title: Thiopurine effectiveness in patients with Crohn's disease: a study of genetic and clinical predictive factors.
abstract: BACKGROUND
  Thiopurines are efficacious in the treatment of Crohn's disease and were recently shown to induce T-cell apoptosis by modulation of Rac1 activation. To assess whether polymorphisms in Rac1 and other apoptosis-related genes, combined with clinical parameters, can predict response to thiopurines.
  
  
  METHODS
  A retrospective cohort of 156 thiopurine-treated patients with Crohn's disease was genotyped for 11 single-nucleotide polymorphisms (SNPs): 9 SNPs in Rac1, 1 SNP in the Fas ligand -843 T>C, and 1 SNP in the Caspase-9 93 C>T. Clinical data were extracted from the medical charts. Odds ratios (ORs) and 95% confidence intervals (CIs) of the association between demographic, clinical, and genetic variables and thiopurine response rates were calculated.
  
  
  RESULTS
  The overall response rate to thiopurines was 74% (115/156). The Rac1 SNP rs34932801 heterozygote genotype GC was associated with a lower response rate compared with the wild-type GG genotype (46% versus 76%; OR = 0.26; 95% CI, 0.08-0.91; P = 0.036). Only wild-type homozygotes were found for 5 Rac1 SNPs. None of the other 3 Rac1 SNPs were associated with response to thiopurines. Patients with Montreal B3 behavior pattern responded worse than those with a B1 behavior pattern (59%, versus 80%; OR = 0.37; 95% CI, 0.17-0.83; P = 0.016). Sephardic Jews had a lower response rate to thiopurines compared with Jews of Ashkenazi or mixed ancestry (60% versus 82%; OR = 0.32; 95% CI, 0.15-0.69, P = 0.003).
  
  
  CONCLUSIONS
  Rac1 SNP rs34932801carriage, Montreal B3 disease behavior, and a Sephardic Jewish origin were associated with unfavorable response to thiopurines. Corroboration of these associations in larger cohorts is warranted.
authors.affiliation: Department of Gastroenterology, Rambam Health Care Campus, Haifa, Israel. e_koifman@rambam.health.gov.il
authors.forename: Eduard
authors.initials: E
authors.lastname: Koifman
authors.forename: Amir
authors.initials: A
authors.lastname: Karban
authors.forename: Yoav
authors.initials: Y
authors.lastname: Mazor
authors.forename: Irit
authors.initials: I
authors.lastname: Chermesh
authors.forename: Matti
authors.initials: M
authors.lastname: Waterman
authors.forename: Ronit
authors.initials: R
authors.lastname: Almog
authors.forename: Shomron
authors.initials: S
authors.lastname: Ben-Horin
authors.forename: Rami
authors.initials: R
authors.lastname: Eliakim
authors.forename: Norberto
authors.initials: N
authors.lastname: Krivoy
authors.forename: Edna
authors.initials: E
authors.lastname: Efrati
authors.forename: Yehuda
authors.initials: Y
authors.lastname: Chowers
mesh_terms: D000293:Adolescent; D000328:Adult; D001379:Azathioprine / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003424:Crohn Disease / Q000188:drug therapy / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008297:Male; D015122:Mercaptopurine / Q000627:therapeutic use*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D011446:Prospective Studies; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D007166:Immunosuppressive Agents; D015122:Mercaptopurine; D001379:Azathioprine