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Genome-wide association study identifies GIMAP as a novel susceptibility locus for Behçet's disease
  1. Yun Jong Lee1,2,
  2. Yukihiro Horie3,
  3. Graham R Wallace4,
  4. Yong Seok Choi1,
  5. Ji Ah Park2,
  6. Ji Yong Choi2,
  7. Ran Song2,
  8. Young-Mo Kang5,
  9. Seong Wook Kang6,
  10. Han Joo Baek7,
  11. Nobuyoshi Kitaichi8,
  12. Akira Meguro9,
  13. Nobuhisa Mizuki9,
  14. Kenichi Namba3,
  15. Susumu Ishida3,
  16. Jinhyun Kim6,
  17. Edyta Niemczyk4,
  18. Eun Young Lee2,
  19. Yeong Wook Song2,
  20. Shigeaki Ohno10,
  21. Eun Bong Lee2
  1. 1Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnamsi, Korea
  2. 2Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
  3. 3Department of Ophthalmology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
  4. 4Academic Unit of Ophthalmology, School of Immunity and Infection, University of Birmingham, Birmingham, UK
  5. 5Department of Internal Medicine, Kyungpook National University Hospital, Taegu, Korea
  6. 6Department of Internal Medicine, Chungnam National University Hospital, Taejeon, Korea
  7. 7Department of Internal Medicine, Gacheon University, Incheon, Korea
  8. 8Department of Ophthalmology, Health Sciences University of Hokkaido, Sapporo, Japan
  9. 9Department of Ophthalmology and Visual Science, Yokohama City University Graduate School of Medicine, Yokohama, Japan
  10. 10Department of Ocular Inflammation and Immunology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
  1. Correspondence to Dr Eun Bong Lee, Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-744, Korea; leb7616{at}snu.ac.kr

Abstract

Objectives To identify non-major histocompatibility complex susceptible genes that might contribute to Behçet's disease (BD).

Methods We performed a genome-wide association study using DNA samples from a Korean population consisting of 379 BD patients and 800 controls. A replication study was performed in a Japanese population (363 BD patients and 272 controls). To evaluate the functional implication of the target single nucleotide polymorphisms (SNP), gene expression levels in peripheral T cells, allele-specific modulation of promoter activity and biological effect of mRNA knockdown were investigated.

Results We found a novel association of BD to the GIMAP locus, mapped to chromosome 7q36.1 (rs1608157, p=6.01×10−8 in a minor allele dominant model; rs11769828, allele based p=1.60×10−6). A fine mapping study identified an association with four additional SNP: rs1522596 (OR=1.45, p=7.70×10−6) in GIMAP4; rs10266069 (OR=1.32, p=2.67×10−4) and rs10256482 (OR=1.27, p=5.27×10−4) in GIMAP2; and rs2286900 (OR=1.61, p=3.53×10−5) in GIMAP1 areas. Replication study using DNA samples from the Japanese population validated the significant association between BD and the GIMAP locus. The GIMAP4 promoter construct plasmid with the minor allele of rs1608157 displayed significantly lower activity than one with the major allele. Moreover, CD4 T cells from BD patients showed a lower level of GIMAP4 mRNA, and GIMAP4 knockdown was protective against Fas-mediated apoptosis.

Conclusions These results suggest that a GIMAP cluster is a novel susceptibility locus for BD, which is involved in T-cell survival, and T-cell aberration can contribute to the development of BD.

  • Behcet's disease
  • Gene Polymorphism
  • T Cells

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