Abstract
ObjectivesTo determine whether genetic variation within genes related to the Toll-like receptor, inflammasome and interferon-γ pathways contributes to the differences in treatment response to tumour necrosis factor inhibitors (anti-TNF) in patients with rheumatoid arthritis (RA).MethodsIn a retrospective case-case study, we assessed 23 functional single nucleotide polymorphisms (SNPs) in 15 genes. We included 538 anti-TNF naïve Danish RA patients from the nationwide DANBIO database. Multivariable logistic regression analyses were performed to detect associations (p-value<0.05) between genotypes and European League Against Rheumatism (EULAR) treatment responses. False Discovery Rate corrections for multiple testing (q-value) and stratified analyses were performed to investigate association with individual therapies and IgM-rheumatoid factor (RF) status.ResultsSix of twenty successfully genotyped polymorphisms were nominally associated with EULAR treatment response. Three of these were in weak to moderate linkage disequilibrium with polymorphisms previously reported associated with anti-TNF treatment response. TLR5(rs5744174) variant allele carriers (odds ratio(OR) = 1.7(1.1–2.5),p = 0.010,q = 0.46) and TLR1(rs4833095) homozygous variant carriers (OR = 2.8(1.1–7.4),p = 0.037,q = 0.46) had higher odds for a positive treatment response. NLRP3(rs10754558) variant allele carriers (odds ratio(OR) = 0.6(0.4–1.0),p = 0.045,q = 0.46) were more likely to have a negative treatment response.The association in TLR5(rs5744174) remained significant after correction for multiple comparisons among patients negative for RF (OR = 6.2(2.4–16.3),p = 0.0002,q = 0.024). No other association withstood correction for multiple testing. Post hoc analyses showed that change in Patient Global score on a visual analogue scale (VAS) and change in pain VAS were the main factors responsible for the association.ConclusionsWe reproduced previously reported associations between genetic variation in the TLR10/1/6 gene cluster, TLR5, and NLRP3 loci and response to anti-TNF treatment in RA. Changes in VAS pain and patient global scores were the main contributors to the association found for TLR5. Furthermore, we identified other candidate genes that require replication in independent cohorts.
Highlights
Predictive biomarkers capable of stratifying patients into responders and non-responders to treatment with tumour necrosis factor inhibitors will enable selection of the optimal treatment for the individual patients and thereby improve patient care
To determine whether genetic variation within genes related to the Toll-like receptor, inflammasome and interferon-γ pathways contributes to the differences in treatment response to tumour necrosis factor inhibitors in patients with rheumatoid arthritis (RA)
Changes in visual analogue scale (VAS) pain and patient global scores were the main contributors to the association found for TLR5
Summary
Predictive biomarkers capable of stratifying patients into responders and non-responders to treatment with tumour necrosis factor inhibitors (anti-TNF) will enable selection of the optimal treatment for the individual patients and thereby improve patient care. Such biomarkers, are scarce and none are applicable in a clinical setting. Associations between genetic polymorphisms and anti-TNF response are characterized by small effect sizes. Together with e.g. expression profiling, epigenetic, para-clinical, or clinical markers the growing number of polymorphisms associated with anti-TNF treatment response may be potentially useful for prediction [3]. Associations between genetic variation and treatment outcome may provide insight into aberrant molecular pathways and form the basis for developing new treatment strategies
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