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

doi:10.2337/dc10-0452

Variation at the NFATC2 Locus Increases the Risk of Thiazolinedinedione-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, PhD (jamie.engert{at}mcgill.ca)¹,⁹,
Sonia Anand, MD, PhD, FRCPc²,³,⁸ and
on behalf of the DREAM investigators

1. Department of Human Genetics, McGill University, Montreal, Quebec, H3A 1B1, Canada
2. Population Health Research Institute, McMaster University, Hamilton, Ontario, L8L 2X2, Canada
3. Department of Clinical Epidemiology and Biostatistics, McMaster University, Ontario, L8N 3Z5, Canada
4. McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, H3A 1A4, Canada
5. Estudios Clínicos Latino américa, Jujuy 1415, Rosario 2000, Argentina
6. Madras Diabetes Research Foundation, Gopalapuram, Chennai, 600 086, India
7. Institute of Human Genetics, University of Newcastle, Newcastle Upon Tyne, NE1 3BZ, UK
8. Department of Medicine, McMaster University, Hamilton, Ontario, L8S 4L8, Canada
9. Department of Medicine, McGill University, Montreal, Quebec, H3A 1A1, Canada

Abstract

Objective: Thiazolidinediones are used to treat type-2 diabetes. Their use has been associated with peripheral edema and congestive heart failure (CHF), outcomes that may have a genetic etiology.

Research Design and Methods: We genotyped 4,197 participants of the multi-ethnic DREAM trial with a 50k SNP array, which captures approximately 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 (OR=1.89, 95% CI:1.47–2.42, p=5.32×10⁻⁷, corrected p=0.017). Homozygous individuals had the highest edema rate (HR=2.89, p=4.22×10⁻⁴) when compared to individuals homozygous for the protective allele, with heterozygous individuals having an intermediate risk. The interaction between the SNP and rosiglitazone on edema was significant (p=7.68×10⁻³). Six SNPs were significant in both Europeans and Latin Americans (p<0.05).

Conclusion: Genetic variation at NFATC2 locus contributes to edema among individuals who receive rosiglitazone.