title: Genetic polymorphisms of tumour necrosis factor receptor superfamily 1b and fas ligand are associated with clinical efficacy and/or acute severe infusion reactions to infliximab in Crohn's disease.
abstract: BACKGROUND
  Single nucleotide polymorphisms (SNPs) in TNF receptor superfamily (TNFRSF) 1A and 1B, and Fas ligand (FASLG) genes, have been associated with responsiveness to infliximab (IFX) in Crohn's disease.
  
  
  OBJECTIVE
  To investigate if SNPs in TNFRSF1A and 1B, and FAS (TNFRSF6) and FASLG (TNFSF6), associated with short- or long-term clinical and biological efficacy and with acute severe infusion reactions.
  
  
  METHODS
  Observational, retrospective and explorative cohort study of IFX-treated Caucasian patients with Crohn's disease classified as primary nonresponders (n = 21), response failures on maintenance therapy (n = 37), maintained remission (n = 47) and occurrence of acute severe infusion reactions (n = 20).
  
  
  RESULTS
  During IFX maintenance therapy, minor allele carriage of TNFRSF1B, rs976881 is associated with loss of response [OR 3.3 (1.2-9.1), P = 0.014]. Minor allele homozygosity increased the risk substantially (OR estimated 19, P = 0.006), and furthermore associated with a mean CRP increase of 17 mg/L as compared to a mean decrease of 17 mg/L in all others (P = 0.036). In contrast, minor allele carriage of TNFRSF1B, rs1061622 is associated with beneficial response to IFX induction [OR 4.2 (1.2-18.2), P = 0.014], and with persistence of remission during maintenance therapy [OR 5.5 (1.5-25.5), P = 0.007]. Carriage of the minor allele of FASLG, rs76110 increased risk of severe infusion reactions [OR 4.0 (1.1-22.4), P = 0.041]; minor allele carriage of TNFRSF1B, rs652625 decreased the risk (OR estimated 0.2, P = 0.043 ).
  
  
  CONCLUSIONS
  The TNFRSF1B polymorphisms may contribute to predict efficacy of infliximab. Moreover, FASLG and TNFRSF1B polymorphisms may confer genetic susceptibility to severe infusion reactions. These findings could potentially aid clinical decisions if confirmed in larger studies.
authors.affiliation: Department of Gastroenterology, Herlev Hospital, Denmark. steenholdt@brygge.dk
authors.forename: C
authors.initials: C
authors.lastname: Steenholdt
authors.forename: C
authors.initials: C
authors.lastname: Enevold
authors.forename: M A
authors.initials: MA
authors.lastname: Ainsworth
authors.forename: J
authors.initials: J
authors.lastname: Brynskov
authors.forename: O Ø
authors.initials: OØ
authors.lastname: Thomsen
authors.forename: K
authors.initials: K
authors.lastname: Bendtzen
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D000911:Antibodies, Monoclonal / Q000009:adverse effects* / Q000627:therapeutic use*; D015331:Cohort Studies; D003424:Crohn Disease / Q000188:drug therapy* / Q000235:genetics; D003718:Denmark; D004342:Drug Hypersensitivity / Q000235:genetics*; D053222:Fas Ligand Protein / Q000235:genetics*; D005260:Female; D005765:Gastrointestinal Agents / Q000009:adverse effects / Q000627:therapeutic use; D020022:Genetic Predisposition to Disease; D006801:Humans; D000069285:Infliximab; D008297:Male; D020641:Polymorphism, Single Nucleotide; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics*; D012189:Retrospective Studies; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha; D044465:White People; D055815:Young Adult; D019014:fas Receptor / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; C491901:FAS protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D005765:Gastrointestinal Agents; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; C506235:TNFRSF1A protein, human; C415902:TNFRSF1B protein, human; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D000069285:Infliximab