title: The Pro12Ala variant of the PPARG gene is a risk factor for peroxisome proliferator-activated receptor-gamma/alpha agonist-induced edema in type 2 diabetic patients.
abstract: BACKGROUND
  Activation of peroxisome proliferator-activated receptors (PPARs)-gamma by thiazolidinediones (pioglitazone, rosiglitazone) and dual-acting PPARalpha/gamma agonists (pargluva, ragaglitazar) is a widely used pharmacological principle to treat insulin resistance and type 2 diabetes. Clinically, however, fluid retention and edema are worrying side effects with these drugs.
  
  
  OBJECTIVE
  The objective of the present study was to investigate any variation in the PPARG and PPARA genes associated with the risk of fluid retention and development of peripheral edema in patients with type 2 diabetes treated with the dual-acting PPARalpha/gamma agonist ragaglitazar.
  
  
  METHODS
  Single-nucleotide polymorphism and haplotype analyses of the PPARA and PPARG genes were performed on DNA obtained from 345 type 2 diabetic patients randomized to 26-wk monotherapy with the dual-acting PPARalpha/gamma agonist ragaglitazar.
  
  
  RESULTS
  At 26 wk, edema was recorded in 48 of the patients (14%) treated with ragaglitazar, and Cox regression analyses identified the common Pro12Ala variant of the PPARG gene as biologically the most important risk factor (hazard ratio 4.42, P = 0.0081) for edema. Other risk factors included female gender (hazard ratio 3.34, P = 0.0005) and weight change during treatment (hazard ratio 1.20, P = 0.0017).
  
  
  CONCLUSIONS
  A population-attributable risk of approximately 50% for the Pro12Pro genotype indicates that testing for the Pro12Ala of the PPARG gene in addition to the already identified clinical risk factors may become a useful tool to further reduce the risk of PPARgamma agonist-induced fluid retention and edema in patients with type 2 diabetes.
authors.affiliation: Novo Nordisk A/S, D.M.S.C., Krogshoejvej 53A, 9E2.48, DK-2880 Bagsvaerd, Denmark. larh@novonordisk.com
authors.forename: Lars
authors.initials: L
authors.lastname: Hansen
authors.forename: Claus T
authors.initials: CT
authors.lastname: Ekstrøm
authors.forename: René
authors.initials: R
authors.lastname: Tabanera Y Palacios
authors.forename: Madan
authors.initials: M
authors.lastname: Anant
authors.forename: Karsten
authors.initials: K
authors.lastname: Wassermann
authors.forename: Rickey R
authors.initials: RR
authors.lastname: Reinhardt
mesh_terms: D004247:DNA / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D004487:Edema / Q000139:chemically induced* / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005905:Glyburide / Q000009:adverse effects / Q000627:therapeutic use; D006239:Haplotypes; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D016015:Logistic Models; D008297:Male; D008687:Metformin / Q000009:adverse effects / Q000627:therapeutic use; D010078:Oxazines / Q000009:adverse effects* / Q000627:therapeutic use; D047493:PPAR alpha / Q000819:agonists / Q000097:blood / Q000235:genetics; D047495:PPAR gamma / Q000819:agonists* / Q000235:genetics*; D010666:Phenylpropionates / Q000009:adverse effects* / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models
chemical_list: D007004:Hypoglycemic Agents; D010078:Oxazines; D047493:PPAR alpha; D047495:PPAR gamma; D010666:Phenylpropionates; D004247:DNA; D008687:Metformin; C432703:ragaglitazar; D005905:Glyburide