Genome-wide association study identifies GIMAP as a novel susceptibility locus for Behcet's disease

Research output: Contribution to journalArticle

Authors

  • Yun Jong Lee
  • Yukihiro Horie
  • Yong Seok Choi
  • Ji Ah Park
  • Ji Yong Choi
  • Ran Song
  • Young-Mo Kang
  • Seong Wook Kang
  • Han Joo Baek
  • Nobuyoshi Kitaichi
  • Akira Meguro
  • Nobuhisa Mizuki
  • Kenichi Namba
  • Susumu Ishida
  • Jinhyun Kim
  • Eun Young Lee
  • Yeong Wook Song
  • Shigeaki Ohno
  • Eun Bong Lee

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.

Details

Original languageEnglish
Pages (from-to)1510-6
Number of pages7
JournalAnnals of the Rheumatic Diseases
Volume72
Issue number9
Publication statusPublished - 1 Sep 2013

Keywords

  • Adult, Asian Continental Ancestry Group, Behcet Syndrome, Cell Survival, Chromosome Mapping, Chromosomes, Human, Pair 7, Female, GTP-Binding Proteins, Gene Knockdown Techniques, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Japan, Male, Polymorphism, Single Nucleotide, RNA Interference, RNA, Messenger, T-Lymphocytes