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


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.
Bailey
Swneke D
SD
Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
Xie
Changchun
C
Do
Ron
R
Montpetit
Alexandre
A
Diaz
Rafael
R
Mohan
Viswanathan
V
Keavney
Bernard
B
Yusuf
Salim
S
Gerstein
Hertzel C
HC
Engert
James C
JC
Anand
Sonia
S
D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000209:etiology*; D004487:Edema / Q000139:chemically induced* / Q000235:genetics*; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D050778:NFATC Transcription Factors / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000187:drug effects; D017257:Ramipril / Q000494:pharmacology / Q000627:therapeutic use*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*
D007004:Hypoglycemic Agents; D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human; D045162:Thiazolidinediones; D000077154:Rosiglitazone; C089946:2,4-thiazolidinedione; D017257:Ramipril