Association Of TNFAIP3 And TNIP1 Gene Polymorphisms With Ankylosing Spondylitis Susceptibility

Objective: Ankylosing spondylitis(AS)is a chronic inflammatory autoimmune disease,which mainly invades the central axis and sacroiliac joints of patients,and can involve peripheral joints,tendons,ligament attachment points and other tissues,severely affecting patients’ functional activities and quality of life.Many studies have shown that TNFAIP3 and TNIP1 gene polymorphisms are associated with susceptibility to a variety of autoimmune diseases,while few studies have investigated the association between single nucleotide polymorphisms of TNFAIP3 and TNIP1 genes and the risk of AS.Therefore,the purpose of this study was to investigate the relationship between the nine single nucleotide polymorphisms(SNPs)of TNFAIP3 and TNIP1 genes and AS susceptibility.Methods: A case-control design was used for the study.The cases were 667 AS patients treated in the rheumatology and immunology clinic of the First Affiliated Hospital of Anhui Medical University from January 2013 to January 2018,and 667 gender and age-matched health checkups in the same period were selected as healthy controls.After consulting the literature and searching the database,five SNPs in TNFAIP3 gene(rs610604,rs10499194,rs13207033,rs2230926,and rs6920220)and four SNPs in TNIP1 gene(rs2233287,rs3792783,rs4958881,and rs6889239)were finally included and genotyped by the improved SNPscan method.SPSS 23.0 software was used for data analysis.Data that conformed to the normal distribution were described by mean ±standard deviation.Comparisons between groups were analyzed by t test.Data that do not fit the normal distribution are described using the median and upper and lower quartiles.The comparison between groups was performed using the Mann-Whitney U test.The qualitative data are described by frequency and percentage,and compared by chi-square test or Fisher exact test.The distribution of allele frequencies,genotypes,and genetic models in AS patients and healthy controls was analyzed.Haploview 4.2 software was used to achieve linkage disequilibrium and haplotype analysis.Calculate the individual’s weighted genetic risk score(w GRS),and then use receiver-operating characteristic(ROC)curves and area under the curve(AUC)to assess w GRS for predicting disease ability.Analysis of gene-to-gene interactions was conducted by multi-factor dimensionality reduction.Bonferroni correction was used to correct the multiple comparison results,and the two-sided P-value < 0.05 was considered statistically significant.In addition,gene function annotation was performed on important SNPs.Results: The genotype distribution and allele frequency of the rs10499194 of the TNFAIP3 gene were significantly different between the AS group and the control group(genotype distribution: P = 0.007;allele frequency: OR = 0.619,95% CI = 0.430-0.889,P = 0.009),while the other 8 SNPs had no statistically significant difference in genotype distribution and allele frequency between AS patients and healthy controls(all P > 0.05).However,after Bonferroni correction,there was no significant difference in genotype distribution and allele frequency between the two groups at rs10499194(P > 0.05).Genetic model analysis showed that carriers of mutant heterozygote CT genotype at the rs10499194 had significantly lower AS risk than the carriers of wild-type CC genotype(OR = 0.603,95% CI = 0.416-0.875;P = 0.007).But after Bonferroni correction,the P value is no longer statistically significant(P > 0.05).The results of stratified analysis showed that in men and the subgroup ≥ 29 years of age,compared with wild genotype CC,the risk of AS in CT genotypes was significantly reduced(all P < 0.05);in addition,there was also a significant difference in genotype distribution between the HLA-B27 positive patients,patients with BASDAI < 4 and patients with BASFI < 4 T AS and healthy controls(all P < 0.05).The results of haplotype analysis showed that rs13207033A-rs10499194 T haplotype was significantly associated with a reduction in AS risk(OR = 0.601,95% CI = 0.416-0.868;P = 0.006).The w GRS was calculated based on the five SNPs of the TNFAIP3 gene.The results showed that there were statistically significant differences in w GRS between AS patients and healthy controls,and between HLA-B27 positive AS patients and negative patients(both P < 0.05),but the ability to use w GRS to distinguish AS patients from healthy controls were weak.In addition,the gene function annotation results suggested that the rs10499194 mutation has potential functions.Conclusion: The mutation of the rs10499194 of the TNFAIP3 gene reduces the risk of AS,and the rs13207033A-rs10499194 T haplotype is associated with decreased susceptibility to AS.Functional annotation results also indicate the potential function of the rs10499194 mutation.