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

Abstract

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 5.32 107, corrected P 0.017). Homozygous individuals had the highest edema rate (hazard ratio 2.89, P 4.22 104) 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 7.68 103). 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.