April 2014
Volume 55, Issue 13
ARVO Annual Meeting Abstract  |   April 2014
Identification of multiple genetic susceptibility loci for Behçet’s disease
Author Affiliations & Notes
  • Masaki Takeuchi
    National Institutes of Health, Bethesda, MD
    Ophthalmology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
  • Nobuhisa Mizuki
    Ophthalmology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
  • Akira Meguro
    Ophthalmology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
  • Ilknur Tugal-tutkun
    Istanbul University, Istanbul, Turkey
  • Yilmaz Ozyazgan
    Istanbul University, Istanbul, Turkey
  • Shigeaki Ohno
    Ophthalmology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
  • Ahmet Gül
    Istanbul University, Istanbul, Turkey
  • Daniel L Kastner
    National Institutes of Health, Bethesda, MD
  • Elaine F Remmers
    National Institutes of Health, Bethesda, MD
  • Footnotes
    Commercial Relationships Masaki Takeuchi, None; Nobuhisa Mizuki, None; Akira Meguro, None; Ilknur Tugal-tutkun, None; Yilmaz Ozyazgan, None; Shigeaki Ohno, None; Ahmet Gül, None; Daniel Kastner, None; Elaine Remmers, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science April 2014, Vol.55, 6419. doi:
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      Masaki Takeuchi, Nobuhisa Mizuki, Akira Meguro, Ilknur Tugal-tutkun, Yilmaz Ozyazgan, Shigeaki Ohno, Ahmet Gül, Daniel L Kastner, Elaine F Remmers; Identification of multiple genetic susceptibility loci for Behçet’s disease. Invest. Ophthalmol. Vis. Sci. 2014;55(13):6419.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose: Behçet’s disease (BD) is a systemic vasculitis that manifests with oral ulcers, uveitis, skin inflammation, genital ulcers and inflammation in other organs. Although HLA-B*51, IL10, IL12RB2, IL23R, CCR1, STAT4, KLRC4, and ERAP1 have been reported to be susceptibility genes in previous studies, the pathogenesis of BD remains unclear. The purpose of this study was to perform dense genotyping of loci associated with immune diseases to identify novel susceptibility loci for BD.

Methods: In this study, 2014 Turkish BD patients and 1826 controls were densely genotyped using the Immunochip. After quality control, we performed association tests. For novel loci with association test P value < 5×10-6, additional SNPs in the region were imputed using 1000 Genomes data as the reference panel. Imputed SNPs with info > 0.8 were included in the comprehensive association analysis. For replication, we imputed the genotype data of Japanese 608 cases and 737 controls from the previous GWAS. After imputation, the Cochran-Mantel-Haenszel test was performed for meta-analysis. P value < 5×10-8 and P value < 1.67×10-8 were considered thresholds for genome-wide significance in the basic allele test analysis and the three model (additive, dominant, recessive) genotypic analysis, respectively.

Results: The basic allele association test confirmed 2 loci, IL10 and CCR1, previously associated with BD and identified 4 novel loci, IL1A-IL1B, SCHIP1-IL12A, IRF8, and PTPN1, which exceeded genome-wide significance. In addition, the FUT2 locus showed dominant model genome-wide significance in the three model genotypic analysis. Imputation data provided an additional novel locus with genome-wide significance, EGR2. Meta-analysis of the Turkish and Japanese population data revealed novel loci, RIPK2 and LACC1. BD associated SNPs in EGR2 were also identified by meta-analysis.

Conclusions: This immunochip dense-genotyping study identified 6 new BD susceptibility loci, IL1A-IL1B, SCHIP1-IL12A, EGR2, IRF8, FUT2 and PTPN1 in theTurkish population. Meta-analysis of Turkish and Japanese populations identified 3 new BD susceptibility loci, RIPK2, EGR2 and LACC1. These results have greatly expanded the list of genes with common variants that influence BD susceptibility and implicate variants influencing both innate and adaptive immunity in disease pathogenesis.

Keywords: 432 autoimmune disease • 539 genetics • 557 inflammation  

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