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, BSC1,
- Changchun Xie, PHD2,3,
- Ron Do, MSC1,
- Alexandre Montpetit, PHD4,
- Rafael Diaz, MD5,
- Viswanathan Mohan, MD, PHD, DSC, FRCP6,
- Bernard Keavney, MD, FRCP7,
- Salim Yusuf, MD, DPHIL, FRCPC2,3,8,
- Hertzel C. Gerstein, MD, MSC, FRCPC2,3,8,
- James C. Engert, PHD1,9,
- Sonia Anand, MD, PHD, FRCPC2,3,8 and
- on behalf of the DREAM investigators
- 1Department of Human Genetics, McGill University, Montreal, Quebec, Canada;
- 2Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada;
- 3Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada;
- 4McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada;
- 5Estudios Clínicos Latinoamérica, Rosario, Jujuy, Argentina;
- 6Madras Diabetes Research Foundation, Gopalapuram, Chennai, India;
- 7Institute of Human Genetics, University of Newcastle, Newcastle Upon Tyne, U.K.;
- 8Department of Medicine, McMaster University, Hamilton, Ontario, Canada;
- 9Department of Medicine, McGill University, Montreal, Quebec, Canada.
- Corresponding author: James C. Engert, .
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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- Received March 8, 2010.
- Accepted July 9, 2010.
- © 2010 by the American Diabetes Association.
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