Meta Analysis Of SNP Related To Side Effects Of MTX Treatment Of RA And Its Correlation With Cold-heat Syndrome

Background:Characterized by the destruction of bone and cartilage,the deformity of joints,and the formation of vasospasm,Rheumatoid arthritis(RA)is a chronic immune disease that mainly invades the small joints of the human body.The pathogenesis of RA which is a systemic inflammatory disease,remains unclear.Additionally,curative therapy for RA has not been established.There are four main types of drugs for the treatment of RA:non-steroidal anti-inflammatory drugs,improved disease drugs,glucocorticoids and biological agents.One DMARDS,methotrexate(MTX),is widely used worldwide to treat RA because it is inexpensive,effective and safe.However,the effective rate of MTX is about 30%,the inefficiency is about 30%,and the number of patients with side effects is about 30%,which brings limitations and uncontrollability for MTX treatment of RA.There are currently no clear indicators and methods to solve this problem.In recent years,with the continuous development of genomics and precision medicine,more and more studies have reported that gene polymorphism is associated with the efficacy and side effects of MTX in the treatment of RA.These genes are mostly related to MTX Metabolites,transporters and drug targets.In different regions and different populations,the relationship between gene polymorphism and the efficacy and adverse drug reactions(ADRs)of MTX in the treatment of RA are not completely consistent.Although this type of research is controversial,with the continuous advancement of pharmacogenomics,such research is still expected to serve clinical.In addition,studies have reported that there are individual differences in the efficacy and side effects of MTX in the treatment of RA,and it is associated with the TCM syndrome of cold syndrome in RA patients.RA is a traditional Chinese medicine "arthralgia" category,and in the traditional Chinese medicine treatment of RA,dialectics is the foundation.Traditional Chinese medicine adopts the method of syndrome differentiation and treatment for "sickness syndrome".Patients with different syndromes have different clinical manifestations,and therefore,treatment is various.There is a certain similarity between the dialectical treatment of Chinese medicine and the individualized treatment in modern medicine.Part 1Obj ective:We performed an updated Meta-analysis aiming to verify the correlations between gene polymorphisms and adverse events in MTX treated rheumatoid arthritis(RA)patients.Then,we conducted a retrospective cohort study of Han Chinese in China to verify the evidence-based results.Methods:Relevant studies were collected from PubMed database and Embase database up to December 2017.Pre-allele,dominant,recessive,codominant and homozygotic model were applied.In addition,a retrospective cohort study enrolling 162 RA patients treated with MTX was included to verify these evidence-based findings.Single nucleotide polymorphisms(SNPs)genotyping was analyzed by PCR.Results:A total of 39 studies were included in 17 Meta-analyses,the Meta-analysis showed a significant association between MTX-related toxicity and MTHFR 677C>T(rs1801133)polymorphism in the East Asian RA patients,moreover,a significant association between MTX-related toxicity and ATIC 347C>G(rs2372536),RFC-1 80G>A(rs1051266),ABCB1 3435C>T(rs1045642)polymorphisms in the European RA patients.However,in the validation retrospective cohort study,we failed to find a positive association between MTX-related toxicity and MTHFR 677C>T(rs1801133),ATIC 347C>G(rs2372536)and ABCB13435C>T(rs1045642)polymorphisms,but a significant association between MTX-related toxicity and RFC-1 80G>A(rs1051266)polymorphism in Han Chinese RA patients.Conclusion:Evidence-based results suggested that MTHFR 677C>T(rs1801133),ATIC 347C>G(rs2372536),RFC-1 80G>A(rs1051266),ABCB1 3435C>T(rs1045642)polymorphisms were associated with MTX-related toxicity.Larger and more stringent study designs may provide more accurate findings for the effect of these SNPs on the MTX-related toxicity,moreover,larger sample-size studies in the Chinese Han population should be conducted to further validation.Part 2Obj ective:The objective of this study is to explore the relationship between Methylenetetrahydrofolate reductase(MTHFR)677C>T(rs1801133),aminoimidazole carboxamide ribonucleotide transformylase(ATIC)347C>G(rs2372536),reduced folate carrier(RFC)180G>A(rs1051266)and Adenosine triphosphate Binding cassette B1(ABCB1)(rs1045642)genetic polymorphisms and outcomes of methotrexate(MTX)therapy for rheumatoid arthritis(RA)with cold and hot pattern in China.Patients and methods:MTHFR 677C>T(rs1801133),ATIC 347C>G(rs2372536),RFC-1 80G>A(rs1051266),ABCB1 3435C>T(rs1045642)genetic polymorphisms may be related with adverse drug reactions(ADRs)of MTX,according to our previous Meta-analysis.A total of 110 patients with RA who are defined by cold and hot pattern were included in our study to find the relationship between single nucleotide polymorphisms(SNPs)according to the treatment of MTX and cold and hot pattern.Polymerase chain reaction(PCR)and sequencing was used to evaluate the SNPs.Disease activity score 28(DAS28)calculated by ESR was used to evaluate the clinical response,and adverse drug reactions(ADRs)were collected after physical examinations of the patients.Results:All the four SNPs didn't show a relationship between the cold and hot pattern.But in the RA patients of hot pattern,MTHFR 677C>T(rs1801133)was associated with the ADRs of MTX.TYMS also has a trend of associated with the efficacy of MTX in the hot pattern.Conclusion:Rheumatoid Arthritis with cold and hot Pattern in Traditional Chinese Medicine shows correlation with ADRs in MTHFR 677C>T(rs1801133)genetic polymorphisms.So maybe hot and cold pattern of RA patients in traditional Chinese and MTHFR 677C>T(rs1801133)genetic polymorphisms could guide the medication of MTX in clinical treatment.And further studies are required to validate these findings.