title: A candidate-gene association study of topiramate-induced weight loss in obese patients with and without type 2 diabetes mellitus.
abstract: OBJECTIVE
  Clinical response to topiramate can vary greatly in obese patients. Identifying genetic variants associated with treatment response could help gain insight into the mechanism of action of topiramate. Little is known about the relationship between genetic variability and topiramate treatment response. We performed a large-scale candidate-gene study to identify genetic risk factors predictive of topiramate-induced weight loss.
  
  
  METHODS
  We collected DNA samples from patients who had previously participated in clinical trials to assess the efficacy of topiramate for the treatment of obesity. A custom chip containing single nucleotide polymorphisms from ∼ 480 candidate genes was utilized to genotype a discovery cohort of 445 obese patients from a clinical study. Variants predictive of topiramate-induced weight loss were identified and further tested in an independent replication cohort of drug-naive, obese patients with type 2 diabetes (N=139).
  
  
  RESULTS
  We identified a haplotype in INSR that may contribute to differential topiramate-induced weight loss. Carriers and noncarriers of an INSR haplotype lost 9.1 and 7.0% of body weight, respectively (P = 6.5 × 10(-6), P adj = 0.001). This finding was replicated, with carriers and noncarriers losing 9.5 and 7.3% of body weight, respectively (P Bonf=0.02), in the independent replication cohort. We also identified an SNP in HNF1A that may be associated with topiramate response and an SNP in GRIA3 that may be associated with nonpharmacologic treatment response.
  
  
  CONCLUSIONS
  According to our preliminary findings, genetic variation in the INSR and HNF1A genes may differentially affect weight loss in obese individuals treated with topiramate and genes related to insulin action are implicated in modulating topiramate response. However, these findings need to be further replicated in additional larger samples.
authors.affiliation: aNeuroscience Therapeutic Area, Janssen Research & Development, LLC, Titusville, New Jersey bCVM Therapeutic Area, Janssen Research & Development, LLC, Spring House, Pennsylvania cPerlegen Sciences, Mountain View, California dAthanasiou Consulting, LLC, Fond du Lac, Wisconsin, USA.
authors.forename: Qingqin S
authors.initials: QS
authors.lastname: Li
authors.forename: James M
authors.initials: JM
authors.lastname: Lenhard
authors.forename: Yiping
authors.initials: Y
authors.lastname: Zhan
authors.forename: Karel
authors.initials: K
authors.lastname: Konvicka
authors.forename: Maria C
authors.initials: MC
authors.lastname: Athanasiou
authors.forename: Richard S
authors.initials: RS
authors.lastname: Strauss
authors.forename: Stephan
authors.initials: S
authors.lastname: Francke
mesh_terms: D000328:Adult; D019440:Anti-Obesity Agents / Q000627:therapeutic use*; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000235:genetics; D005260:Female; D005632:Fructose / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000150:complications / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D020641:Polymorphism, Single Nucleotide; D000077236:Topiramate; D015431:Weight Loss / Q000187:drug effects*
chemical_list: D019440:Anti-Obesity Agents; D000077236:Topiramate; D005632:Fructose