Genome-wide association analysis of Vogt-Koyanagi-Harada syndrome identifies two new susceptibility loci at 1p31.2 and 10q21.3

Abstract

To identify new genetic risk factors for Vogt-Koyanagi-Harada (VKH) syndrome, we conducted a genome-wide association study of 2,208,258 SNPs in 774 cases and 2,009 controls with follow-up in a collection of 415 cases and 2,006 controls and a further collection of 349 cases and 1,588 controls from a Han Chinese population. We identified three loci associated with VKH syndrome susceptibility (IL23R-C1orf141, rs117633859, P(combined) = 3.42 × 10(-21), odds ratio (OR) = 1.82; ADO-ZNF365-EGR2, rs442309, P(combined) = 2.97 × 10(-11), OR = 1.37; and HLA-DRB1/DQA1, rs3021304, P(combined) = 1.26 × 10(-118), OR = 2.97). The five non-HLA genes were all expressed in human iris tissue. IL23R was also expressed in the ciliary body, and EGR2 was expressed in the ciliary body and choroid. The risk G allele of rs117633859 in the promoter region of IL23R exhibited low transcriptional activation in a cell-based reporter assay and was associated with diminished IL23R mRNA expression in human peripheral blood mononuclear cells.

Association ofATG5Gene Polymorphisms With Behçet's Disease andATG10Gene Polymorphisms With VKH Syndrome in a Chinese Han Population

“…During our genome-wide association studies (GWAS) for VKH, we discovered 2 SNPs in ATG10 that may confer risk to VKH (5 3 10 À8 < P < 0.05). 30 Although these SNPs did not reach the GWAS P-value threshold, we decided to include them in the current study with a larger patient sample size. The protective effect of the AA genotype of ATG10/rs4703863 could be confirmed but is modest, whereby 60% of controls and 50% of VKH patients carry this genotype.…”

“…[17][18][19][20][21][22][23][24][25][28][29][30] 20 1 SNP (rs11175593) of Leucine-rich repeat kinase2 (LRRK2), 19 1 SNP (rs17146441) of ATG2A, 23 1 SNP (rs267939) of death-associated protein (DAP), 22 1 SNP (rs12303764) of UNC-51-like kinase 1(ULK1), 21 and 1 SNP (rs1076160) of tuberous sclerosis complex1 (TSC1).…”

“…29 It is worthwhile to point out that, as mentioned above, our group previously carried out GWAS in both conditions, and no significant association was observed at that time for the ATGs. 30,50 The samples and methods involved in the BD GWAS, VKH GWAS, and the current study were different and the observed discrepancies may be explained as follows. First, the cohorts of patients for our GWAS were not the same as used in the present study.…”

Association of Long Noncoding RNAs Polymorphisms With Ankylosing Spondylitis, Vogt-Koyanagi-Harada Disease, and Behcet's Disease

“…GWAS also identified the variants in the IL10, MHC class I, and IL23R/IL12RB2 regions were associated with the development of BD. [12][13][14] Both AAU and AS are strongly associated with HLA-B27 as well as with a variety on non-HLA genes, such as FOXO1, GATA-3, and FOXP3. 15,16 However, some of the associated regions were located on intergenic regions, suggesting that noncoding RNAs (ncRNAs) may be involved in the development of these diseases.…”

A Rare Case of Unilateral Progressive Vision Loss and Pachymeningitis

“…We know from previous studies that HLA-DR4 (human leukocyte antigen) is strongly associated with VKH disease, but most recently three loci associated with VKHD gene susceptibility have been identified: IL23R-C1orf141, rs117633859; ADO-ZNF365-EGR2, rs442309; and HLA-DRB1/ DQA1, rs3021304. [20][21][22] Despite advances in research, we have yet to come up with a specific serologic testing to diagnose VKH disease. Ancillary ophthalmic examinations such as FFA, indocyanine green angiography (ICGA), electroretinograophy (ERG), ultrasonography, and OCT are often used to assist in the diagnosis and localisation of the pathologic process to the choroid.…”