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

  1. on behalf of the DREAM investigators
  1. 1Department of Human Genetics, McGill University, Montreal, Quebec, Canada;
  2. 2Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada;
  3. 3Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada;
  4. 4McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada;
  5. 5Estudios Clínicos Latinoamérica, Rosario, Jujuy, Argentina;
  6. 6Madras Diabetes Research Foundation, Gopalapuram, Chennai, India;
  7. 7Institute of Human Genetics, University of Newcastle, Newcastle Upon Tyne, U.K.;
  8. 8Department of Medicine, McMaster University, Hamilton, Ontario, Canada;
  9. 9Department of Medicine, McGill University, Montreal, Quebec, Canada.
  1. Corresponding author: James C. Engert, jamie.engert{at}mcgill.ca.

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.

Footnotes

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  • Received March 8, 2010.
  • Accepted July 9, 2010.

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  1. Diabetes Care vol. 33 no. 10 2250-2253
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