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Genetic polymorphisms predict response to anti-tumor necrosis factor treatment in Crohn's disease.

ABSTRACT: To investigate genetic factors that might help define which Crohn's disease (CD) patients are likely to benefit from anti-tumor necrosis factor (TNF) therapy.This was a prospective cohort study. Patients were recruited from a university digestive disease practice database. We included CD patients who received anti-TNF therapy, had available medical records (with information on treatment duration and efficacy) and who consented to participation. Patients with allergic reactions were excluded. Patients were grouped as ever-responders or non-responders. Genomic DNA was extracted from peripheral blood, and 7 single nucleotide polymorphisms (SNPs) were assessed. The main outcome measure (following exposure to the drug) was response to therapy. The patient genotypes were assessed as the predictors of outcome. Possible confounders and effect modifiers included age, gender, race, and socioeconomic status disease, as well as disease characteristics (such as Montreal criteria).121 patients were included. Twenty-one were non-responders, and 100 were ever-responders. Fas ligand SNP (rs763110) genotype frequencies, TNF gene -308 SNP (rs1800629) genotype frequencies, and their combination, were significantly different between groups on multivariable analysis controlling for Montreal disease behavior and perianal disease. The odds of a patient with a Fas ligand CC genotype being a non-responder were four-fold higher as compared to a TC or TT genotype (P = 0.009, OR = 4.30, 95%CI: 1.45-12.80). The presence of the A (minor) TNF gene -308 allele correlated with three-fold higher odds of being a non-responder (P = 0.049, OR = 2.88, 95%CI: 1.01-8.22). Patients with the combination of the Fas ligand CC genotype and the TNF -308 A allele had nearly five-fold higher odds of being a non-responder (P = 0.015, OR = 4.76, 95%CI: 1.35-16.77). No difference was seen for the remaining SNPs.The Fas-ligand SNP and TNF gene -308 SNP are associated with anti-TNF treatment response in CD and may help select patients likely to benefit from therapy.

SUBMITTER: Netz U

PROVIDER: S-EPMC5526766 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Genetic polymorphisms predict response to anti-tumor necrosis factor treatment in Crohn's disease.

Netz Uri U Carter Jane Victoria JV Eichenberger Maurice Robert MR Dryden Gerald Wayne GW Pan Jianmin J Rai Shesh Nath SN Galandiuk Susan S

World journal of gastroenterology 20170701 27

<h4>Aim</h4>To investigate genetic factors that might help define which Crohn's disease (CD) patients are likely to benefit from anti-tumor necrosis factor (TNF) therapy.<h4>Methods</h4>This was a prospective cohort study. Patients were recruited from a university digestive disease practice database. We included CD patients who received anti-TNF therapy, had available medical records (with information on treatment duration and efficacy) and who consented to participation. Patients with allergic ...[more]

PMID: 28785150

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Project description:Background?:Monoclonal antibodies inhibiting tumour necrosis factor-? (TNF?) signalling pathway (anti-TNF?) have been widely used in Crohn's disease (CD). However, treatment response varies among patients with CD and the clinical outcome is dependent on single nucleotide polymorphisms (SNP) in TNF? receptor superfamily 1A and 1B (TNFRSF1A/1B). Methods:We tested nine SNPs in TNF?, TNFRSF1A and TNFRSF1B by TaqMan genotyping from peripheral blood samples of 104 subjects. Additionally, we quantified the effects of these SNPs on their corresponding gene expression by RT-PCR and susceptibility to Mycobacterium avium subsp paratuberculosis (MAP) infection by IS900 nested PCR. Results:Four SNPs (TNF?:rs1800629, TNFRSF1A:rs767455, TNFRSF1B:rs1061624 and TNFRSF1B:rs3397) were over-represented significantly (p<0.05) among patients with CD compared with healthy controls. The TNFRSF1A:rs767455 GG genotype was found in 15/54?patients with CD (28%), while it was only found in 2/50 healthy controls (4%) (OR 9.2, 95%?CI 1.98 to 42.83). The TNFRSF1B:rs3397 TT genotype was found in 15/54?patients with CD (28%) compared with (4/50) healthy controls (8%) (OR 4.4, 95%?CI 1.36 to 14.14). Furthermore, the SNPs TNFRSF1A:rs767455 and TNFRSF1B:rs3397 were associated with downregulating their corresponding genes significantly (p<0.05). MAP infection was predominantly found among patients with CD in comparison to healthy controls (57% vs 8%, respectively), which was also dependent on the SNPs TNFRSF1A:rs767455 and TNFRSF1B:rs3397. Our SNP haplotype analysis of TNFRSF1A:rs767455 and TNFRSF1B:rs3397 indicates that the G-T haplotype is significantly distributed among patients with CD (46%) and MAP infection susceptibility is also associated with this specific haplotype (31%). Conclusion:The SNPs TNFRSF1A:rs767455 and TNFRSF1B:rs3397, which are known to affect anti-TNF? clinical outcome in CD, were associated with lower corresponding gene expression and higher MAP infection susceptibility.

Dataset Information

Genetic polymorphisms predict response to anti-tumor necrosis factor treatment in Crohn's disease.

Publications

Genetic polymorphisms predict response to anti-tumor necrosis factor treatment in Crohn's disease.

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