Association Between Single Nucleotide Polymorphisms Of JAK-STAT Signaling Pathway Related Genes And Ankylosing Spondylitis Susceptibility

Objective:To investigate the role of single nucleotide polymorphisms of JAK-STAT signaling pathway related genes in the susceptibility of ankylosing spondylitis.Methods:A total of 660 patients with AS diagnosed in the Department of Rheumatology and immunology of the First Affiliated Hospital of Anhui Medical University were collected in this study.According to the age and gender composition of AS patients,646 healthy people from Hefei central blood station and the physical examination center of the First Affiliated Hospital of Anhui Medical University were selected as the control group.A total of 15 SNP loci(rs2230587,rs2230588,rs2780815,rs310241,rs2274472,rs2230722,rs2230724,rs10758669,rs10199181,rs1547550,rs2066802,rs45463799,rs6718902,rs3744483,rs1135669)of JAK-STAT signaling pathway related genes were selected,and SNPscan genotyping technology was used.The frequencies of genotypes and alleles and genetic models were analyzed respectively,and the frequencies of candidate loci in the case group,the control group and their subgroups were compared,and and haplotypes were analyzed to understand the haplotypes among loci.Finally,BASDAI and BASFI were selected to analyze the clinical association.Statistical description is expressed as mean±standard deviation for the continuous data conforming to normal distribution,and median(interquartile interval)for the data not conforming to normal distribution.SPSS 23.0 software was used to analyze the data,and two-tailed P<0.05 in this study was considered as statistically significant.Bonferroni method was used to correct the P value for multiple comparisons.Results:There were 660 AS patients with an average age of 29.30±9.57 years,and the ratio of male to female was 527:133(3.96:1);646 healthy controls with an average age of28.61±7.85 years,and the ratio of male to female was 526:120(4.38:1).There was no significant difference in age(t=1.427,P=0.154)and sex(χ~2=0.519,P=0.471)between the case group and the control group by t test andχ~2 test.The two groups were comparable.62.9%of AS patients were HLA-B27 positive.The average course of disease was 2(0,7)years.The median scores of BASFI and BASDAI were 0.8(0,2.6)and 1.8(0.4,3.3),respectively.The results of HWE genetic balance test showed that all 15 loci were in line with the genetic balance.Genotype and allele analysis showed that there was no significant difference between the two groups(P>0.05).After sex stratification,the rs6718902 locus of STAT1 gene was found to be associated with AS susceptibility in male population(χ~2=9.272,OR[95%CI]=0.765[0.644-0.909],P=0.002),but not in female population,The results showed that the genotype frequencies of rs3744483 on STAT3 and rs1135669 on STAT5A were significantly different between the two groups with different BASFI scores(rs3744483:χ~2=9.808,P=0.007;rs1135669:χ~2=10.469,P=0.005),while the allele frequencies of rs10199181 on STAT1 were significantly higher in patients with HLA-B27 positive or not,there was significant difference in allele frequency distribution between the two groups(χ~2=11.007,OR[95%CI]=0.642[0.493-0.835],P=0.001).Genetic model analysis showed that there was significant difference between the case group and the control group in the recessive model of JAK2 gene rs2230724(χ~2=6.728,OR[95%CI]=0.680[0.507-0.911],P=0.009),and the dominant model(χ~2=22.982,OR[95%CI]=0.186[0.087-0.399],P<0.001)and homozygous model(χ~2=21.592,OR[95%CI]=0.193[0.090-0.415],P<0.001)of STAT1 gene were also found,There were significant differences between the dominant model(χ~2=10.591,OR[95%CI]=1.570[1.195-2.062],P=0.001)and homozygous model(χ~2=8.550,OR[95%CI]=1.674[1.184-2.368],P=0.003)of rs6718902 locus in males.The linkage disequilibrium between rs310241 and rs2230588(D’=0.98,r~2=0.93),rs3744483 and rs1135669(D’=0.99,r~2=0.98)was found in the 15 loci.The haplotype analysis did not identify the haplotype combination that might affect AS susceptibility.Association analysis of clinical indicators:BASFI scores in rs6718902 genotypes were statistically different between groups(P=0.033),and no statistical difference was observed in other groups.Stratified analysis of AS patients according to gender showed that the distribution of BASDAI score among rs2230724genotypes in male patients was statistically significant(P=0.034);in female patients,when rs2230588,rs2780815 and rs310241 were used AS grouping variables,the distribution of BASFI score was statistically significant(rs2230588:P=0.026;rs2780815:P=0.006;rs310241:P=0.015),In addition,the distribution of BASDAI score among rs2230588genotypes was statistically different(P=0.025).Conclusion:The genotypes of JAK1 gene rs2230588,rs2780815 and rs310241 are associated with the severity of AS in female patients;the mutation of JAK2 gene rs2230724 may increase the risk of AS,and the genotype of JAK2 gene affects the disease function index of male AS patients;The T allele of STAT1 gene rs6718902 polymorphism may be a protective factor for the onset of AS in Chinese Han male population,and the genotype may affect the disease activity of AS patients.The mutation of rs1547550 allele may be associated with the onset of AS,and the allele frequency of rs10199181 may be associated with HLA-B27;The genotype frequencies of STAT3 gene rs3744483 and STAT5A gene rs1135669 may be related to the functional status of AS.