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.

Polymorphisms in TNF Receptor Superfamily 1B (TNFRSF1B:rs3397) are Linked to Mycobacterium avium paratuberculosis Infection and Osteoporosis in Rheumatoid Arthritis

“…The data strongly associates TNFRSF1B:rs3397 with MAP infection and low osteocalcin levels in RA. This confirms earlier findings in CD with unique SNPs in TNFα receptors (TNFRS1A:rs767455 and TNFRS1B:rs3397) [11].…”

“…Leukocytes from 1.0 mL of blood were isolated in a 2.0 mL RNase free microcentrifuge tube, suspended in 1.0 mL of TRIzol ® reagent (Invitrogen) and then subjected to RNA extraction as described earlier [11]. RNA pellets were air-dried for 15-30 min, suspended in 20 µL of RNase free H 2 O, and finally heated at 60 • C for 10 min.…”

“…SNPs in TNF Receptor Superfamily Member 1A/1B (TNFRSF1A and TNFRSF1B) have downregulated the expression of their corresponding genes significantly, which resulted in increased susceptibility to MAP infection in CD [11].…”

Role of Infections in the Pathogenesis of Rheumatoid Arthritis: Focus on Mycobacteria

“…According to several mutational screenings, mutations in SLC11A1 are linked to autoimmune diseases, such as RA [ 109 , 115 ], multiple sclerosis [ 116 , 117 ], inflammatory bowel disease [ 110 , 118 ], and type 1 diabetes mellitus [ 111 , 119 ]. Examination of SNPs in TNF-α gene, and its receptors ( TNFRSF1A/TNFRSF1B ), in RA patients compared to HCs, reported that some SNPs, TNFRSF1A:rs767455 and TNFRSF1B:rs3397, are linked to TNFRSF1B downregulation, increased susceptibility to MAP infection, increased inflammation and osteocalcin deficiency, and, possibly, increased osteoporosis [ 120 ]. Sharp et al showed that the SNPs in PTPN2/22 genes (protein tyrosine phosphatase non-receptor type 2 and 22) are linked to increased sensitivity to MAP infection and, therefore, increased T lymphocyte response, and IFN-γ expression in RA patients [ 112 ] ( Figure 1 , Table 1 ).…”

Association of RETN and TNFRSF1B polymorphisms with TNF-α inhibitor response in rheumatoid arthritis patients

“…Although the outcomes of these studies were different from that of our study, the CT and TT alleles of rs3397 were associated with lower expression of TNFRSF1B and increased susceptibility to Mycobaterium avium subsp paratuberculosis infection in Crohn's disease patients following TNFi treatment. [20] But, in a systematic review of the TNFi response in patients with inflammatory bowel diseases, rs3397 was a nonsignificant SNP, suggesting that the data on its effect on TNFi response are inconclusive. [21] Also, studies on the role of rs3397 in susceptibility to tuberculosis yielded inconsistent results.…”