Genetic Polymorphisms Of Cell Adhesion Molecules And Autophagy-relate Genes In Behcet’s Disease And Vogt-Koyanagi-Harada Syndrome

PART I GENETIC POLYMORPHISMS OF AUTOPHAGY-RELATE GENES IN BEHCET’S DISEASE AND VOGT-KOYANAGI-HARADA SYNDROMEBackground: Uveitis is a prevailing eye disease causing blindness worldwide. Behcet’s disease(BD) and Vogt-Koyanagi-Harada(VKH) syndrome are two common uveitis entities in China. VKH syndrome is a systemic autoimmune disorder. BD is a chronic and relapsing autoinflammatory disease. Autophagy plays vital roles in cells participating in either the innate or adaptive immune system. Recent studies have shown that genetic variants of autophagy-related genes(ATGs) play a role in the predisposition to the development of various autoimmune diseases and carcinoma. To date the association of ATGs with uveitis has not been investigated and was therefore the purpose of the studies described here.Purposes : This study was conducted to explore the association of autophagy-related genes(ATGs) single nucleotide polymorphisms(SNPs) with Beh?et’s disease(BD) and Vogt-Koyanagi-Harada(VKH) syndrome. Methods:An association study was carried out in 940 BD, 1061 VKH and 2007 normal controls. Genotyping for genetic variants of 10 autophagy family genes were performed using polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP) or Taq Man SNP assays. Genotype distributions and allele frequencies were compared using χ2 analysis between BD patients, VKH syndrome patients and normal controls. Gene expression was quantified by real-time PCR.RESULTS: In the cohort of BD patients, the TT genotype of rs573775/ATG5 decreased susceptibility to BD(Pc=8.35×10-6, OR=0.49). In the case of VKH patients, the AC genotype of rs4703863/ATG10 increased susceptibility to VKH syndrome(Pc=9.94×10-5, OR=1.44), while the A allele and AA genotype of rs4703863(Pc=7.06×10-5, OR=0.745; Pc=6.34×10-6, OR=0.669, respectively) acted as protective factors for VKH. No significant association of the other 14 SNPs with VKH or BD was found. Functional experiments showed an increased ATG5 expression by LPS stimulated PBMCs in TT cases of rs573775 compared to controls.Conclusions: This study demonstrated an association of ATG5 rs573775 with BD and ATG10 rs4703863 with VKH syndrome in a Chinese Han population.PART Ⅱ GENETIC POLYMORPHISMS OF CELL ADHESION MOLECULES IN BEHCET’S DISEASE AND VOGT-KOYANAGI-HARADA SYNDROMEBackground: Cell adhesion molecules(CAMs) are a group of proteins involved in cell binding or interaction between extracellular matrix and cells. Various studies have focused on protein expression of CAMs in patients with inflammatory and autoimmune diseases. Although some studies have addressed the association of selected CAMs with uveitis, no reports are available concerning the association between genetic polymorphisms of the complete family of cell adhesion molecules with ocular BD or VKH syndrome.Purposes: This study was conducted to investigate the association of single nucleotide polymorphisms of CAMs with Beh?et’s disease and VKH syndrome.Methods: An association study was carried out in 1149 BD patients, 399 VKH syndrome patients and 2107 normal controls. Genotyping of 43 SNPs was performed using Mass ARRAY System(Sequenom), polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP) and Taq Man SNP assays. Genotype distributions and allele frequencies were compared using χ2 analysis between BD patients, VKH syndrome patients and normal controls. The expression of CD6 and CD11 c was examined by real-time PCR and cytokine production was measured by ELISA.Results: A significantly higher frequency of the CT genotype(Pc=3.266×10-7, OR=1.63), and a lower frequency of the CC genotype(Pc= 1.097×10-8, OR=0.60) and C allele(Pc=7.594×10-9, OR=0.64) of CD6 rs11230563 were observed in BD as compared with controls. Analysis of CD11 c rs2929 showed that patients with BD had a significantly higher frequency of the GG genotype(Pc=5.573×10-6, OR=1.56) and G allele(Pc=1.398×10-5, OR=1.45), and a lower frequency of the AG genotype(Pc=2.087×10-5, OR=0.64) as compared with controls. Functional experiments showed an increased CD11 c expression and increased production of TNF-α and IL-1beta by LPS stimulated PBMCs in GG carriers of CD11 c rs2929 compared to AA/AG carriers.Conclusions: This study shows an association between PTPN2-rs7234029 and Beh?et’s disease.