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

Sakono, Takuto; Meguro, Akira; Takeuchi, Masaki; Yamane, Takahiro; Teshigawara, Takeshi; Horie, Yukihiro; Namba, Kenichi; Ohno, Shigeaki; Nakao, Kumiko; Sakamoto, Taiji; Sakai, Tsutomu; Nakano, Tadashi; Keino, Hiroshi; Okada, Annabelle A.; Takeda, Atsunobu; Ito, Takako; Mashimo, Hisashi; Ohguro, Nobuyuki; Oono, Shinichirou; Enaida, Hiroshi; Okinami, Satoshi; Horita, Nobuyuki; Ôta, Masao; Mizuki, Nobuhisa

doi:10.1371/journal.pone.0233464

Cited by 9 publications

(7 citation statements)

References 43 publications

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“…This study identified two new susceptibility loci associated with VKH disease reached genome-wide significance, IL23R-C1orf141 (rs117633859) and ADO-ZNF365-EGR2 (rs442309), it being of particular interest that these associations are shared by uveitis associated with both BD and AAU. These findings have recently been replicated in a Japanese case-control candidate gene association study [ 49 ]. Hou et al also demonstrated association between HLA genes and VKH disease, showing the strongest association with SNP at HLA-DRB1/DQA1 locus (rs3021304).…”

Section: Vogt-koyanagi-harada Diseasementioning

confidence: 72%

Progress in the genetics of uveitis

Huang

Brown

2022

Genes Immun

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Uveitis is the most common form of intraocular inflammatory disease and is a significant cause of visual impairment worldwide. Aetiologically, uveitis can also be classified into infectious uveitis and non-infectious uveitis. The common non-infectious forms of uveitis include acute anterior uveitis (AAU), Behçet’s disease (BD), Vogt-Koyanagi-Harada (VKH) disease, birdshot chorioretinopathy (BSCR), sarcoid uveitis. In addition, a few monogenic autoinflammatory disorders can also cause uveitis, such as Blau Syndrome and haploinsufficiency of A20 (HA20). Although the exact pathogenesis of non-infectious uveitis is still unclear, it is well-recognised that it involves both genetic and environmental risk factors. A hallmark of uveitis is its strong associations with human leucocyte antigens (HLA). For examples, AAU, BD and BSCR are strongly associated with HLA-B27, HLA-B51, and HLA-A29, respectively. In uveitis studies, multiple GWAS have successfully been conducted and led to identification of novel susceptibility loci, for example, IL23R has been identified in BD, VKH and AAU. In this review, we summarize the latest progress on the genetic associations of both HLA and non-HLA genes with major forms of uveitis, including AAU, BD, VKH, BSCR, sarcoid uveitis, Blau Syndrome and HA20, and potential future research directions.

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Section: Vogt-koyanagi-harada Diseasementioning

confidence: 72%

Progress in the genetics of uveitis

Huang

Brown

2022

Genes Immun

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“…The C1orf141 gene, with uncharacterized protein function, has overlapping regions with IL23R . Variants in the IL23R-C1orf141 region have been associated with susceptibility to Vogt-Koyanagi-Harada disease, a multi-system autoimmune disorder that affects pigmented tissues, in Chinese and Japanese populations [ 31 , 54 ]. The ZFR gene encodes the highly conserved zinc finger RNA-binding protein, which is shown to prevent excessive type I interferon activation by regulating alternative pre-mRNA splicing [ 30 ].…”

Section: Resultsmentioning

confidence: 99%

Kernel-based genetic association analysis for microbiome phenotypes identifies host genetic drivers of beta-diversity

Liu

Ling²,

Hua

et al. 2023

Microbiome

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Background Understanding human genetic influences on the gut microbiota helps elucidate the mechanisms by which genetics may influence health outcomes. Typical microbiome genome-wide association studies (GWAS) marginally assess the association between individual genetic variants and individual microbial taxa. We propose a novel approach, the covariate-adjusted kernel RV (KRV) framework, to map genetic variants associated with microbiome beta-diversity, which focuses on overall shifts in the microbiota. The KRV framework evaluates the association between genetics and microbes by comparing similarity in genetic profiles, based on groups of variants at the gene level, to similarity in microbiome profiles, based on the overall microbiome composition, across all pairs of individuals. By reducing the multiple-testing burden and capturing intrinsic structure within the genetic and microbiome data, the KRV framework has the potential of improving statistical power in microbiome GWAS. Results We apply the covariate-adjusted KRV to the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) in a two-stage (first gene-level, then variant-level) genome-wide association analysis for gut microbiome beta-diversity. We have identified an immunity-related gene, IL23R, reported in a previous microbiome genetic association study and discovered 3 other novel genes, 2 of which are involved in immune functions or autoimmune disorders. In addition, simulation studies show that the covariate-adjusted KRV has a greater power than other microbiome GWAS methods that rely on univariate microbiome phenotypes across a range of scenarios. Conclusions Our findings highlight the value of the covariate-adjusted KRV as a powerful microbiome GWAS approach and support an important role of immunity-related genes in shaping the gut microbiome composition.

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“…Disease susceptibility has been reported for MHC class II genes, such as HLA-DR4/DRw53, and HLA-DQ4 In VKH disease (68) A GWAS of a Chinese cohort including 1,538 cases and 5,603 controls reported disease susceptibility loci of IL23R and ADO-EGR2 (41). Disease susceptibility of IL23R was confirmed in the Han Chinese Singaporean and Japanese populations, and ADO-EGR2 was confirmed in the Japanese and Thai populations (42,43).…”

Section: Vogt-koyanagi-harada Diseasementioning

confidence: 96%

Pathogenesis of Non-Infectious Uveitis Elucidated by Recent Genetic Findings

2021

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Uveitis is a generic term for inflammation of the uvea, which includes the iris, ciliary body, and choroid. Prevalence of underlying non-infectious uveitis varies by race and region and is a major cause of legal blindness in developed countries. Although the etiology remains unclear, the involvement of both genetic and environmental factors is considered important for the onset of many forms of non-infectious uveitis. Major histocompatibility complex (MHC) genes, which play a major role in human immune response, have been reported to be strongly associated as genetic risk factors in several forms of non-infectious uveitis. Behçet’s disease, acute anterior uveitis (AAU), and chorioretinopathy are strongly correlated with MHC class I-specific alleles. Moreover, sarcoidosis and Vogt-Koyanagi-Harada (VKH) disease are associated with MHC class II-specific alleles. These correlations can help immunogenetically classify the immune pathway involved in each form of non-infectious uveitis. Genetic studies, including recent genome-wide association studies, have identified several susceptibility genes apart from those in the MHC region. These genetic findings help define the common or specific pathogenesis of ocular inflammatory diseases by comparing the susceptibility genes of each form of non-infectious uveitis. Interestingly, genome-wide association of the interleukin (IL)23R region has been identified in many of the major forms of non-infectious uveitis, such as Behçet’s disease, ocular sarcoidosis, VKH disease, and AAU. The interleukin-23 (IL-23) receptor, encoded by IL23R, is expressed on the cell surface of Th17 cells. IL-23 is involved in the homeostasis of Th17 cells and the production of IL-17, which is an inflammatory cytokine, indicating that a Th17 immune response is a common key in the pathogenesis of non-infectious uveitis. Based on the findings from the immunogenetics of non-infectious uveitis, a personalized treatment approach based on the patient’s genetic make-up is expected.

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

Cited by 9 publications

References 43 publications

Progress in the genetics of uveitis

Progress in the genetics of uveitis

Kernel-based genetic association analysis for microbiome phenotypes identifies host genetic drivers of beta-diversity

Pathogenesis of Non-Infectious Uveitis Elucidated by Recent Genetic Findings

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