title: Rac1 Polymorphisms and Thiopurine Efficacy in Children With Inflammatory Bowel Disease.
abstract: OBJECTIVE
  Thiopurines are effective for maintenance of remission in inflammatory bowel disease (IBD) in only about half of patients. Predictors of response may assist in selecting the most appropriate patients for thiopurine therapy. Thiopurines inhibit Rac1, a GTPase that exerts an antiapoptotic effect on T-lymphocytes. A genetic association was recently demonstrated between a Rac1 single nucleotide polymorphism (SNP) and poorer response to thiopurines in adult patients with Crohn disease. We aimed to determine whether Rac1 SNPs are associated with response to thiopurines in children with IBD.
  
  
  METHODS
  Children with IBD treated with thiopurines were prospectively followed for 1 year and were genotyped for 3 Rac1 SNPs previously found to be relevant to IBD: rs10951982, rs4720672, and rs34932801. The rate of sustained steroid-free remission (SSFR) without treatment escalation by 12 months was compared between wild types (WTs) and heterozygotes.
  
  
  RESULTS
  A total of 59 patients were studied (63% boys, 80% having Crohn disease, mean age 13 ± 4.1). Nineteen of the 41 WT (46%) and 9 of the 15 (60%) heterozygotes for rs10951982 were in SSFR (P = 0.55). Similarly, 21 of the 45 (47%) WT and 8 of the 12 (67%) heterozygotes for rs4720672 were in remission (P = 0.33). Finally, 21 of the 45 (47%) WT and 3 of the 5 (60%) heterozygotes for rs34932801 were in remission (P = 0.66). All of the 3 comparisons remained nonsignificant in a sensitivity analysis of only the patients with Crohn disease.
  
  
  CONCLUSIONS
  We did not find an association between 3 Rac1 SNPs and thiopurine effectiveness by 12 months in a prospective study of children with IBD. Other predictors of response should be sought to optimize patient selection for thiopurine therapy.
authors.affiliation: *Juliet Keidan Institute of Pediatric Gastroenterology and Nutrition †Medical Genetics Institute ‡Clinical Gastroenterology Laboratory, Shaare Zedek Medical Center, Jerusalem, Israel §Department of Gastroenterology, Rambam Health Care Campus ||Rappaport Institute for Research in the Medical Sciences, Technion-Israel Institute of Technology #Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Hospital for Sick Children, Toronto, Canada.
authors.forename: Raffi
authors.initials: R
authors.lastname: Lev-Tzion
authors.forename: Paul
authors.initials: P
authors.lastname: Renbaum
authors.forename: Rachel
authors.initials: R
authors.lastname: Beeri
authors.forename: Oren
authors.initials: O
authors.lastname: Ledder
authors.forename: Raphael
authors.initials: R
authors.lastname: Mevorach
authors.forename: Amir
authors.initials: A
authors.lastname: Karban
authors.forename: Eduard
authors.initials: E
authors.lastname: Koifman
authors.forename: Edna
authors.initials: E
authors.lastname: Efrati
authors.forename: Aleixo M
authors.initials: AM
authors.lastname: Muise
authors.forename: Yehuda
authors.initials: Y
authors.lastname: Chowers
authors.forename: Dan
authors.initials: D
authors.lastname: Turner
mesh_terms: D000293:Adolescent; D001379:Azathioprine / Q000627:therapeutic use*; D002648:Child; D015331:Cohort Studies; D003093:Colitis, Ulcerative / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D003424:Crohn Disease / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D004351:Drug Resistance; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D056726:Genetic Association Studies; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D007557:Israel; D008137:Longitudinal Studies; D008297:Male; D015122:Mercaptopurine / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide; D012074:Remission Induction; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; C107953:RAC1 protein, human; D015122:Mercaptopurine; D020830:rac1 GTP-Binding Protein; D001379:Azathioprine