Association Of Environmental Factors And Th17 Pathway-related Gene Polymorphisms With The Pathogenesis And Clinical Phenotype Of Crohn's Disease

Background:Crohn's disease(CD)is a chronic non-specific gastrointestinal inflammatory disease.Environmental,genetic,immune and microecological factors play an important role in the pathogenesis of CD.In the past two decades,the prevalence of CD in China has an upward trend,so it is necessary to look for the risk factors of CD disease in China.Environmental factors are important factors for CD.Single nucleotide polymorphism(SNP)is associated with CD susceptibility and clinical phenotype.However,there were few studies on the relationship between Th17 pathway related genes polymorphism and CD pathogenesis in the Chinese Han population.And the interaction between Th17 related genes and environmental factors was rarely reported,which is very important for exploring the relationship between immunity and gene.Objective:(1)To explore the correlation between environmental factors before the onset of CD and the incidence of CD through a case-control study.And to obtain the independent risk factors related to CD,which is expected to provide basic data for the prevention of CD disease in the future.(2)To analyze the relationship between Th17 cell differentiation pathway related genes IFNGR2 rs2284553,IL-23R rs7517847,IRF4 rs7773324,PER3 rs2797685 and TNFSF15 rs4263839 polymorphism and CD susceptibility and clinical phenotype.(3)To elucidate the relationship between Th17 pathway related genes and environment interaction on CD clinical phenotype,and to explain the relationship among heredity,environment and immunity in the pathogenesis of CD.Methods:1.159 CD patients and 671 healthy controls were selected from Peking Union Medical College Hospital from January 2016 to December 2018.Through propensity score matching(including age,sex,nationality,blood type,IBD family history),100 CD patients and 229 healthy controls were successfully matched.X2 test(or Mann-Whitney U test)was used to analyze the differences in the distribution of environmental factors,including personal history,past history,regional economic and social relations,dietary nutrition factors and sleep factors between the CD group and the control group.The variables related to the above analysis results were included in the multivariate logistics model analysis.2.159 CD patients and 316 healthy controls were selected from Peking Union Medical College Hospital from January 2016 to December 2018.DNA was extracted from whole blood cells isolated from peripheral venous blood.SNP was detected by a single base extension reaction including IFNGR2 rs2284553,IL-23R rs7517847,IRF4 rs7773324,PER3 rs2797685,TNFSF15 rs4263839 related to Th17 cell differentiation pathway.X2 test(or Fisher exact test)was used to compare the difference in distribution of genotype and allele frequency between the two groups and the relationship between genotype frequency and the clinical characteristics.Multifactor dimensionality reduction(MDR)was used to analyze the relationship between gene-environment interaction and clinical phenotype of CD.Results:Part one:The risk factors of CD were smoking history(P=0.002)and children living in cities(P=0.004).The protective factors were drinking history(P<0.0001),Helicobacter pylori infection(P<0.0001),milk consumption(P<0.0001),pepper consumption(P=0.003)and moderate to severe physical labor intensity(P=0.015 and P=0.001).Part two:1.Compared with the control group,the proportion of IFNGR2 rs2284553 A allele was lower(OR=0.743,95%CI 0.562?0.981,P=0.036),and the proportion of PER3 rs2797685 T allele was higher in CD group(OR=1.405,95%CI 1.061?1.861,P=0.017).The distribution of TNFSF15 rs4263839 allele frequency(P<0.001)and genotype frequency(P<0.001)were statistically different.The proportion of rs4263839 A allele in CD group was lower than that in control group(OR=0.573,95%CI 0.433?0.759,P<0.001).2.In different clinical phenotypes of CD,the proportion of TNFSF15 rs4263839 in patients with different ages and different locations was statistically significant.The proportion of IL-23R rs7517847 in patients with different severity was statistically significant.The proportion of PER3 rs2797685 in patients with perianal disease was also notably significant.3.In the interactive model with age of onset,frequently eating food storage in refrigerator,less daily sunshine duration,rs2284553 GG,rs2797685 TT and rs4263839 GG,increased the risk of CD onset earlier than 40 years old.In the interaction model with CD lesion involving the small intestine,the best interaction model was composed of infectious enteritis history,no history of breast feeding,rs2284553 GG,rs7517847 TT and rs4263839 GG.In the interaction model of intestinal stricture in CD patients,the best interaction model is composed of infectious enteritis history,no history of breast feeding,rs2284553 GG,rs2797685 TT and rs4263839 GG.In the interaction model of CD patients undergoing surgery,the best interaction model is no history of breast feeding,smoking history,less daily sunshine duration,rs7517847 TT,rs2797685 TT and rs4263839 GG.In the model of whether CD is associated with perianal lesions,the best interaction model is no history of breast feeding and eating refrigerator food for more than 3 days.In the model of whether CD lesions involve upper digestive tract,the best interaction model is drinking milk and rs4263839 GG.Conclusions:1.Environmental factors such as residence and diet may be involved in the pathogenesis of CD.Smoking and children living in cities are the risk factors of CD.While drinking,helicobacter pylori infection,milk consumption,pepper consumption and moderate to severe physical labor intensity are protective factors.2.SNPs of genes related toTh17 cell differentiation pathway are related to CD pathogenesis and CD phenotype.SNPs and different environmental factors may lead to different phenotypes of CD.