Genetic Polymorphisms of TYMS, MTHFR, ATIC, MTR, and MTRR Are Related to the Outcome of Methotrexate Therapy for Rheumatoid Arthritis in a Chinese Population.

Shuang Lv,Cheng Xiao,Xiaoming Shu,Hui Yang,Lu Zhang,Huizhen Fan,Xiaoya Li,Jing Huang,Yuan Xu,Jieyu Zuo,Jiang Li

doi:10.3389/fphar.2018.01390

Abstract

Objective: Analysis of the relationship between single nucleotide polymorphisms (SNPs) and outcomes of methotrexate (MTX) therapy for rheumatoid arthritis (RA) in China.Materials and Methods: TYMS 28 bp VNTR (rs34743033), MTHFR [677C>T (rs1801133) and 1298A>C (rs1801131)], ATIC 347C>G (rs2372536), MTR A2756G (rs1805087), and MTRR 66A>G (rs1801394) enzyme proteins may be related to the outcomes of MTX therapy, according to our previous meta-analysis. A total of 162 patients with RA were included in our study. SNPs were evaluated using polymerase chain reaction (PCR). Disease Activity Score 28 (DAS28) was used to evaluate the clinical response, and adverse drug reactions (ADRs) were collected after physical examinations of the patients.Results: The MTHFR 677C>T gene showed a relationship with the ADRs of MTX in the Recessive model [TT vs. (CC+CT)] (p = 0.04, OR = 2.20, 95% CI: 1.01, 4.77). In the Codominant model [CT vs. (CC+TT)], the MTHFR 677C>T gene also showed a trend of association with ADRs (p = 0.08, OR = 0.52, 95% CI: 0.25, 1.08). No significant difference was found between TYMS, MTHFR, ATIC, MTR, and MTRR gene polymorphisms and the RA response or ADRs related to MTX in our study.Conclusion: Our results showed that the MTHFR [677C>T (rs1801133)] TT genotype is associated with ADRs to MTX in Chinese RA patients. Other SNPs, including TYMS 28bp VNTR (rs34743033), MTHFR [677C>T (rs1801133) and 1298A>C (rs1801131)], ATIC 347C>G (rs2372536), MTR A2756G (rs1805087), and MTRR 66A>G (rs1801394) gene polymorphisms, were not associated with MTX treatment outcomes. Further studies are required to validate these findings.

Highlights

Rheumatoid arthritis (RA) is characterized by synovial inflammation, cartilage damage and bone erosion (Walter et al, 2016; Fessler et al, 2017)
Our results showed no differences in terms of age, sex, DAS28 results, MTX dose, treatment duration, erythrocyte sedimentation rate (ESR), CPR, rheumatoid factor (RF) positive status, cyclic citrullinated peptide (CCP) positive status, anti-keratin antibody (AKA) positive status, antinuclear antibody (ANA) positive status, individual variables of DAS28 and smoking and drinking habits between the responder and non-responder groups
Among the 162 RA patients, 99 RA patients responded to MTX therapy, and 63 RA patients did not

Summary

Introduction

Rheumatoid arthritis (RA) is characterized by synovial inflammation, cartilage damage and bone erosion (Walter et al, 2016; Fessler et al, 2017). The pathogenesis of RA, which is a systemic inflammatory disease, remains unclear. Curative therapy for RA has not been established. Disease-modifying anti-rheumatic drugs (DMARDs) are usually used to delay symptom progression and achieve pain relief (Kojima et al, 2016). One DMARD, methotrexate (MTX), is widely used worldwide to treat RA because it is inexpensive, effective and safe (Swierkot et al, 2015); 30–40% of patients on MTX therapy fail to attain remission (Ranganathan and McLeod, 2006), and 30–40% of patients have problems with safety and tolerability (Wevers-de Boer et al, 2012). Six single nucleotide polymorphisms (SNPs) that encode proteins involved in MTX metabolism are examined in our meta-analysis (Qiu et al, 2017a,b)

Methods

Results

Discussion

Conclusion