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. 2010 Oct;33(10):2250-3.
doi: 10.2337/dc10-0452. Epub 2010 Jul 13.

Variation at the NFATC2 locus increases the risk of thiazolidinedione-induced edema in the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) study

Swneke D Bailey  1 , Changchun Xie, Ron Do, Alexandre Montpetit, Rafael Diaz, Viswanathan Mohan, Bernard Keavney, Salim Yusuf, Hertzel C Gerstein, James C Engert, Sonia Anand; DREAM investigators
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Variation at the NFATC2 locus increases the risk of thiazolidinedione-induced edema in the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) study

Swneke D Bailey et al. Diabetes Care. 2010 Oct.

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 × 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.

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Figures

Figure 1
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, sex, BMI, and use of ramipril and CCBs, as well as the first 10 principal components of the alleles shared identity by state among the European and Latin American individuals. Individuals taking diuretics were excluded from the analysis. The dashed lines indicate Bonferroni corrected and nominal significance. Inset: Results of the initial association scan of 32,088 SNPs and TZD-induced peripheral edema in Europeans (n = 965) receiving rosiglitazone. The −log of the P values are plotted against SNP location for each chromosome. B: Survival curves estimated from the Cox proportional hazards model of time to the first occurrence of edema according to the rs6123045 genotype. European individuals homozygous for the risk allele (CC) have an increase in the rate to the first report of edema in comparison with the individuals heterozygous (CT) or homozygous (TT) for the protective allele (adjusted HR 1.76, P = 3.43 × 10−5 and adjusted HR 2.89, P = 4.22 × 10−4, respectively). Inset: The effect of the rs6123045 SNP on peripheral edema among European individuals receiving rosiglitazone or placebo. 33.6% (158 of 470) of individuals homozygous for the risk allele, 20.8% (84 of 403) of heterozygous individuals, and 12.9% (12 of 93) of individuals homozygous for the protective allele developed edema while receiving rosiglitazone compared with 18.0% (85 of 473), 13.8% (56 of 404), and 16.5% (13 of 79), respectively, while receiving placebo. The per-allele OR and 95% CI of the logistic regression analysis are shown.
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