Genetic Variations Of NLR Genes In Behcet’s Disease And Vogt-Koyanagi-Harada Syndrome

Background: Nod-like receptors(NLRs) play an important role in the recognition of microbial products. More recent studies demonstrate that variation in NLRs genes are associated with autoimmune and inflammatory diseases. Vogt-Koyanagi-Harada(VKH) syndrome and Behcet’s disease(BD) are two common kinds of uveitis in Asian population. Although the etiology and pathogenesis of BD and VKH syndrome remain unclear, previous studies have revealed that the interaction between immune responses triggered by environmental factors and genetic factors is involved in the initiation and maintenance of these diseases. Recent studies have identified the associations of several genes with the two diseases.Objective: The objective of the current study was to explore whether single nucleotide polymorphisms(SNPs) of the six NLR family genes(NOD1, NOD2,NLRP1, NLRP3, NLRP5 and CIITA) are associated with BD and VKH syndrome in a Chinese Han population.Methods: According to the published data and Previous genome-wide association study(GWAS) for VKH syndrome performed by our group, we selected twenty SNPs of NLR family genes including NOD1//(rs2075818, rs2907748, rs2907749), NOD2//(rs8057431, rs3135499), NLRP1//(rs6502867, rs878329, rs12150220, rs8079034), NLRP3//(rs10754558, rs10925019, rs4925648, rs3806265, rs2027432), NLRP5//rs7255920 and CIITA//(rs12932187, rs1107438, rs8048002, rs6498122, rs4774). Genotyping was carried out by polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP) or Taq Man? SNP assay. The first-stage study comprised 384 BD patients, 384 VKH syndrome patients and 576 healthy subjects from a Chinese Han population. The second stage included another 566 BD patients and 864 controls. Allele and genotype frequencies were compared between patients and controls using the x2 test. Gene m RNA expression was quantified by real-time PCR and cytokine production was detected by ELISA.Results: In the first-stage study of BD, significantly decreased frequencies of the CIITA//rs12932187 C allele(Pc=1.668E-02, OR=0.713, 95%CI=0.591-0.861) and NOD1//rs2075818 G allele(Pc=4.694E-02, OR=0.698, 95%CI=0.562-0.868) were found in BD patients as compared to controls. The second stage and combined study confirmed the association of CIITA//rs12932187 and NOD1//rs2075818 with BD. In CIITA//rs12932187, the frequencies of the CC genotype and C allele were significantly lower in BD than in controls(Pc=3.331E-06, OR=0.617, 95% CI=0.519-0.735; Pc=6.004E-07, OR=0.709, 95% CI=0.629-0.799, respectively). In NOD1//rs2075818, the GG genotype and G allele showed significantly decreased frequencies in BD patients when compared to controls(Pc=1.022E-02, OR=0.536, 95% CI=0.386-0.745; Pc=6.811E-05, OR=0.720, 95%CI=0.629-0.824, respectively). Functional experiments showed that carriers with the CC genotype in CIITA//rs12932187 had a lower CIITA m RNA expression level and an enhanced IL-10 secretion as compared to GG and CG carriers, after the stimulation of LPS. No association between the gene polymorphisms described above and VKH could be detected.Conclusion: This study provides evidence that the CIITA and NOD1 genes are involved in the susceptibility to Behcet’s disease in Chinese Han.