Replication of genome-wide association analysis identifies new susceptibility loci at long noncoding RNA regions for Vogt-Koyanagi-Harada disease

Abstract

PURPOSE. This study was aimed at investigating the association of long noncoding RNA (lncRNA)–related single nucleotide polymorphisms (SNPs) with Vogt-Koyanagi-Harada (VKH) disease. METHODS. LncRNA-related SNPs were selected by multi-omics analysis. Genotyping, expression of lncRNA and mRNA, cell proliferation, and cytokine production were tested by MassARRAY System, real-time PCR, CCK8, and ELISA. RESULTS. A significant association with VKH was found for lnc-TOR3A-1:1/rs3829794, which is located in a non-HLA region (CC genotype: Bonferroni corrected P values [PC] = 2.98 3 10−8, odds ratio [OR] = 0.62; TT genotype: PC = 1.64 3 10−8, OR = 1.57; C allele: PC = 1.39 3 10−12, OR = 0.71). Additionally, an association was found for four lncRNA SNPs located in the HLA region. Functional experiments in rs3829794 genotyped individuals showed decreased ABL2 (ABL proto-oncogene 2, nonreceptor tyrosine kinase) expression, decreased proliferation of anti-CD3 plus anti-CD28–stimulated peripheral blood mononuclear cells (PBMCs), and an increased production of IL-10 in CC carriers compared to TT carriers (P = 0.0073, P = 0.0011, and P = 0.002, respectively). CONCLUSIONS. Our study identified five new loci associated with VKH susceptibility and identified a functional variant (lnc-TOR3A-1:1/rs3829794) that confers risk for VKH, which is possibly mediated by modulating gene expression, proliferation of lymphocytes, and regulation of anti-inflammatory cytokine production.