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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
Author(s) -
Steenholdt C.,
Enevold C.,
Ainsworth M. A.,
Brynskov J.,
Thomsen O. Ø.,
Bendtzen K.
Publication year - 2012
Publication title -
alimentary pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.308
H-Index - 177
eISSN - 1365-2036
pISSN - 0269-2813
DOI - 10.1111/apt.12010
Subject(s) - medicine , minor allele frequency , infliximab , single nucleotide polymorphism , allele , gastroenterology , retrospective cohort study , cohort , crohn's disease , fas ligand , genotype , immunology , disease , genetics , gene , biology , apoptosis , programmed cell death
Summary Background Single nucleotide polymorphisms ( SNP s) 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. Aim To investigate if SNP s in TNFRSF 1A and 1B, and FAS ( TNFRSF 6) and FASLG ( TNFSF 6), 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 TNFRSF 1B, 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 TNFRSF 1B, 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 TNFRSF 1B, rs652625 decreased the risk ( OR estimated 0.2, P = 0.043 ). Conclusions The TNFRSF 1B polymorphisms may contribute to predict efficacy of infliximab. Moreover, FASLG and TNFRSF 1B polymorphisms may confer genetic susceptibility to severe infusion reactions. These findings could potentially aid clinical decisions if confirmed in larger studies.