| Part(Ⅰ)The prognosis of Inflammatory bowel disease patients was significantly improved by anti-TNF therapy.However,the effectiveness of the treatment is quite different in the individual patient,which can partly be explained by gene polymorphism.The research methods of single nucleotide polymorphism generally include candidate gene association analysis and whole-genome association analysis.Because of the heterogeneity of present research,the result od former mehoed were conflicting.Thus,currently,it is difficult to determine whether the previously observed genetic correlation really exists.The later method does not need to construct any etiology hypothesis in advance.However,it is rarely used at present.Part(Ⅱ)Objective: To investigate the relationship between the gene polymorphism of TNF and its receptor superfamily(TNF / TNFR)and the efficacy of anti-TNF therapy in inflammatory bowel disease patients.Methods: Pub Med and Cochrane Library databases were searched according to the searching strategy.The searching time was FRom March1999 to March 2019,and the relevant references and systematic analysis were traced to ensure the comprehensiveness of searching.Data analysis was carried out by Using Stata 15.1 software,and statistical analysis was carried out by combining statistics,sensitivity analysis,heterogeneity test,publication bias.Results: 12 trials involving 3739 IBD patients were included.Combined statistical results found that the response rate of anti-TNF treatment in patients with a mutation of rs1800629 was lower than that in patients with wild type(or = 0.51,95% CI: 0.31-0.83,P =0.007).However,no significant difference was found in long-term follow-up patients(or = 1.04,95% CI: 0.77-1.41,P = 0.0805).The response rate in rs766455 mutaion type was 0.61 times lower than of wild type(or =0.61,95% CI = 0.39-0.96,P = 0.031).There had a critical statistical significance of rs414957 polymorphism and anti TNF effency,and the anti TNF response rate of mutant type was 1.33 times higher than that of wild type(GG)gene(or = 1.33,95% CI = 0.99-1.79,P = 0.057).There was no correlation among other genotypes of rs1799724,rs361525,rs1061624,rs3397 and rs101622.Sensitivity analysis suggested that the results of the study were not affected by a single study,and there is no significant publication bias.Conclusion: the polymorphism of rs1800629,rs414957 and rs767455 were related to the response of anti-TNF therapy.However,there is not enough evidence to prove that the polymorphism of the TNF/TNFR gene is related to the efficiency of anti-TNF therapy.Part(Ⅲ)Objective: To mine a new SNPs which can predict the efficacy of anti-TNF though integrated Gene Expression analysis Method: Six transcriptional datasets were downloaded and preprocessed from the gene chip database.Utilizing ES statistical methods,we screened the differentially expressed genes in the patients with the response and non-response to TNF treatment.We conducted a functional enrichment analysis and extracted hub genes from the protein-protein interaction network.The proportion of immune cell types was estimated via CIBERSORT.By cross-comparing the SNP precisely reported,we search the genes that are both regulated by genetic variation sites of IBD and related to the anti-TNF efficacy.Results: A total of 287 DEGs were obtained from the integrated dataset.Polarization from M2 to M1 macrophages was relatively high in non-response individuals.We found nine hub genes(TLR4,TLR1,TLR8,CCR1,CD86,CCL4,HCK,and FCGR2A),mainly related to the interaction between Toll-like Receptor(TLR)pathway and FcγR signaling in non-response anti-TNFα individuals.rs1801274 and rs6142618 may associated with efficacy of anti-TNF therapy,which is closely related to FCGR2 A and HCK.Conclusion: Rs1801274 and rs6142618 ibd may be predictize to the efficacy of anti-TNF therapy.The over activation of FCγr-TLR axis of innate immune cells may be used to identify non-responsive individuals. |
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