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. 2023 Feb 18;24(4):4110.
doi: 10.3390/ijms24044110.

MTHFR c.665C>T and c.1298A>C Polymorphisms in Tailoring Personalized Anti-TNF-α Therapy for Rheumatoid Arthritis

Amin Ravaei  1 , Lia Pulsatelli  2 , Elisa Assirelli  3 , Jacopo Ciaffi  3 , Riccardo Meliconi  3 , Carlo Salvarani  4   5 , Marcello Govoni  6   7 , Michele Rubini  1   8
Affiliations

MTHFR c.665C>T and c.1298A>C Polymorphisms in Tailoring Personalized Anti-TNF-α Therapy for Rheumatoid Arthritis

Amin Ravaei et al. Int J Mol Sci. .

Abstract

Rheumatoid arthritis (RA) is an inflammatory autoimmune disease with a prevalence of 1%. Currently, RA treatment aims to achieve low disease activity or remission. Failure to achieve this goal causes disease progression with a poor prognosis. When treatment with first-line drugs fails, treatment with tumor necrosis factor-α (TNF-α) inhibitors may be prescribed to which many patients do not respond adequately, making the identification of response markers urgent. This study investigated the association of two RA-related genetic polymorphisms, c.665C>T (historically referred to as C677T) and c.1298A>C, in the MTHFR gene as response markers to an anti-TNF-α therapy. A total of 81 patients were enrolled, 60% of whom responded to the therapy. Analyses showed that both polymorphisms were associated with a response to therapy in an allele dose-dependent manner. The association for c.665C>T was significant for a rare genotype (p = 0.01). However, the observed opposite trend of association for c.1298A>C was not significant. An analysis revealed that c.1298A>C, unlike c.665C>T, was also significantly associated with the drug type (p = 0.032). Our preliminary results showed that the genetic polymorphisms in the MTHFR gene were associated with a response to anti-TNF-α therapy, with a potential significance for the anti-TNF-α drug type. This evidence suggests a role for one-carbon metabolism in anti-TNF-α drug efficacy and contributes to further personalized RA interventions.

Keywords: MTHFR; TNF-α inhibitors; biomarkers; genetic association; personalized medicine; pharmacogenetics; rheumatoid arthritis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Odds ratio of association of MTHFR c.665C>T and c.1298A>C genotypes with response to anti-TNF-α therapy (GR+MR vs. NR) under a co-dominant model and considering wild-type homozygotes as a reference. * Significant nominal p-value.
Figure 2
Figure 2
Odds ratio of association of MTHFR c.665C>T and c.1298A>C polymorphisms with the level of response to anti-TNF-α therapy considering wild-type homozygotes as a reference. * Significant nominal p-value. GR: good response; MR: moderate response.
Figure 3
Figure 3
Odds ratio of association of MTHFR c.665C>T and c.1298A>C genotypes with response to anti-TNF-α drug subtypes considering wild-type homozygotes as a reference. * Significant nominal p-value. mAb: monoclonal antibody; FP: fusion protein.
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