Background/Purpose: Patients with rheumatoid arthritis (RA)  rate pain relief as the highest priority in treatment outcome, and tumor necrosis factor inhibitors (anti-TNF) have proven very successful in pain reduction. Interestingly, recent research indicates that inflammation and pain pathways are important, but partly independent, targets of anti-TNF. Therefore the identification of genetic factors predicting pain relief is important in efforts to personalize treatment.

Objective:We aimed to identify and replicate genetic factors predicting pain reduction upon anti-TNF treatment in patients with RA using a genome-wide association approach.

Methods: We included 508 RA patients treated with anti-TNF agents from the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry. Single nucleotide polymorphism (SNP) markers were genotyped using the Illumina HumanHap550-Duo or Human660W-Quad BeadChip. Association analysis using the change of Visual analogue scale of pain (VASpain) after 14 weeks of treatment initiation as outcome was performed on an imputed dataset under an additive genetic model with adjustment for baseline VASpain. SNPs demonstrating association with VASpain change with a p-value<10^-5were selected for replication in 207 RA patients treated with anti-TNF from the Danish DANBIO registry. We performed a meta-analysis using METAL. Pathway analysis was performed in Ingenuity.

Results: 2,557,253 SNPs and 406 patients passed quality control. No findings reached the threshold for genome-wide significance (p-value ≤1×10-8) in the Dutch discovery cohort. 46 SNPs showed p-values<10-5, five of these (rs7921473, rs2237199, rs2237204, rs1424441, rs2615233) reached nominal significance (p<0.05) in the Danish DANBIO registry. Meta-analysis led to the identification of three SNPs with a p-value <1x10^-7. These SNPs can be linked to functions that might involve pain processing in the brain. They are located within or nearby ATXN1 (rs2237204, rs2237199), a gene involved in the pathology of spinocerebellar ataxia type 1, a neurodegenerative disorder characterized by progressive degeneration of cerebellum and NRG3 (rs7921473) which influences neuroblast proliferation, migration and differentiation. Pathway analysis, including all SNPs with a p-value<10^-3 (n=2649) from the discovery cohort also point to the brain. The analysis shows that genes involved in neuritogenesis are overrepresented in our dataset (p=6.78×10^-6). In addition, six SNPs map to the α-adrenergic signaling pathway (p=6.16×10^-4), an important target for pain medication.

Conclusion: Significant findings will be replicated in a third patient population. Confirmed biomarkers can be used to personalize medication for the individual patient.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/genome-wide-association-analysis-of-pain-reduction-in-rheumatoid-arthritis-patients-treated-with-anti-tnf-medication-results-of-the-dream-and-danbio-registries/