Session Title: Genetics and Genomics of Rheumatic Diseases
Session Type: Abstract Submissions (ACR)
Due to the wide range of highly specific and effective biologic response modifiers that are available today for the treatment of RA it has become of great importance to identify biomarkers for the prediction of therapy outcome, supporting an individualized therapy. Most studies in this field analysed potential markers for a single biological or substance group, respectively. In this study we analysed the association of genotypes of the single nucleotide polymorphism (SNP) rs10414216 in the 3′ UTR of the MED29 gene with the outcome of two biologic response modifiers, targeting different pathways.
We studied 275 RA patients treated first with the TNF-blocker etanercept (ETN) and a subgroup of 62 patients treated later in the course of the disease with a B-cell directed therapy, with rituximab (RTX). The frequency of the SNP rs10414216 MED29 C/T was analysed using a validated TaqMan™ genotyping assay containing sequence-specific primers and fluorescence-labelled allele-specific probes. Disease activity and therapy response were assessed according to the EULAR improvement criteria (http://www.das-score.nl). The primary response of the ETN therapy was assessed 3-4 months after initiation of therapy, the outcome of rituximab after 4-6 months after the first infusion of RTX.
The genotype distribution of the SNP rs10414216 MED29 C/T in 275 RA patients was comparable with a cohort of non-affected controls. There were no differences in the genotype frequencies in subgroups of ACPA- positive and -negative RA patients. There was no association of genotypes with disease activity observed. The DAS28 at baseline before start of ETN or RTX treatment was comparable for all genotypes. After 3-4 months of ETN treatment the DAS28 decreased by 1.670±1.377, 2.083±1.348 and 2.382±1.286 (mean±SD) for the C/C, C/T and T/T genotypes, respectively. The improvement of the DAS28 was significantly better for the T/T genotype compared to C/C (p=0.003). 58% of T/T carriers but only 27.2 % of the C/C carriers were identified as good responders to ETN. However, in RTX treated patients the carriers of the C/C genotype were identified as better responders, after 4-6 months the DAS28 decreased by 2.277±1.558 for the C/C genotype compared to 1.310±1.347 for the C/T genotype (p=0,025). 46.2% of C/C and only 27.3% of C/T carriers were good responders to RTX. The T/T carriers were underrepresented in the RTX subgroup, probably as a result of a better outcome of the TNF-blocker therapy in these patients.
Our data clearly indicate that a single SNP has the potential to predict the outcome to different therapeutic approaches. The functional importance of this genetic variation has not yet been characterized. However, this SNP is located in the gene region of MED29, a subunit of the mediator complex which plays a substantial role in the regulation of gene expression. Further analysis of this SNP and the respective gene locus could provide further insight into the mechanisms which determine the outcome of different targeted therapies
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-unique-single-nucleotide-polymorphism-in-the-3-utr-of-the-med29-gene-on-chromosome-19-is-associated-with-the-clinical-outcome-of-different-biologic-response-modifiers/