Genetic markers could determine TNF inhibitor response in RA
medwireNews: Researchers have found two genetic markers that could influence response to tumor necrosis factor (TNF) inhibitors among patients with rheumatoid arthritis (RA).
The two markers – LINC02549 rs7767069 single nucleotide polymorphism (SNP) and either copy of the LARRC55 rs717117G allele – were identified from 27 possible SNPs selected through a literature search of relevant genome-wide association studies.
All of the SNPs were assessed for an association with changes in DAS28 after 3 or 6 months of treatment with TNF inhibitors in 1361 patients with RA from the REPAIR consortium and the DANBIO registry. The most relevant SNPs were then replicated in a validation cohort of 706 patients from the DREAM registry.
As reported at the EULAR 2021 Virtual Congress, meta-analysis of all three cohorts showed a significant association between the LINC02549 rs7767069 SNP and change in DAS28, with a 17% decreased reduction in scores among carriers relative to non-carriers, after taking into account age, sex, and country of origin.
This was also the case for either copy of the LARRC55 rs717117G allele but only in patients positive for rheumatoid factor (RF). For these individuals, carrying either allele was associated with a significant 33% decreased reduction in DAS28. The opposite was true for patients testing negative for RF, however; in that carriers had a 38% greater reduction in DAS28 relative to non-carriers, although this did not reach statistical significance.
Presenting the findings, José Manuel Sánchez-Maldonado (Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research, Granada, Spain) commented that “to date, only a few genome-wide association studies or well powered candidate gene association studies have been conducted” to evaluate the relationship between genetics and drug response.
He noted that the meta-analysis also showed “potentially interesting but not statistically significant” overall and RF-specific associations between MAFB rs6071980 and CNTN5 rs1813443 SNPs and change in DAS28 that warrant further investigation.
Functional evaluations of the most relevant SNPs were also conducted using data on 530 individuals from the Human Functional Genomic Project.
The results so far show increased numbers of CD45RO- and CD45RA-positive T cells in carriers of the LINC02549 rs7767069 allele, as well as increased serum levels of soluble scavenger CD5 and CD6 receptors.
Carriers of the LARRC55 rs717117G allele had decreased interleukin (IL)-6 production after stimulation of peripheral blood mononuclear cells with Borrelia burgdorferi and Escherichia coli bacteria, which the researchers indicate could suggest impaired IL-6-mediated anti-inflammatory effects.
Sánchez-Maldonado concluded: “This study confirmed the influence of the LINC02549 and LPRC55 loci to determine the response to TNF inhibitors in RA patients.”
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