had the highest edema rate (hazard ratio 2.89, P = 4.22 × 10(-4)) when compared with individuals homozygous for the protective allele, with heterozygous individuals having an intermediate risk. The interaction between the SNP and rosiglitazone for edema was significant (P = 7.68 × 10(-3)). Six SNPs in NFATC2 were significant in both Europeans and Latin Americans (P < 0.05). CONCLUSIONS: Genetic variation at the NFATC2 locus contributes to edema among individuals who receive rosiglitazone.