title: Variation at the NFATC2 locus increases the risk of thiazolidinedione-induced edema in the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) study.
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.
  
  
  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.
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
authors.forename: Swneke D
authors.initials: SD
authors.lastname: Bailey
authors.forename: Changchun
authors.initials: C
authors.lastname: Xie
authors.forename: Ron
authors.initials: R
authors.lastname: Do
authors.forename: Alexandre
authors.initials: A
authors.lastname: Montpetit
authors.forename: Rafael
authors.initials: R
authors.lastname: Diaz
authors.forename: Viswanathan
authors.initials: V
authors.lastname: Mohan
authors.forename: Bernard
authors.initials: B
authors.lastname: Keavney
authors.forename: Salim
authors.initials: S
authors.lastname: Yusuf
authors.forename: Hertzel C
authors.initials: HC
authors.lastname: Gerstein
authors.forename: James C
authors.initials: JC
authors.lastname: Engert
authors.forename: Sonia
authors.initials: S
authors.lastname: Anand
mesh_terms: 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*
chemical_list: D007004:Hypoglycemic Agents; D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human; D045162:Thiazolidinediones; D000077154:Rosiglitazone; C089946:2,4-thiazolidinedione; D017257:Ramipril