| BackgroudRheumatoid arthritis(RA)is a systemic autoimmune disease characterized by chronic synovial joint inflammation,which leads to disability and diminished quality of life.Foreign studies show that the morbidity of RA is about 0.5-1%,while a recent study in our country shows that the morbidity of RA in China is about 0.34%.The main objectives for managing RA are to control pain,prevent or control joint damage and avoid long-term loss of function.Methotrexate(MTX)is widely used and considered a first-line disease modifying anti-rheumatic drug(DMARD)cornerstone drug for the treatment of rheumatoid arthritis.However,the effective rate of RA treatment is about 60%,estimates indicated that in 10%to 30%of the patients,MTX therapy is discontinued because of adverse effects,the individual reaction of the patients after taking medicine is quite different.With the development of pharmacogenomics,it is known that genetic differences among individuals are important reasons for the efficacy and adverse effects of drugs.Genetic polymorphisms in drug metabolizing enzymes,transporters,and other drug target genes can lead to individual differences in drug response.In the past ten years,there has been a great deal of research on the relationship between the polymorphisms of MTX related drugs,metabolizing enzymes and transporters and the effectiveness of MTX in the treatment of RA,but there are some differences in the results of these studies,however,the majority of the findings were inconclusive and inconsistent.RA is a traditional Chinese medicine "arthralgia" category,and in the traditional Chinese medicine treatment of RA,dialectics is the foundation.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 1ObjectiveTo estimate the association between gene polymorphisms and MTX efficacy in RA patients.MethodsSearching EMBASE and PubMed in February 2016 for polymorphisms and pharmacogenomics study of the efficacy of MTX monotherapy in RA patients,While using the method of literature date back,hand searching the topic of references reviewed to ensure the comprehensiveness of the search.In strict accordance with the inclusion and exclusion criteria into line with the literature,data acquisitions by the two researchers independently.STATA 13 software was used for data analysis.The synthetic conclusions were obtained by combining statistics,heterogeneity test,drawing forest maps and funnel plots and subgroup analysis.Result1 The initial search identified 696 publications(PubMed:235;and Embase:461).The full text of 80 articles was reviewed in detail and 30 publications were included in the SR and 21 studies were included in 9 meta-analyses.A total of 34 genes with 125 gene SNPs associated with the transporters,enzymes,and metabolites of MTX or the progression of RA were evaluated to explore the association between the gene polymorphisms and the patient responses to MTX.7 genes with 9 gene SNPs were included in the meta-analysis.Ten studies were included in the meta-analysis of MTHFR 677C>T(rs1801133),which contained data from a combined total of 579 responders and 677 nonresponders and included six European studies(423 responders and 438 nonresponders)and three South Asian studies(94 responders and 208 nonresponders);eight studies were included in the meta-analysis of MTHFR 1298A>C(rs1801131),which contained data from a combined total of 425 responders and 527 nonresponders and included four European studies(270 responders and 288 nonresponders),two East Asian studies(79 responders and 48 nonresponders)and two South Asian studies(76 responders and 191 nonresponders);five studies were included in the meta-analysis of ATIC 347C>G(rs2372536),which contained data from a combined total of 458 patients and 398 controls and included two European studies(132 responders and 134 nonresponders),one East Asian study(72 responders and 33 nonresponders)and two South Asian studies(254 responders and 231 nonresponders);three studies were included in the meta-analysis of TYMS 28 bp VNTR(rs34743033),which contained data from a combined total of 335 responders and 264 nonresponders;two studies were included in the meta-analysis of MTRR 66A>G(rs 1801394),which contained data from a combined total of 126 responders and 198 nonresponders;four studies were included in the meta-analysis of RFC-1 80G>A(rs1051266),which contained data from a combined total of 298 responders and 423 nonresponders;two studies were included in the meta-analysis of SLC19A1 G>A(rs7499),which contained data from a combined total of 246 responders and 224 nonresponders;two studies were included in the meta-analysis of SLC19A1 A>G(rs2838956),which contained data from a combined total of 246 responders and 225 nonresponders;Two studies were included in the meta-analysis of ABCB1 3435C>T(rsl 045642),which contained data from a combined total of 177 responders and 161 nonresponders.2.1 The association between the MTHFR 1298A>C(rs1801131)3 allele frequency(AA,AC and CC)and MTX response status was not significant in pre-allele model(OR=1.004,95%Cl:0.749-1.346,Z = 0.03,P = 0.979),dominant model(OR = 0.908,95%Cl:0.596-1.382,Z?0.45,P = 0.652),recessive model(OR = 0.861,95%CI = 0.494-1.503,Z = 0.53,P = 0.599),codominant model(OR = 1.205,95%CI = 0.772-1.882,Z = 0.82,P = 0.412),and homozygotic model(OR = 0.987,95%CI = 0.626-1.554,Z = 0.06,P = 0.954),Stratification by ethnicity identify a significant association between the MTHFR A1298C(rs1801131)3 allele frequency(AA,AC and CC)and MTX response in the South Asian populations in recessive(OR = 0.454,95%CI:0.228-0.906,Z = 2.24,P = 0.025)and codominant model(OR = 2.319,95%CI:1.317-4.086,Z = 2.91,P = 0.004)but not in other models and other populations;2.2 A significant association between the ATIC 347C>G(rs2372536)3 allele frequency(CC,CG and GG)and MTX response status was identified in dominant model(OR = 1.612,95%CI:1.168-2.224,Z = 2.91,P= 0.004)and codominant model(OR = 0.634,95%Cl:0.468-0.858,Z = 2.95,P = 0.003),but not in pre-allele model(OR = 1.263,95%CI:0.958-1.666,Z = 1.65,P = 0.098),recessive model(OR = 1.068,95%CI:0.699-1.630,Z = 0.30,P=0.762)and homozygotic model(OR = 1.229,95%CI:0.749-2.015,Z = 0.82,P = 0.415),Stratification by ethnicity identified a significant association between the ATIC 347C>G(rs2372536)3 allele frequency(CC,CG and GG)and MTX response status in Europeans in pre-allele model(OR = 1.736,95%CI 1.176-2.564,Z = 2.77,P = 0.006),dominant model(OR = 2.346,95%Cl 1.407-3.910,Z = 3.27,P = 0.001),and codominant model(OR = 0.458,95%CI 0.274-0.764,Z = 2.99,P = 0.003)but not in other model and in the South Asian populations;2.3 The association between the RFC-1 80G>A(rs1051266)allele frequency(GG,GA and AA)and MTX response status was significant in pre-allele(OR = 0.716,95%CI 0.545-0.941,Z =2.39,P = 0.017),dominant(OR = 0.645,95%CI:0.449-0.926,Z = 2.38,P = 0.017),recessive(OR = 1.653,95%CI = 1.115-2.451,Z = 2.5,and P = 0.012),and homozygotic model(OR = 0.488,95%CI = 0.302-0.789,Z = 2.93,P = 0.003),but not in codominant model(OR = 1.018,95%CI = 0.743-1.396,Z = 0.11,P = 0.91),Stratification by ethnicity identified a significant association between the RFC-1 80G>A(rs1051266)allele frequency(GG,GA and AA)and MTX response status in Europeans in pre-allele model(OR =0.561,95%CI 0.356-0.884,Z = 2.49,P = 0.013),recessive Model(OR = 2.343,95%CI 1.169-4.694,Z=2.40,P = 0.016),and homozygotic Model(OR = 0.301,95%CI 0.114-0.796,Z = 2.42,P ?0.016),and South Asian populations in Pre-allele model(OR =0.705,95%CI 0.523-0.951,Z?2.29,P = 0.022),dominant model(OR =0.642,95%CI 0.415-0.993,Z = 1.99,P = 0.046),and homozygotic model(OR =0.473,95%CI 0.252-0.887,Z = 2.33,P = 0.020),but not in other models;2.4 The association between the SLC19A1 G>A(rs7499)3 allele frequency(GG,GA and AA)and MTX response status was significant in pre-allele(OR =1.536,95%CI 1.176-2,005,Z = 3.15,P = 0.002),dominant(OR = 1.681,95%CI:1.146-2.467,Z = 2.66,P = 0.008),recessive(OR = 0.528,95%CI = 0.316-0.884,Z = 2.43,P = 0.015),and homozygotic model(OR = 2.397,95%CI = 1.359-4.229,Z = 3.02,P = 0.003),but not in the codominant model(OR = 0.861,95%CI = 0.596-1.242,Z = 0.80,P = 0.423);2.5 The association between the SLC19A1 A>G(rs2838956)3 allele frequency(AA,AG and GG)and MTX response status was significant in pre-allele model(OR =1.366,95%CI 1.051-1.776,Z = 2.33,P=0.020),recessive model(OR = 0.592,95%CI = 0.361-0.969,Z = 2.08,P = 0.037)and homozygotic model(OR = 1.973,95%CI = 1.131-3.443,Z = 2.39,P = 0.017),but not in the dominant(OR = 1.426,95%CI = 0.965-2.109,Z = 1.78,P = 0.075)and the codominant model(OR = 0.98,95%CI = 0.635-1.512,Z = 0.09,P = 0.927);2.6 There are not significant association between MTHFR 677C>T(rs1801133),TYMS 28 bp VNTR(rs34743033),MTRR 66A>G(rs1801394)and ABCB1 3435C>T(rs1045642)and MTX efficacy in RA patients.ConclusionThis SR and meta-analysis demonstrated associations between MTX response in RA patients in MTHFR 1298A>C(rs1801131),ATIC 347C>G(rs2372536),RFC-1 80G>A(rs1051266),SLC19A1 A>G(rs2838956)and SLC19A1 G>A(rs7499)genetic polymorphisms,but not observed between the MTHFR 677C>T(rs1801133),TYMS 28 bp VNTR(rs34743033),MTRR 66A>G(rs1801394),and ABCB1 3435C>T(rs1045642)genetic polymorphisms and the response to MTX in RA patients.Part 2ObjectiveTo observe correlation between MTHFR 677C>T and MTHFR 1298A>C gene polymorphism and distribution of Chinese medicine syndrome in RA patients.MethodsPeripheral blood was collected from 88 RA patients who took MTX to examine the MTHFR 677C>T and MTHFR 1298A>C gene polymorphism by means of PCR technique and sanger direct sequencing,while TCM syndrome distribution was also observed.Result Cold syndrome group of 43 people,heat syndrome group of 45 people,gender,age,course of the two groups had no difference.The genotype frequency(CC,CT and TT)of MTHFR 677C>T in cold syndrome group was 21.95%,53.66%,24.39%and 24.4%,60.0%,15.6%in heat syndrome group,there was no significant association between the MTHFR 677C>T genotype and TCM syndrome(P>0.5);The genotype frequency(AA,AC and CC)of MTHFR 1298A>C in cold syndrome group was 69.8%,30.2%,0 and 68.9%,31.2%,0 in heat syndrome group,there was no significant association between the 1298A>C genotype and TCM syndrome(P>0.5);the allele frequency of MTHFR 677C>T in cold syndrome group was 48.8%,51.2%and 54.4%,45.6%in heat syndrome group,there was no significant association between the MTHFR 677C>T allele frequency and TCM syndrome(P>0.5);the allele frequency of MTHFR 1298A>C in cold syndrome group was 84.9%,15.1%and 84.4%,15.6%in heat syndrome group,there was no significant association between the MTHFR 677C>T allele frequency and TCM syndrome(P>0.5).ConclusionThere were not statistically relationship between MTHFR 677C>T and MTHFR 1298A>C gene polymorphism and distribution of Chinese medicine syndrome in RA patients. |
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