Abstract
Vogt-Koyanagi-Harada (VKH) disease is a systemic inflammatory disorder that affects pigment cell-containing organs such as the eye (e.g., chronic and/or recurrent granulomatous panuveitis). While the exact etiology and pathogenic mechanism of VKH disease are unclear, HLA-DR4 alleles have been documented to be strongly associated with VKH disease in various ethnic groups. Recently, a genome-wide association study (GWAS) found two new genetic risk factors (IL23R-C1orf141 and ADO-ZNF365-EGR2) in a non-HLA region from a Han Chinese population. In this study, we replicated these GWAS findings in a Japanese population. A total of 1,643 Japanese samples (380 cases with VKH disease and 1,263 healthy controls) were recruited. We assessed four single nucleotide polymorphisms (SNPs) shown in previous GWAS: rs78377598 and rs117633859 in IL23R-C1orf141, and rs442309 and rs224058 in ADO-ZNF365-EGR2. A significant allelic association with VKH disease was observed for all of the four SNPs (rs78377598: pc = 0.0057; rs117633859: pc = 0.0017; rs442309: pc = 0.021; rs224058: pc = 0.035). In genotypic association analysis, the minor alleles of IL23R-C1orf141 rs78377598 and rs117633859 had the strongest association with disease susceptibility under the additive model (pc = 0.0075 and pc = 0.0026, respectively). The minor alleles of ADO-ZNF365-EGR2 rs442309 and rs224058 were most strongly associated with disease susceptibility under the dominant model (pc = 0.00099 and pc = 0.0023, respectively). The meta-analysis of the current and previous studies found that all of the four SNPs exhibited a significantly strong association with VKH disease (meta-p < 0.00001: rs78377598, meta-odds ratio (OR) = 1.69; rs1176338, meta-OR = 1.82; rs442309, meta-OR = 1.34; rs224058, meta-OR = 1.33). In summary, our study replicated significant associations with VKH disease susceptibility reported in a previous GWAS. Thus, the IL23R-C1orf141 and ADO-ZNF365-EGR2 loci may play important roles in the development of VKH disease through genetic polymorphisms.
Highlights
VKH disease is a systemic polymorphic autoimmune disorder that targets organs with melanocytes such as the eye, meninges, inner ear, skin, and hair [1]
We investigated an association between VKH disease and four single nucleotide polymorphisms (SNPs), namely rs78377598 and rs117633859 on 1p31.2 and rs1142309 and rs224058 on 10q21.3, which have been previously reported [17,18]
A number of studies have shown that genetic polymorphisms including human leukocyte antigen (HLA) genes and non-HLA genes affect the susceptibility of VKH disease
Summary
VKH disease is a systemic polymorphic autoimmune disorder that targets organs with melanocytes such as the eye, meninges, inner ear, skin, and hair [1]. A recent genome-wide association study (GWAS) of patients with VKH disease from a Han Chinese population identified two new non-HLA candidate regions, namely interleukin 23. IL23R-C1orf141 and ADO-ZNF365-EGR2 variants associated with Vogt-Koyanagi-Harada disease receptor (IL23R)-chromosome 1 open reading frame 141 (C1orf141) on 1p31.2 and 2-aminoethanethiol dioxygenase (ADO)-zinc finger protein 365 (ZNF365)-early growth response 2 (EGR2) on 10q21.3 [17]. These two new loci were assessed in replication studies that included the Han Chinese in Singapore, a non-Han Chinese population in southwestern China, and patients with VKH disease from Thailand and Korea. We performed a random-effects meta-analysis of the odds ratios (ORs) of four SNPs in Japanese and other Asian populations
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