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Variants in IL23R-C1orf141 and ADO-ZNF365-EGR2 are associated with susceptibility to Vogt-Koyanagi-Harada disease in Japanese population

  • Takuto Sakono,

    Roles Data curation, Formal analysis, Investigation, Methodology, Writing – original draft, Writing – review & editing

    Affiliation Department of Ophthalmology and Visual Science, Yokohama City University Graduate School of Medicine, Kanagawa, Japan

  • Akira Meguro ,

    Roles Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Writing – review & editing

    akmeguro@yokohama-cu.ac.jp

    Affiliation Department of Ophthalmology and Visual Science, Yokohama City University Graduate School of Medicine, Kanagawa, Japan

  • Masaki Takeuchi,

    Roles Data curation, Formal analysis, Investigation, Methodology, Writing – review & editing

    Affiliation Department of Ophthalmology and Visual Science, Yokohama City University Graduate School of Medicine, Kanagawa, Japan

  • Takahiro Yamane,

    Roles Data curation, Formal analysis, Investigation, Methodology, Writing – review & editing

    Affiliation Department of Ophthalmology and Visual Science, Yokohama City University Graduate School of Medicine, Kanagawa, Japan

  • Takeshi Teshigawara,

    Roles Data curation, Formal analysis, Investigation, Methodology, Writing – review & editing

    Affiliations Department of Ophthalmology and Visual Science, Yokohama City University Graduate School of Medicine, Kanagawa, Japan, Yokosuka Chuoh Eye Clinic, Kanagawa, Japan, Tsurumi Chuoh Eye Clinic, Kanagawa, Japan

  • Nobuyoshi Kitaichi,

    Roles Data curation, Investigation, Resources, Writing – review & editing

    Affiliation Department of Ophthalmology, Health Sciences University of Hokkaido, Hokkaido, Japan

  • Yukihiro Horie,

    Roles Data curation, Investigation, Resources, Writing – review & editing

    Affiliation Department of Ophthalmology, Health Sciences University of Hokkaido, Hokkaido, Japan

  • Kenichi Namba,

    Roles Data curation, Investigation, Resources, Writing – review & editing

    Affiliation Department of Ophthalmology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Hokkaido, Japan

  • Shigeaki Ohno,

    Roles Data curation, Investigation, Resources, Writing – review & editing

    Affiliation Department of Ophthalmology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Hokkaido, Japan

  • Kumiko Nakao,

    Roles Data curation, Investigation, Resources, Writing – review & editing

    Affiliation Department of Ophthalmology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan

  • Taiji Sakamoto,

    Roles Data curation, Investigation, Resources, Writing – review & editing

    Affiliation Department of Ophthalmology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan

  • Tsutomu Sakai,

    Roles Data curation, Investigation, Resources, Writing – review & editing

    Affiliation Department of Ophthalmology, Jikei University School of Medicine, Tokyo, Japan

  • Tadashi Nakano,

    Roles Data curation, Investigation, Resources, Writing – review & editing

    Affiliation Department of Ophthalmology, Jikei University School of Medicine, Tokyo, Japan

  • Hiroshi Keino,

    Roles Data curation, Investigation, Resources, Writing – review & editing

    Affiliation Department of Ophthalmology, Kyorin University School of Medicine, Tokyo, Japan

  • Annabelle A. Okada,

    Roles Data curation, Investigation, Resources, Writing – review & editing

    Affiliation Department of Ophthalmology, Kyorin University School of Medicine, Tokyo, Japan

  • Atsunobu Takeda,

    Roles Data curation, Investigation, Resources, Writing – review & editing

    Affiliation Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

  • Takako Ito,

    Roles Data curation, Investigation, Resources, Writing – review & editing

    Affiliation Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

  • Hisashi Mashimo,

    Roles Data curation, Investigation, Resources, Writing – review & editing

    Affiliation Department of Ophthalmology, Japan Community Health care Organization Osaka Hospital, Osaka, Japan

  • Nobuyuki Ohguro,

    Roles Data curation, Investigation, Resources, Writing – review & editing

    Affiliation Department of Ophthalmology, Japan Community Health care Organization Osaka Hospital, Osaka, Japan

  • Shinichirou Oono,

    Roles Data curation, Investigation, Resources, Writing – review & editing

    Affiliations Department of Ophthalmology, Saga University Faculty of Medicine, Saga, Japan, Hoshiai Eye Clinic, Saitama, Japan

  • Hiroshi Enaida,

    Roles Data curation, Investigation, Resources, Writing – review & editing

    Affiliation Department of Ophthalmology, Saga University Faculty of Medicine, Saga, Japan

  • Satoshi Okinami,

    Roles Data curation, Investigation, Resources, Writing – review & editing

    Affiliations Department of Ophthalmology, Saga University Faculty of Medicine, Saga, Japan, Department of Ophthalmology, Kurashiki Central Hospital, Okayama, Japan

  • Nobuyuki Horita,

    Roles Data curation, Formal analysis, Investigation, Methodology, Software, Writing – review & editing

    Affiliation Department of Pulmonology, Yokohama City University Graduate School of Medicine, Kanagawa, Japan

  • Masao Ota,

    Roles Data curation, Formal analysis, Investigation, Writing – review & editing

    Affiliations Department of Ophthalmology and Visual Science, Yokohama City University Graduate School of Medicine, Kanagawa, Japan, Division of Hepatology and Gastroenterology, Department of Medicine, Shinshu University School of Medicine, Nagano, Japan

  •  [ ... ],
  • Nobuhisa Mizuki

    Roles Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Writing – review & editing

    Affiliation Department of Ophthalmology and Visual Science, Yokohama City University Graduate School of Medicine, Kanagawa, Japan

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Variants in IL23R-C1orf141 and ADO-ZNF365-EGR2 are associated with susceptibility to Vogt-Koyanagi-Harada disease in Japanese population

  • Takuto Sakono, 
  • Akira Meguro, 
  • Masaki Takeuchi, 
  • Takahiro Yamane, 
  • Takeshi Teshigawara, 
  • Nobuyoshi Kitaichi, 
  • Yukihiro Horie, 
  • Kenichi Namba, 
  • Shigeaki Ohno, 
  • Kumiko Nakao
PLOS
x

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.

Introduction

VKH disease is a systemic polymorphic autoimmune disorder that targets organs with melanocytes such as the eye, meninges, inner ear, skin, and hair [1]. VKH disease, along with sarcoidosis and Behcet’s disease, is one of the causes of endogenous uveitis and an ophthalmological condition that is most common in the Japanese population [2,3]. VKH disease in the acute stage is characterized by the development of bilateral uveitis associated with multifocal exudative retinal detachment (RD) in the posterior pole and inflammation signs often observed in the anterior ocular, such as mutton-fat keratic precipitates, iris nodules, and shallow anterior chamber. Early-phase of fluorescein angiography (FA) in the acute stage shows multiple focal areas of leakage at the level of retinal pigment epithelium, and late-phase of FA shows dye pooling within subretinal fluid (SRF). In the chronic stage of VKH disease, sunset glow fundus characterized by orange-red discoloration due to depigmentation of the choroid is found [46]. The incidence of VKH disease varies worldwide. The disease occurs more frequently among people with dark skin pigmentation, as well as in those of Asian descent, Native Americans, and Hispanics compared to Caucasians [4,7]. In Japan, VKH disease accounts for about 7% of all uveitis patients [3]. In contrast, VKH disease patients represent only about 1% to 4% of all uveitis cases in the United States [1].

Although the exact etiology of VKH disease remains unclear, genetic factors may play an important role in disease development. A strong association of VKH disease with human leukocyte antigen (HLA)-DR4 has been reported by some ethnic groups [811]. The pathogenesis of VKH disease may be implicated by multifactorial factors through environmental triggers and susceptibility genes such as HLA and non-HLA [12,13].

The characteristic clinical findings of tissue depigmentation in VKH disease point to the possible involvement of melanocytes in the pathogenesis. The tyrosinase gene family (e.g., tyrosinase, tyrosinase-related protein (TRP) 1, TRP2 and dopachrome tautomerase) is expressed specifically in melanocytes and involve in pigmentation. In earlier studies, TRP1 and TRP2 induced an experimental autoimmune disease in Lewis rats. The clinical course and histological findings resembled human VKH disease [14]. It is also reported that human VKH-like disease is induced in Akita dogs by immunizing them with TRP1 [15]. Further, lymphocytes obtained from VKH disease patients were reactive to peptides derived from tyrosinase gene family [16]. These studies suggest that tyrosinase gene family may be responsible for human VKH disease. However, the association of VKH disease with genes in the tyrosinase gene family has been showed negative results in Japanese patients with VKH disease [13].

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 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 also 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. In these studies, IL23R-C1orf141 on 1q31.2 was associated with VKH disease among patients of Han Chinese descent in Singapore but not in those of other Asian ethnicities. The association between ADO-ZNF365-EGR2 on 10q21.3 and VKH disease has only been confirmed in a Thai population [18].

To further explore these issues, we conducted a replication study in Japanese patients with VKH disease. 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]. In addition, we performed a random-effects meta-analysis of the odds ratios (ORs) of four SNPs in Japanese and other Asian populations.

Materials and methods

Participants

We recruited 380 unrelated Japanese patients with VKH disease (41.6% male, mean age 51.3 ± 14.7 years [range 21 to 81 years]) and 1,263 unrelated Japanese healthy controls (46.8% male, mean age 54.6 ± 14.3 years [range 20 to 87 years]) (Table 1). The patients were diagnosed between 2003 and 2015 according to the “Revised Diagnostic Criteria for VKH Disease” at the Uveitis Survey Clinic of Yokohama City University, Hokkaido University, Kagoshima University, Jikei University, Kyorin University, Kyusyu University, Japan Community Healthcare Organization Osaka Hospital, and Saga University. All patients met the criteria established by the 2001 First International Workshop on Vogt-Koyanagi-Harada Disease [9]. The details of criteria are (i) no history of penetrating ocular trauma / surgery before uveitis onset, (ii) no clinical / laboratory evidence of other ocular disease, (iii) bilateral ocular involvement: diffuse choroiditis (focal regions of SRF, bullous serous RD) and FA (focal areas of delay in choroidal perfusion, multifocal areas of hyperfluorescence, pooling within SRF, and optic nerve staining), (iv) cerebrospinal fluid pleocytosis, and (v) integumentary findings (alopecia, poliosis and vitiligo) [19]. Clinical presentation showed little variation among patients. The control subjects were all healthy volunteers of similar ethnic origin as the patients, and were not related to each other or to the VKH disease patients. All controls had no clinical manifestations or family history of any type of immune-related diseases. All participants gave their written informed consent. The study was approved by the ethics committees of Yokohama City University, Hokkaido University, Kagoshima University, Jikei University, Kyorin University, Kyusyu University, Japan Community Healthcare Organization Osaka Hospital, and Saga University and conducted in accordance with the Declaration of Helsinki and its subsequent revisions.

SNP genotyping within IL23R-C1orf141 and ADO-ZNF365-EGR2 genes

We assessed the four SNPs that showed a strong association with VKH disease in a previous GWAS: rs78377598 and rs117633859 in IL23R-C1orf141 on the 1p31.2 locus, and rs442309 and rs224058 in ADO-ZNF365-EGR2 on the 10q21.3 locus [17]. Genomic DNA was extracted from peripheral blood samples using the QIAamp DNA Blood Mini Kit (Qiagen, Hilden, Germany). Standardized conditions were used to prevent variation in DNA quality. SNP genotyping was performed using the TaqMan 5' exonuclease assay with primers supplied by Applied Biosystems (Foster City, CA, USA). Polymerase chain reaction (PCR) was performed in a 10 μL reaction mixture containing 1× TaqMan Universal PCR Master Mix (Applied Biosystems), 24 nm of each primer-probe set, and 3 ng genomic DNA. The PCR conditions were as follows: 95°C for 10 min, followed by 40 cycles of denaturation at 92°C for 15 s and annealing/extension at 60°C for 1 min. The probe’s fluorescence signal was detected using the StepOnePlus Real-Time PCR System (Applied Biosystems).

Statistical analysis

We performed allelic and genotypic association analyses, and calculated Hardy-Weinberg equilibrium using SNP and Variation Suite 8.4.0 software (Golden Helix, Inc., Bozeman, MT, USA, http://www.goldenhelix.com). For genotypic association analysis, we applied three different genetic models to assess each minor allele: additive (2/2 vs. 1/2 vs. 1/1), dominant (2/2+1/2 vs. 1/1), and recessive (2/2 vs. 1/2+1/1) models (assuming that 2 is the minor allele and 1 is the major allele). Differences in allele and genotype frequencies between cases and controls were assessed by correlation/trend test. The p-values and ORs in genotype models were adjusted for age and sex. The obtained p-values were corrected for multiple testing using Bonferroni’s method based on the number of tested SNPs (n = 4). A corrected p-value (pc) < 0.05 was considered significant.

Random-effects meta-analysis

We conducted a random-effects meta-analysis of the current and previous studies using the generic inverse variance method and logarized OR. The pooled OR corresponding to one risk allele increase in allelic model for each SNP was calculated [2022]. The heterogeneity was estimated using I2 statistics as follows: 0%: indicates no heterogeneity; 0% to 30%: might not be important; 30% to 50%: may represent moderate heterogeneity; 50% to 75%: may represent substantial heterogeneity; 75% to 100%: considerable heterogeneity [22]. We used Review Manager ver. 5.3 (Cochrane Collaboration, Oxford, UK) to perform meta-analysis.

Results

We performed genotyping of four SNPs in the VKH disease patient and control groups. The genotype frequencies of all four SNPs were all in Hardy-Weinberg equlibirum for the cases and controls. Table 2 shows the allelic association results for the four SNPs. Two SNPs (rs78377598 and rs117633859) in IL23R-C1orf141 were significantly associated with VKH disease in the Japanese population (p = 0.0014 and p = 0.00043, respectively). Statistical significance was kept following Bonferroni's correction (rs78377598: pc = 0.0057 and rs117633859: pc = 0.0017). The T allele of rs78377598 and the G allele of rs117633859 were more frequent alleles in patients with VKH disease than the control group, indicating that these alleles were susceptible to VKH disease (OR = 1.65 and OR = 1.71, respectively). The variants in the ADO-ZNF365-EGR2 locus also showed a significant association with the disease (rs442309: p = 0.0053, pc = 0.021 and rs224058: p = 0.0088, pc = 0.035). Both allele frequencies of the T allele of rs442309 and the A allele of rs224058 were higher in VKH disease patients compared to the controls (OR = 1.27 and OR = 1.25, respectively).

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Table 2. Allelic association results for rs78377598 and rs117633859 in IL23R-C1orf141, and rs442309 and rs224058 in ADO-ZNF365-EGR2.

https://doi.org/10.1371/journal.pone.0233464.t002

The results of genotypic association analysis for the four SNPs under different genetic models are presented in Table 3. The minor alleles of rs78377598 and rs117633859 in IL23R-C1orf141 had the strongest association with the risk of VKH disease under the additive model (rs78377598: p = 0.0019, pc = 0.0075, OR = 1.64 and rs117633859: p = 0.00066, pc = 0.0026, OR = 1.70). These alleles were also significantly associated with VKH disease under the dominant model (rs78377598: p = 0.0031, pc = 0.012, OR = 1.68 and rs117633859: p = 0.0011, pc = 0.0043, OR = 1.75). The minor alleles of rs442309 and rs224058 in ADO-ZNF365-EGR2 were most strongly associated with the risk of VKH disease under the dominant model (rs442309: p = 0.00025, pc = 0.00099, OR = 1.58 and rs224058: p = 0.00057, pc = 0.0023, OR = 1.53) and also showed a significant association with the disease under the additive model (rs442309: p = 0.0061, pc = 0.025, OR = 1.26 and rs224058: p = 0.0092, pc = 0.037, OR = 1.24). No significant association was found for any of the four SNPs in the recessive model (p > 0.05).

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Table 3. Genotypic association results for rs78377598 and rs117633859 in IL23R-C1orf141, and rs442309 and rs224058 in ADO-ZNF365-EGR2.

https://doi.org/10.1371/journal.pone.0233464.t003

The results of a random-effects meta-analysis of the current and previous studies are showed in Figs 14. The meta-analysis revealed that all of the tested SNPs exhibited a significantly strong association with the risk of VKH disease (meta-p < 0.00001, rs78377598: meta-OR = 1.69; rs117633859: meta-OR = 1.82; rs442309: meta-OR = 1.34; rs224058: meta-OR = 1.33). rs78377598 and rs1176338 in IL23R-C1orf141 had an increased risk of VKH disease in all ethnic populations (Figs 1 and 2). On the other hand, rs442309 and rs224058 in ADO-ZNF365-EGR2 did not always have an increased risk in all popuations (OR ≤ 1.0 in the Han Chinese group in Singapore and the non-Han Chinese group) (Figs 3 and 4).

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Fig 1. Forest plot of the meta-analysis of the association of IL23R-C1orf141 rs78377598 and VKH disease.

The lines with squares in the middle correspond to the study-specific 95% CI and OR. The central vertical solid line indicates the OR for the null hypothesis. The diamond represents the summary OR with its corresponding 95% CI.

https://doi.org/10.1371/journal.pone.0233464.g001

thumbnail
Fig 2. Forest plot of the meta-analysis of the association of IL23R-C1orf141 rs1176338 and VKH disease.

The lines with squares in the middle correspond to the study-specific 95% CI and OR. The central vertical solid line indicates the OR for the null hypothesis. The diamond represents the summary OR with its corresponding 95% CI.

https://doi.org/10.1371/journal.pone.0233464.g002

thumbnail
Fig 3. Forest plot of the meta-analysis of the association of ADO-ZNF365-EGR2 rs442309 and VKH disease.

The lines with squares in the middle correspond to the study-specific 95% CI and OR. The central vertical solid line indicates the OR for the null hypothesis. The diamond represents the summary OR with its corresponding 95% CI.

https://doi.org/10.1371/journal.pone.0233464.g003

thumbnail
Fig 4. Forest plot of the meta-analysis of the association of ADO-ZNF365-EGR2 rs224058 and VKH disease.

The lines with squares in the middle correspond to the study-specific 95% CI and OR. The central vertical solid line indicates the OR for the null hypothesis. The diamond represents the summary OR with its corresponding 95% CI.

https://doi.org/10.1371/journal.pone.0233464.g004

Discussion

VKH disease is a systemic autoimmune inflammatory disorder. A number of studies have shown that genetic polymorphisms including HLA genes and non-HLA genes affect the susceptibility of VKH disease. Hou et al. identified new non-HLA candidate genes, namely IL23R-C1orf141 on 1p31.2 and ADO-ZNF365-EGR2 on 10q21.3, by GWAS targeting a group of Han Chinese patients with VKH disease [17]. In this study, we also found that these two genes are susceptibility genes involved in the pathogenesis of VKH disease in Japanese patients.

A previous report showed that the interleukin 23 receptor (IL23R) is expressed in the iris and ciliary bodies of healthy subjects, while C1orf141 is only expressed in the iris of healthy subjects [17]. Furthermore, genetic variants in IL23R are associated with multiple immune-related diseases such as Behcet’s disease, Crohn’s disease, ulcerative colitis, psoriasis, and ankylosing spondylitis [2331]. IL23R is expressed in type 17 helper T cells (Th17) cells, which are implicated in the pathogenesis of various immune-mediated diseases. IL23 signaling through the IL23R promotes the proliferation, maintenance, and activation of Th17 inducing neutrophil inflammation and autoimmune diseases [3234]. Liang et al. reported that VKH disease patients with active uveitis had significantly higher percentages of Th17 and IL-23 as compared with inactive VKH disease patients and healthy controls [35]. C1orf141 is involved in psoriasis [36]; however, its function remains to be elucidated. These reports indicate that an activation of Th17 through the IL23R is involved in the pathogenesis of VKH disease. In the current study, we confirmed the significant association of rs78377598 and rs117633859 in IL23R-C1orf141 with VKH disease in the Japanese popualtion. Taken together, IL23R are likely involved in the development of VKH disease through genetic variants of IL23R-C1orf141.

In this study, we succeeded in replicating previous GWAS findings showing that ADO-ZNF365-EGR2 is susceptibility locus involved in the development of VKH disease in the Japanese population. However, these findings were not reproduced in the Han Chinese Singaporeans and, the non-Han Chinese population from southwestern China [18]. This difference in results may be due to the small sample size in the previous replication study, which may increase the risk of false negative results, called type II errors. Our study recruited 380 Japanese patients with VKH disease. In contrast, the previous study was conducted with 32 cases from the Han Chinese Singaporeans, 38 cases from a non-Han Chinese population in southwestern China, 81 cases from Thai, and 34 cases from Koreans [18]. Obviously, these sample sizes were not enough to produce effective statistical results: hence, it is suggested that the previous study could not detect the association between VHK disease and ADO-ZNF365-EGR2 in the Han Chinese Singaporeans and the non-Han Chinese. In addition, it has been hypothesized that VKH disease may be triggered by virus infections, such as the Epstein-Barr virus and the cytomegalovirus [37,38]. This hypothesized factors may be dependent on environmental factors, Asian countries have different environmental factors [39]. Therefore, the etiology and disease mechanisms underlying VKH disease development may be elucidated by the effects of gene-environment interactions. ADO, ZNF365, and EGR2 are expressed in the iris and EGR2 is expressed in ciliary bodies and the choroid [18]. Moreover, these genes are reportedly associated with multiple immune-related diseases such as Behcet’s disease, Crohn’s disease, ulcerative colitis, atopic dermatitis, and systemic lupus erythematosus [25,26,4044]. Thus, ADO-ZNF365-EGR2 may play suggestive effects in pathogenesis and mechanism of VKH disease in Japanese patients.

There were some differences in the disease-risk allele frequencies of IL23R-C1orf141 and ADO-ZNF365-EGR2 among control groups of Asian populations used in the current and previous studies (IL23R-C1orf141 rs78377598 and rs117633859: 4.5–5.9% in Japanese, Han Chinese Singaporeans [18], Thai [18], and Koreans [18], 9.5–9.7% in Han Chinese [17], 13.9–14.2% in non-Han Chinese from southwestern China [18]; ADO-ZNF365-EGR2 rs442309 and rs224058: 37.2–37.3% in Japanese, 25.6% in Han Chinese [17], 22.3% in Han Chinese Singaporeans [18], 30.8% in non-Han Chinese from southwestern China [18], 18.2% in Thai [18], 33.0% in Koreans [18]). However, the differences did not reflect the differences in association between VKH disease and the two loci among the Asian populations. The disease-risk allele frequencies of IL23R-C1orf141 are lower in Caucasians (2.5% in Caucasians from 1000 Genomes Project Phase 3 [45]) that have a low prevalence of VKH disease than in Asians, and those of ADO-ZNF365-EGR2 in Caucasians (52.0% [45]) are higher in Asians.

In conclusion, the current study confirmed a significant association between VKH disease and the two loci, IL23R-C1orf141 and ADO-ZNF365-EGR2, in the Japanese population, suggesting that genetic variants in these loci play important roles in disease development. To confirm and validate the correlation between VKH disease and these loci, future genetic studies with larger samples of Asian and other ethnic populatitons are needed.

Acknowledgments

We sincerely thank all of the participants in this study, and all of the medical staff involved in the sample collection and diagnosis.

References

  1. 1. Damico FM, Kiss S, Young LH. Vogt-Koyanagi-Harada disease. Semin Ophthalmol. 2005;20: 183–190. pmid:16282153
  2. 2. Goto H, Mochizuki M, Yamaki K, Kotake S, Usui M, Ohno S. Epidemological survey of intraocular inflammation in Japan. Jpn J Ophthalmol. 2007;51: 41–44. pmid:17295139
  3. 3. Ohguro N, Sonoda KH, Takeuchi M, Matsumura M, Mochizuki M. The 2009 prospective multi-center epidemiologic survey of uveitis in Japan. Jpn J Ophthalmol. 2012;56: 432–435. pmid:22752308
  4. 4. Moorthy RS, Inomata H, Rao NA. Vogt- Koyanagi-Harada syndrome. Surv.Ophthalmol. 1995;39: 265–292. pmid:7725227
  5. 5. Yamaguchi Y, Otani T, Kishi S. Tomographic features of serous retinal detachment with multilobular dye pooling in acute Vogt-Koyanagi-Harada disease. Am J Ophthalmol. 2007;144: 260–265. pmid:17533104
  6. 6. Keino H, Goto H, Mori H, Iwasaki T, Usui M. Association between severity of inflammation in CNS and development of sunset glow fundus in Vogt-Koyanagi-Harada disease. Am J Ophthalmol. 2006;141: 1140–1142. pmid:16765691
  7. 7. Yang P, Ren Y, Li B, Fang W, Meng Q, Kijlstra A. Clinical characteristics of Vogt- Koyanagi-Harada syndrome in Chinese patients. Ophthalmology. 2007;114: 606–614. pmid:17123618
  8. 8. Islam SM, Numaga J, Fujino Y, Hirata R, Matsuki K, Maeda H, et al. HLA class II genes in Vogt- Koyanagi-Harada disease. Invest Ophthalmol Vis Sci. 1994;35: 3890–3896. pmid:7928186
  9. 9. Read RW, Holland GN, Rao NA, Tabbara KF, Ohno S, Arellanes-Garcia L, et al. Revised diagnostic criteria for Vogt- Koyanagi-Harada disease: report of an international committee on nomenclature. Am J Ophthalmol. 2001;131: 647–652. pmid:11336942
  10. 10. Shindo Y, Ohno S, Yamamoto T, Nakamura S, Inoko H. Complete association of the HLA-DRB1*04 and–DQB1*04 alleles with Vogt- Koyanagi-Harada disease. Hum Immunol. 1994;39: 169–176. pmid:8026985
  11. 11. Shi T, Lv W, Zhang L, Chen J, Chen H. Association of HLA-DR4/HLA-DRB1*04 with Vogt- Koyanagi-Harada disease: a systemic review and meta-analysis. Sci Rep. 2014;4: 6887. pmid:25382027
  12. 12. Ng JY, Luk FO, Lai TY, Pang CP. Influence of molecular genetics in Vogt- Koyanagi-Harada disease. J Ophthlmic Inflamm Infact. 2014;4: 20.
  13. 13. Horie Y, Takemoto Y, Miyazaki A, Namba K, Kase S, Yoshida K, et al. Tyrosinase gene family and Vogt- Koyanagi-Harada disease in Japanease patients. Mol Vis. 2006;12: 1601–1605. pmid:17200659
  14. 14. Yamaki K, Kondo I, Nakamura H, Miyano M, Konno S, Sakuragi S. Ocular and extraocular inflammation induced by immunization of tyrosinase related protein 1 and 2 in Lewis rats. Exp Eye Res. 2000;71: 361–369. pmid:10995557
  15. 15. Yamaki K, Takiyama N, Itho N, Mizuki N, Seiya M, Sinsuke W, et al. Experimentally induced Vogt-Koyanagi-Harada disease in two Akita dogs. Exp Eye Res. 2005;80: 273–280. pmid:15670805
  16. 16. Yamaki K, Gocho K, Hayakawa K, Kondo I, Sakuragi S. Tyrosinase family proteins are antigens specific to Vogt-Koyanagi-Harada disease. J Immunol. 2000;165: 7323–7329. pmid:11120868
  17. 17. Hou S, Du L, Lei B, Pang CP, Zhang M, Zhuang W, et al. Genome-wide association analysis of Vogt- Koyanagi-Harada syndrome identifies two new susceptibility loci at 1p31.2 and 10q21.3. Nat Genet. 2014;46: 1007–1011. pmid:25108386
  18. 18. Cao S, Chee SP, Yu HG, Sukavatcharin S, Wu L, Kijlstra A, et al. Investigation of the association of Vogt- Koyanagi-Harada syndrome with IL23R-C1orf141 in Han Chinese Singaporean and ADO-ZNF365-EGR2 in Thai. Br J Ophthalmol. 2016;100: 436–442. pmid:26628628
  19. 19. Ito R, Ota M, Meguro A, Katsuyama Y, Uemoto R, Nomura E, et al. Investigation of association between TLR9 gene polymorphisms and VKH in Japanese patients. Ocul Immunol Inflamm. 2011;19: 202–205. pmid:21595536
  20. 20. Stewart LA, Clarke M, Rovers M, Riley RD, Simmonds M, Stewart G, et al. Preferred reporting items for systematic review and meta-analyses of individual participant data: the PRISMA-IPD Statement. JAMA. 2015;313: 1657–1665. pmid:25919529
  21. 21. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of observational studies in epidemiology (MOOSE) group. JAMA. 2000;283: 2008–2012. pmid:10789670
  22. 22. Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0. 2011. Available from: http://handbook.cochrane.org/.
  23. 23. Mizuki N, Meguro A, Ota M, Ohno S, Shiota T, Kawagoe T, et al. Genome-wide association studies identify IL23R-IL12RB2 and IL10 as Behçet's disease susceptibility loci. Nat Genet. 2010;42: 703–706. pmid:20622879
  24. 24. Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ, et al. A genome-wide association study identifies IL23R as inflammatory bowel disease gene. Science. 2006;314: 1461–1463. pmid:17068223
  25. 25. Rioux JD, Xavier RJ, Taylor KD, Silverberg MS, Goyette P, Huett A, et al. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat Genet. 2007;39: 596–604. pmid:17435756
  26. 26. Barrett JC, Hansoul S, Nicolae DL, Cho JH, Duerr RH, Rioux JD, et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease. Nat Genet. 2008;40: 955–962. pmid:18587394
  27. 27. Silverberg MS, Cho JH, Rioux JD, McGovern DP, Wu J, Annese V, et al. Ulcerative colitis-risk loci on chromosomes 1p36 and 12q15 found by genome-wide association study. Nat Genet. 2009;41: 216–220. pmid:19122664
  28. 28. Cargill M, Schrodi SJ, Chang M, Garcia VE, Brandon R, Callis KP, et al. A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk gene. Am J Hum Genet. 2007;80: 273–290. pmid:17236132
  29. 29. Nair RP, Duffin KC, Helms C, Ding J, Stuart PE, Goldgar D, et al. Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways. Nat Genet. 2009;41: 199–204. pmid:19169254
  30. 30. Wellcome Trust Case Control Consortium; Australo-Anglo-American Spondylitis Consortium (TASC), Burton PR, Clayton DG, Cardon LR, Craddock N, Deloukas P, et al. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet. 2007;39: 1329–1337. pmid:17952073
  31. 31. Evans DM, Spencer CC, Pointon JJ, Su Z, Harvey D, Kochan G, et al. Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility. Nat Genet. 2011;43: 761–767. pmid:21743469
  32. 32. Iwakura Y, Ishigame H. The IL-23/IL-17 axis in inflammation. J Clin Invest. 2006;116: 1218–1222. pmid:16670765
  33. 33. Steinman L. Mixed results with modulation of TH-17 cells in human autoimmune diseases. Nat Immunol. 2010;11: 41–44. pmid:20016509
  34. 34. Khader SA, Gaffen SL, Kolls JK. Th17 cells at the crossroads of innate and adaptive immunity against infectious diseases at the mucosa. Mucosal Immunol. 2009;2: 403–411. pmid:19587639
  35. 35. Liang L, Peng XY, Wang H. Th lymphocyte subsets in patients with Vogt-Koyanagi-Harada disease. Int J Ophthalmol. 2019;12: 207–211. pmid:30809474
  36. 36. Zuo X, Sun L, Yin X, Gao J, Sheng Y, Xu J, et al. Whole-exome SNP array identifies 15 new susceptibility loci for psoriasis. Nat Commun. 2015;6: 6793. pmid:25854761
  37. 37. Bassili SS, Peyman GA, Gebhardt BM, Daun M, Ganiban GJ, Rifai A. Detection of Epstein-Barr virus DNA by polymerase chain reaction in the vitreous from a patient with Vogt-Koyanagi-Harada syndrome. Retina. 1996;16: 160–161. pmid:8724962
  38. 38. Sugita S, Takase H, Kawaguchi T, Taguchi C, Mochizuki M. Cross-reaction between tyrosinase peptides and cytomegalovirus antigen by T cells from patients with Vogt-Koyanagi-Harada disease. Int Ophthalmol. 2007;27: 87–95. pmid:17253112
  39. 39. Liu Y, Chen Y, Liao B, Luo D, Wang K, Li H, et al. Epidemiology of urolithiasis in Asia. Asian J Urol. 2018;5: 205–214. pmid:30364478
  40. 40. Takeuchi M, Mizuki N, Meguro A, Ombrello MJ, Kirino Y, Satorius C, et al. Dense genotyping of immune-related loci implicates host responses to microbial exposure in Behçet's disease susceptibility. Nat Genet. 2017;49: 438–443. pmid:28166214
  41. 41. Latiano A, Palmieri O, Latiano T, Corritore G, Bossa F, Martino G, et al. Investigation of multiple susceptibility loci for inflammatory bowel disease in an Italian cohort of patients. PLoS One. 2011;6: e22688. pmid:21818367
  42. 42. Sun LD, Xiao FL, Li Y, Zhou WM, Tang HY, Tang XF, et al. Genome-wide association study identifies two new susceptibility loci for atopic dermatitis in the Chinese Han population. Nat Genet. 2011;43: 690–694. pmid:21666691
  43. 43. Hirota T, Takahashi A, Kubo M, Tsunoda T, Tomita K, Sakashita M, et al. Genome-wide association study identifies eight new susceptibility loci for atopic dermatitis in the Japanese population. Nat Genet. 2012;44: 1222–1226. pmid:23042114
  44. 44. Myouzen K, Kochi Y, Shimane K, Fujio K, Okamura T, Okada Y, et al. Regulatory polymorphisms in EGR2 are associated with susceptibility to systemic lupus erythematosus. Hum Mol Genet. 2010;19: 2313–2320. pmid:20194224
  45. 45. 1000 Genomes Project Consortium, Auton A, Brooks LD, Durbin RM, Garrison EP, Kang HM, et al. A global reference for human genetic variation. Nature. 2015;526: 68–74. pmid:26432245