title: Genome-wide association study identifies GIMAP as a novel susceptibility locus for Behcet's disease.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnamsi, Korea.
authors.forename: Yun Jong
authors.initials: YJ
authors.lastname: Lee
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Horie
authors.forename: Graham R
authors.initials: GR
authors.lastname: Wallace
authors.forename: Yong Seok
authors.initials: YS
authors.lastname: Choi
authors.forename: Ji Ah
authors.initials: JA
authors.lastname: Park
authors.forename: Ji Yong
authors.initials: JY
authors.lastname: Choi
authors.forename: Ran
authors.initials: R
authors.lastname: Song
authors.forename: Young-Mo
authors.initials: YM
authors.lastname: Kang
authors.forename: Seong Wook
authors.initials: SW
authors.lastname: Kang
authors.forename: Han Joo
authors.initials: HJ
authors.lastname: Baek
authors.forename: Nobuyoshi
authors.initials: N
authors.lastname: Kitaichi
authors.forename: Akira
authors.initials: A
authors.lastname: Meguro
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Mizuki
authors.forename: Kenichi
authors.initials: K
authors.lastname: Namba
authors.forename: Susumu
authors.initials: S
authors.lastname: Ishida
authors.forename: Jinhyun
authors.initials: J
authors.lastname: Kim
authors.forename: Edyta
authors.initials: E
authors.lastname: Niemczyk
authors.forename: Eun Young
authors.initials: EY
authors.lastname: Lee
authors.forename: Yeong Wook
authors.initials: YW
authors.lastname: Song
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Ohno
authors.forename: Eun Bong
authors.initials: EB
authors.lastname: Lee
mesh_terms: D000328:Adult; D044466:Asian People; D001528:Behcet Syndrome / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology; D002470:Cell Survival; D002874:Chromosome Mapping; D002897:Chromosomes, Human, Pair 7; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics*; D055785:Gene Knockdown Techniques; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D007564:Japan; D008297:Male; D020641:Polymorphism, Single Nucleotide; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology
chemical_list: C485688:GIMAP4 protein, human; D012333:RNA, Messenger; D019204:GTP-Binding Proteins