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. 2021 Oct;21(5):608-621.
doi: 10.1038/s41397-021-00238-4. Epub 2021 Jul 23.

AHR-dependent genes and response to MTX therapy in rheumatoid arthritis patients

Anna Wajda  1 , Ewa Walczuk  2 , Barbara Stypińska  2 , Jakub Lach  3   4 , Danat Yermakovich  5 , Larysa Sivitskaya  5 , Katarzyna Romanowska-Próchnicka  6   7 , Tomasz Wysocki  6 , Małgorzata Jarończyk  8 , Agnieszka Paradowska-Gorycka  2
Affiliations

AHR-dependent genes and response to MTX therapy in rheumatoid arthritis patients

Anna Wajda et al. Pharmacogenomics J. 2021 Oct.

Abstract

Methotrexate (MTX) is the first-line therapy for rheumatoid arthritis. Nevertheless, MTX resistance is quite a common issue in clinical practice. There are some premises that aryl hydrocarbon receptor (AhR) gene battery may take part in MTX metabolism. In the present retrospective study, we analyzed genes expression of AHR genes battery associated with MTX metabolism in whole blood of RA patients with good and poor response to MTX treatment. Additionally, sequencing, genotyping and bioinformatics analysis of AHR repressor gene (AHRR) c.565C > G (rs2292596) and c.1933G > C (rs34453673) have been performed. Theoretically, both changes may have an impact on H3K36me3 and H3K27me3. Evolutionary analysis revealed that rs2292596 may be possibly damaging. Allele G in rs2292596 and DAS28 seems to be associated with a higher risk of poor response to MTX treatment in RA. RA patients with poor response to MTX treatment revealed upregulated AhR and SLC19A1 mRNA level. Treatment with IL-6 inhibitor may be helpful to overcome the low-dose MTX resistance. Analysis of gene expression revealed possible another cause of poor response to MTX treatment which is different from that observed in the case of acute lymphoblastic leukemia.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Missing data proportion in multivariable logistic regression model of poor response to MTX treatment probability in RA patients.
Fig. 2
Fig. 2. Results of the PredictSNP1 analyzed SNPs in AHRR.
A rs2292596, B rs34453673.
Fig. 3
Fig. 3. (A) AhR, (B) Arnt, and (C) SLC19a1 mRNA level normalized to reference gene (GAPDH) in whole blood in the healthy control group (HC, n = 10) and RA patients with good response to MTX treatment (n = 9) and patients with bad response to MTX treatment (n = 14) (red dots—patients with dyspeptic syndromes n = 8, green triangles—broader symptoms of MTX intolerance n = 6).
Results are presented as median with 95% confidential interval. *Significance at p < 0.05 (Color figure online).
Fig. 4
Fig. 4. ATP-binding drug transporters mRNA level normalized to reference gene (GAPDH) in whole blood in RA patients with good response to MTX treatment (n = 9) and patients with poor response to MTX treatment (n = 14) (red dots—patients with dyspeptic syndromes n = 8, green triangles—broader symptoms of MTX intolerance n = 6).
Expression of A ABCC1 mRNA level; B ABCC2 mRNA level; C ABCC3 mRNA level; D ABCC4 mRNA level; E ABCC5 mRNA level; F ABCG2 mRNA level. Results are presented as median with 95% confidential interval. *Significance at p < 0.05 (Color figure online).
See this image and copyright information in PMC

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