Genetic polymorphisms in tumour necrosis factor receptors (TNFRSF1A/1B) illustrate differential treatment response to TNFα inhibitors in patients with Crohn’s disease

Abstract

BackgroundMonoclonal antibodies inhibiting tumour necrosis factor-α (TNFα) signalling pathway (anti-TNFα) 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 TNFα receptor superfamily 1A and 1B (TNFRSF1A/1B).MethodsWe tested nine SNPs inTNFα, TNFRSF1AandTNFRSF1Bby 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 toMycobacterium aviumsubspparatuberculosis(MAP) infection byIS900nested PCR.ResultsFour SNPs (TNFα:rs1800629, TNFRSF1A:rs767455, TNFRSF1B:rs1061624andTNFRSF1B:rs3397) were over-represented significantly (p<0.05) among patients with CD compared with healthy controls. TheTNFRSF1A:rs767455GG 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). TheTNFRSF1B:rs3397TT 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 SNPsTNFRSF1A:rs767455andTNFRSF1B:rs3397were 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 SNPsTNFRSF1A:rs767455andTNFRSF1B:rs3397. Our SNP haplotype analysis ofTNFRSF1A:rs767455andTNFRSF1B:rs3397indicates 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%).ConclusionThe SNPsTNFRSF1A:rs767455andTNFRSF1B:rs3397,which are known to affect anti-TNFα clinical outcome in CD, were associated with lower corresponding gene expression and higher MAP infection susceptibility.