TY - JOUR
T1 - Replication of Genome-Wide Association Analysis Identifies New Susceptibility Loci at Long Noncoding RNA Regions for Vogt-Koyanagi-Harada Disease
AU - Qi, Jian
AU - Du, Liping
AU - Deng, Jing
AU - Qin, Yang
AU - Su, Guannan
AU - Hou, Shengping
AU - Lv, Meng
AU - Zhang, Qi
AU - Kijlstra, Aize
AU - Yang, Peizeng
N1 - Funding Information:
The authors thank all donors enrolled in the present study. Supported by Natural Science Foundation Major International (Regional) Joint Research Project (81720108009), National Natural Science Foundation Project (81770916, 81400389), Chongqing Key Laboratory of Ophthalmology (CSTC, 2008CA5003), Chongqing Science & Technology Platform and Base Construction Program (cstc2014pt-sy10002), Chongqing Science & Technology Foundation Project (cstc2017shmsA130073, cstc2014jcyjA10111). No funding bodies had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
Copyright 2019 The Authors
PY - 2019/11
Y1 - 2019/11
N2 - PURPOSE. This study was aimed at investigating the association of long noncoding RNA (LncRNA)-related single nucleotide polymorphisms (SN'Ps) with Vogt-Koyanagi-Harada 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] = 2.98 x 10(-8), odds ratio [OR] = 0.62; TT genotype: P-C = 1.64 x 10(-8), OR = 1.57; C allele: P-C = 1.39 x 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 IT 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.
AB - PURPOSE. This study was aimed at investigating the association of long noncoding RNA (LncRNA)-related single nucleotide polymorphisms (SN'Ps) with Vogt-Koyanagi-Harada 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] = 2.98 x 10(-8), odds ratio [OR] = 0.62; TT genotype: P-C = 1.64 x 10(-8), OR = 1.57; C allele: P-C = 1.39 x 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 IT 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.
KW - lncRNA
KW - Vogt-Koyanagi-Harada disease
KW - multi-omics analysis
KW - BEHCETS-DISEASE
KW - GENE POLYMORPHISMS
KW - VKH SYNDROME
KW - T-CELLS
KW - EXPRESSION
KW - SNPS
KW - SENSITIZATION
KW - RECOGNITION
KW - VARIANTS
KW - DATABASE
U2 - 10.1167/iovs.19-27708
DO - 10.1167/iovs.19-27708
M3 - Article
C2 - 31747682
SN - 0146-0404
VL - 60
SP - 4820
EP - 4829
JO - Investigative Ophthalmology & Visual Science
JF - Investigative Ophthalmology & Visual Science
IS - 14
ER -