Replication of Genome-Wide Association Analysis Identifies New Susceptibility Loci at Long Noncoding RNA Regions for Vogt-Koyanagi-Harada Disease

Abstract

Citation: Qi J, Du L, Deng J, et al. Replication of genome-wide association analysis identifies new susceptibility loci at long noncoding RNA regions for Vogt-Koyanagi-Harada disease. Invest Ophthalmol Vis Sci. 2019;60:4820-4829. https://doi.org/ 10.1167/iovs.19-27708PURPOSE. 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 [P C ] ¼ 2.98 3 10 À8 , odds ratio [OR] ¼ 0.62; TT genotype: P C ¼ 1.64 3 10 À8 , OR ¼ 1.57; C allele: P C ¼ 1.39 3 10 À12 , OR ¼ 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 ¼ 0.0073, P ¼ 0.0011, and P ¼ 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.

Pathogenesis and prospects for therapeutic clinical application of noncoding RNAs in glaucoma: Systematic perspectives

“…Research is also mainly restricted to the study of miRNAs at present (Conte et al, 2015 ; Hughes et al, 2011 ; Iliff et al, 2012 ; Liu et al, 2016 ). Moreover, while it is important to recognize the roles of lncRNAs and circRNAs in dysregulated networks, it also important to identify the ways that sequence variations may contribute to the pathological phenotypes of glaucoma (Deng et al, 2020 ; Qi et al, 2019 ). There is also a need to standardize experimental methods used to confirm and identify new ncRNA in both cellular and animal models.…”

LncRNA Neat1 targets NonO and miR-128-3p to promote antigen-specific Th17 cell responses and autoimmune inflammation

“…Long noncoding RNAs (lncRNAs), a cluster of non-proteinencoding RNAs with longer than 200 nucleotides, play crucial roles in various physiological and pathological processes, including autoimmune disorders [13][14][15]. A recent study found that single nucleotide polymorphisms (SNPs) rs3829794 in lnc-TOR3A-1:1 conferred susceptibility to Vogt-Koyanagi-Harada disease-associated AU [16], suggesting that lncRNAs are closely related to the pathogenesis of AU. Nevertheless, the roles and mechanisms of lncRNAs in the development of AU remain in need of further investigation.…”