Associations Of Breast Cancer Resistance Protein Gene Polymorphisms In Rheumatoid Arthritis Patients With Drug Resistance In A Chinese Population

BackgroundRheumatoid arthritis (RA) is an autoimmune disease characterized by chronic erosive arthritis. Disease-modifying anti-rheumatic drugs (DMARDs) are recommended as the first-line treatment in clinical practice for decades, with less adverse effect and low price。However, physicians find that part of the RA patients seems to be less efficient with DMARDs, even increasing dosages cannot redress it. DAMRDs Resistance is a common problem in clinic, which undoubtedly affect the prognosis of RA. So far the mechanism leading to the resistance is not clear. Recently, studies showed that multi-drug resistance transporter (MDR) may play an important role in this process through the exocytosis effect to drugs.Breast cancer resistance protein (BCRP) is a member of MDR which has been proved to play an important role in the resistance to chemotherapeutics through the exocytosis effect to chemotherapeutic agents. It is noted that some DMARDs, including methotrexate, leflunomide and salazosulfadimidine are all substrates of BCRP. Previous studies have showed that BCRP expressed on the macrophages of synovial tissue and related to a poor response to DMARDs. Long-term use of salazosulfadimidine can up-regulate the expression of BCRP on T cells and reduce intracellular drug concentration. BCRP is coded by BCRP gene (ABCG2). Single nucleotide polymorphisms (SNPs) of C421A and G34A sites in BCRP gene can affect the expression of BCRP on cancer cells, resulting in pharmacokinetics change of chemotherapeutic agents and resistance to chemotherapeutics. By far there is no report on the relationship between SNPs of these two sites and resistance of DMARDs in RA patients. Objective:To investigate the relationship of single nucleotide polymorphisms (SNPs) of C421A and G34A sites with the drug-resistance of RA in Hunan Han population.Methods:308subjects of Chinese Han origin were genotyped with polymerase chain reaction-restricted fragment length polymorphisms (PCR-RFLP), with204RA patients and104healthy controls. The RA treated were divided into two groups according the response to disease-modifying antirheumatic drugs (DMARDs). There were108patients in the effective group and115patients in the in-effective group. Genotype distribution and allele frequencies were analyzed between the three groups.Results:No deviations from the Hardy-Weinberge quilibrium(HWE) were observed in all study groups. Compared to non-responders, the responders carried more AC genotype (P=0.031, OR=0.521,95%CI:0.287-0.945), and more A allele (P=0.027, OR=0.625,95%CI:0.412-0.949) in C421A site, but with no statistically differences in genotype nor allele frequency between RA and healthy controls. There were significant differences in the genotype frequency and allele frequency in G34A site among three groups (P>0.5).Conclusion:The results from our study suggest that the C421A BCRP gene polymorphism may not be related with the RA susceptibility, but may influence the efficacy of RA therapy with DMARDs. There is no such relationship found in G34A site.