| BackgroundAcute anterior uveitis(AAU)is the most common type of uveitis,accounting for about 30%～50%of the total number of uveitis patients.Ankylosing Spondylitis(AS)is an inflammatory disease characterized by inflammation of the sacroiliac joints and spinal attachments,with asymmetric peripheral osteoarthritis and involvement of specific organs(eyes,lungs and muscles).Among them,ocular lesions represented by AAU are the most common extra-articular manifestations,and about 30%of AS patients can have ocular lesions.Previous showed that HLA-B27 was closely associated with the development of AAU and AS.They are thought to have overlapping genetic backgrounds and pathogenesis.However,genes in the HLA region may not only determine the occurrence of ankylosing spondylitis,but non-MHC region genes may also play an important regulatory role in the occurrence of the disease.Recently,some genome-wide association studies(GWAS)on Chinese Han AS patients had yielded new results,providing us a chance to deeply investigate the molecular genetic markers of AAU.PurposeIn this study,the AS Chinese Han nationality population with or without AAU was taken as the research object.It was expected to analyse the Singe nucleotide polymorphism(SNP)of non-MHC genes related to Chinese AS population that obtained through GWAS or related studies,to determine the correlation between these SNPs and AS with or without AAU in Chinese Han population,and to explore the characteristics and significance of genetic markers of AAU.MethodsA case-control study was conducted,including 769 AS without AAU patients(AS+AAU-),725 AS without AAU patients(AS+AAU+),and 1467 healthy controls.Seventeen SNPs in non-MHC region related to AS in Chinese Han population from previous GWAS studies were selected,and the genotyping of these SNPs was detected by MassARRAY system.The experimental design was divided into two stages.In the first stage,17 candidate SNP sites were preliminarily analyzed,and the chi-square test was used to analyze and screen the sites with statistically significant differences between healthy controls and AS patients(AS+AAU+,AS+AAU-).In the second stage,in the new sample set,the association between SNP loci that showed significant association with AS or AAU in the first stage and disease was further verified.And gender stratification and HLA-B27 stratification were carried out Logistic regression was used to obtain the adjusted odds ratio(ORaj)Bonferroni correction was used to correct the P value(Pc value)for multiple comparisons.Differences among groups were stated to be statistically significant when P-values<0.05.ResultsThrough two-stage analysis,we found that four SNP sites were significantly associated with AS.The four sites include 2 SNP located in the 2p15 gene region(2p15rs6759298,G,Pc=1.50×10-5,OR=1.280,CI=1.152～1.421,ORaj=1.273,CIaj=1.143～1.418;2p15 rs10865331,A,Pc=1.83 ×10-4,OR=1.240,CI=1.118～1.375,ORaj=1.249,CIaj=1.122-1.390),1 SNP in TBKBP1 gene(TBKBP1 rs8070463,C,Pc=2.91×104,OR=1.232,CI=1.111～1.366,ORaj=1.219,CIaj=1.096～1.356)and 1 SNP in ACTA2 gene(ACTA2 rs1800682,A,Pc=1.47×10-2,OR=1.172,CI=1.052～1.304,ORaj=1.171,CIaj=1.049～1.308).When the AS+AAU-group was compared with the normal group,there were statistically significant differences between these two groups,including 2 SNP located in the 2p15 gene region(2p15 rs6759298,G,Pc=1.51×10-3,OR=1.263,CI=1.110～1.436 ORaj=1.291,CIaj=1.133～1.471;2p15 rs10865331,A,Pc=2.14×10-3,OR=1.252,CI=1.102～1.422,ORaj=1.238,CIaj=1.088～1.410).TBKBP1 rs8070463 and ACTA2 rs1800682 had no significant correlation with AS+AAU+.In gender stratification analysis,two SNPs(2p15 rs6759298,G,Pc=8.66× 10-3,OR=1.282,CI=1.093～1.504;2p15 rs10865331,A,Pc=1.35×10-2,OR=1.266,CI=1.081～1.483)were significantly associated with AS+AAU+in males,but not with that in females.In HLA-B27 stratification analysis,two SNPs(2p15 rs6759298,G,Pc=3.55×10-3,OR=1.289,CI=1.127-1.475;2p15 rs10865331,A,Pc=3.15×10-2,OR=1.240,CI=1.082～1.420)were significantly associated with AS+AAU+in HLA-B27+patients,but not with that in HLA-B27-patients.In addition,when the AS+AAAU-patient group was compared with the normal group,4 SNP sites(2p15 rs6759298,G,Pc=2.28×10-4,OR=1.296,CI=1.142～1.471,ORaj=1.262,CIaj=1.107～1.440;2p15 rs10865331,A,Pc=5.04×10-3,OR=1.229,CI=1.084-1.393,ORaj=1.262,CIaj=1.107～1.437;ACTA2 rs1800682,A,Pc=3.49×10-3,OR=1.250,CI=1.096-1.426,ORaj=1.089,CIaj=0.952～1.245;TBKBP1 rs8070463,C,Pc=1.12×10-4,OR=1.306,CI=1.152～1.481,ORaj=1.148,CIaj=1.008～1.307)have statistically significant differences between these two groups.In gender stratification analysis,3 SNPs(2p15 rs6759298,G,Pc=1.13×10-3,OR=1.330,CI=1.140～1.553;2p15 rs10865331,A,Pc=2.61×10-3,OR=1.256,CI=1.101～1.433,TBKBP1 rs8070463,C,Pc=1.43 ×10-2,OR=1.254,CI=1.077～1.461)were significantly associated with AS+AAU-in males Two SNPs(ACTA2 rs1800682,A,Pc=1.09×10-2,OR=1.480,CI=1.144～1.915;TBKBP1 rs8070463,TT,Pc=8.99×10-3,OR=0.531,CI=0.352～0.800)were significantly associated with AS+AAU-in females.In HLA-B27 stratification analysis,two SNPs(2p15 rs6759298,G,Pc=2.47×10-3,OR=1.309,CI=1.139～1.504;2p15 rs10865331,A,Pc=2.23×10-2,OR=1.253,CI=1.091～1.438)were significantly associated with AS+AAU-in HLA-B27+patients.And there was no significant correlation between the above 4 SNPs and AS+AAU-patients with HLA-B27-.Finally,when the AS+AAU+group was compared with the AS+AAU-group,no statistical differences were found in the genotype and allele distribution frequency of the above 4 SNPs between the two groups.But it is worth noting that,when in HLA-B27 stratification analysis,in HLA-B27-patients,the frequency of ACTA2 rs1800682(AG,Pc=2.41×10-2,OR=0.242,CI=0.099～0.590)was significantly decreased in AS+AAU+patients.ConclusionOur study suggests that 2p15 rs6759298 and 2p15 rs10865331 are the overlapping genetic susceptibility sites of AS and AAU in Han Chinese males and HLA-B27+population.TBKBP1 rs8070463 and ACTA2 rs1800682 may be important genetic loci affecting the occurrence of AAU in Chinese Han AS patients.Among them,ACTA2 rs1800682 had a significant effect on the occurrence of of AAU in Han Chinese female AS patients and HLA-B27-patients.And they are of great significance for the diagnosis,prediction and treatment of AAU in the future. |
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