Effect of ATIC, ADA, ITPA, and AMPD1 gene polymorphisms on the efficacy of methotrexate in rheumatoid arthritis

Relevance. Methotrexate (MT) is the most prescribed baseline anti-inflammatory drug for the treatment of rheumatoid arthritis (RA). The reason for withdrawal of the drug is mostly because of its ineffectiveness, which is determined by the genetic characteristics of patients. Predicting the response to MT remains an urgent task in practical medicine.

Objective. To evaluate the influence of single-nucleotide polymorphisms of ATIC, AMPD1, ADA and ITPA genes on MT efficacy in RA.

Materials and methods. The study group included patients with a reliable diagnosis of RA who received MT. After 6 months of therapy, the efficacy was monitored by the dynamics of the DAS28 index (Disease Activity Score). Genotyping of polymorphisms rs2372536 (C347G), rs244076 (T>C), rs17602729 (C34T), and rs1127354 (C94A) was performed by real-time polymerase chain reaction. Allele and genotype distribution frequencies of polymorphisms in patients with different MT efficacy levels were analyzed. To assess the reliability (p) of differences, χ2 was used. The strength of association of traits was evaluated by the odds ratio (OR).

Results. The C allele of the ATIC rs2372536 polymorphism was predominant in responders: 230 (68 %) versus the G allele 110 (32 %) (p = 0.073, OR [95% CI] 0.7 [0.5; 1.0] at the trend level. The frequency of occurrence of the CC genotype of ATIC rs2372536 was significantly higher in responders 80 (47%) than in non-responders 41 (33 %) (p = 0.016, OR = 0.6 [0.3; 0.9]. At the same time, the CG genotype was significantly more prevalent in non-responders 68 (55 %) than in responders 70 (41%) (р = 0.021, OR = 1.7 [1.09; 2.8]. The TC genotype of the ADA rs244076 polymorphism was more frequent at the trend level in non-responders 33 (27 %) versus 33 (18 %) in responders (p = 0.064, OR = 1.7 [0.9; 2.9]. There was no difference in the genotype and allele distribution of ITPA rs1127354 and AMPD1 rs 17602729 polymorphisms between responders and non-responders. The CG genotype of the ATIC rs2372536 polymorphism was associated with the response to MT in codominant and superdominant inheritance models: CG vs. GG, p = 0.042, OR = 1.9 [1.15; 3.13]; CG vs. CC + GG, p = 0.02, OR = 1.73 [1.09; 2.77], respectively. In the dominant model, CG + GG vs. CC genotypes were predominant in responders: p = 0.016, OR = 1.80 [1.11; 2.91]. The dominant model of inheritance was the most significant, with the lowest Akaike information criterion value of 398.5. The data indicate a trend toward a higher frequency of the TC genotype of the ADA rs244076 polymorphism in responders in the super dominant model: TC vs. TT + CC, p = 0.066, OR = 1.69 [0.97; 2.96].

Conclusion. MT efficacy is associated with ATIC rs2372536 and ADA rs 244076 polymorphisms. Single-nucleotide polymorphisms ITPA rs1127354 and AMPD1 rs17602729 do not independently contribute to the therapeutic efficacy of MT in patients with RA. The dominant inheritance pattern of the ATIC rs2372536 gene is the most significant for predicting the efficacy of MT therapy in RA.

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