Genome-wide association analysis of pain reduction in rheumatoid arthritis patients treated with TNF inhibitors

Background/Purpose: Pain is the dominant and prevailing symptom of rheumatoid arthritis (RA). Tumor necrosis factor inihibitors (TNFi) have proven very successful in pain reduction. Interestingly, improvement of pain,is notable rapidly after administration of TNFi agents, and well before anti-inflammatory effects of treatment can be observed. The vast majority of pharmacogenetic studies of response to TNFi utilized the clinical outcome measure, disease activity score 28 (DAS28). This measure is very useful for clinical practice, however it might be less heritable as compared to individual, potentially more homogeneous, disease measures. Usage of less complex phenotypes, such as pain (heritability 28–71%), might significantly aid the identification of genetic markers predicting differential response to TNFi. We aimed to identify and replicate genetic factors predicting pain reduction upon TNFi treatment in patients with RA using genome-wide association approach.

Methods: We included 508 TNFi treated RA patients. Association analysis of change of visual analogue scale of pain (VAS-pain) after 14 weeks of treatment was performed on imputed genome-wide genotyping data under additive genetic model with adjustment for baseline VAS-pain. We alsoconducted a meta-analysis including 1287 RA patients. Gene-based analysis was performed using VEGAS.

Results: No findings reached the threshold for genome-wide significance (P-value 1X10-8) in the discovery cohort. Meta-analysis revealed 213 SNPs suggestively associated (P 10-4) with change in VAS-pain after fourteen weeks of TNFi treatment. The most significant SNP rs2295739 (p 2.21X10-6), located 50kb upstream from the KCNK10 gene. Which belongs to a family of genes involved in sensory perception. The top hit in the gene-based analysis was RET, known to regulate ion channels and receptors participating in detection and transduction of sensory stimuli. Besides Ret-deficient mice show elevated pain responses.

Conclusion: We have identified several suggestive genomic regions, further studies are required to validate if these regions play a role in pain reduction upon TNFi treatment.