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

Abstract

AIMTo investigate genetic factors that might help define which Crohn’s disease (CD) patients are likely to benefit from anti-tumor necrosis factor (TNF) therapy.METHODSThis 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).RESULTS121 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.CONCLUSIONThe 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.

Personalizing Treatment in IBD: Hype or Reality in 2020? Can We Predict Response to Anti-TNF?

“…A combined clinical-genetic model more accurately predicted primary non-response, when compared with a clinical only model (0.93 vs. 0.70; p < 0.001) ( 23 ). Furthermore, the combination of two–risk genotypes, involving both apoptosis and the TNF region, was associated with primary anti-TNF non-response ( 93 ).…”

Systematic review: predictive biomarkers of therapeutic response in inflammatory bowel disease—personalised medicine in its infancy

“…In fistulising CD, Fas ligand‐843 CC/CT genotype was the only predictor of response . Conversely, the CC genotype vs a TC or TT genotype was associated with primary nonresponse in CD (OR 4.3 [1.45‐12.8], P = 0.009) …”

“…Other studies found no significant association between variation in the TNF region (eg, the TNF promoter region) and treatment response . Recently however, the presence of the minor allele (A) for the TNF gene (rs1800629) was associated with primary nonresponse (OR 2.88 [1.1‐8.22], P = 0.049) …”

“…In the risk model for sustained response—comprising 16 SNPs—each one‐point increase was associated with a 60% higher likelihood of sustained response (AUC 0.929; OR 1.6 [1.41‐1.83], P = 2x10 –12 ) . Recently, the combination of two‐risk genotypes, involving both apoptosis and the TNF region, was associated with primary anti‐TNF nonresponse (OR 4.76 [1.35‐16.77], P = 0.015) …”

“…Historically, most research has focused on pharmacogenomics. With regard to anti‐TNF agents, genetic variations involving the Fc receptor, apoptosis, TNF signalling and autophagy have been focuses of interest . Moreover, efforts have been made to combine a number of relevant SNPs leading to a “genetic risk score” for response/nonresponse .…”