title: A putative functional variant within the UBAC2 gene is associated with increased risk of Behçet's disease.
abstract: OBJECTIVE
  Using a genome-wide association scan and DNA pooling, we previously identified 5 novel genetic susceptibility loci for Behçet's disease. We undertook this study to establish the genetic effect within the UBAC2 gene, in the course of which we replicated this genetic association and identified a functional variant within this locus.
  
  
  METHODS
  We studied a total of 676 Behçet's disease patients and 1,096 controls. The discovery set included 156 patients and 167 controls from Turkey, and the replication sets included 376 patients and 369 controls from Turkey and 144 patients and 560 controls from Italy. Genotyping of 14 single-nucleotide polymorphisms (SNPs) within and around UBAC2 was performed using TaqMan SNP genotyping assays.
  
  
  RESULTS
  The genetic association between Behçet's disease and UBAC2 was established, replicated, and confirmed (meta-analysis odds ratio 1.84, P = 1.69 × 10(-7) ). Haplotype analysis identified both a disease-risk haplotype and a protective haplotype (P = 0.00014 and P = 0.0075, respectively). Using conditional haplotype analysis, we identified the SNP rs7999348 (A/G) within UBAC2 as the most likely SNP with a genetic effect independent of the haplotypic effect formed by the remaining associated SNPs in this locus. Indeed, we demonstrated that rs7999348 tags a functional variant associated with increased messenger RNA expression of a UBAC2 transcript variant in peripheral blood mononuclear cells of individuals homozygous for the Behçet's disease-associated "G" allele. Further, our data suggested the possibility of multiple genetic effects that increase susceptibility to Behçet's disease in the UBAC2 locus.
  
  
  CONCLUSIONS
  We established and confirmed the genetic association between UBAC2 and Behçet's disease in 3 independent sets of patients and controls. We identified the minor allele in rs7999348 as a disease-risk allele that tags altered UBAC2 expression.
authors.affiliation: University of Oklahoma Health Sciences Center, Oklahoma City VA Medical Center, Oklahoma City, Oklahoma, USA. amr-sawalha@omrf.ouhsc.edu
authors.forename: Amr H
authors.initials: AH
authors.lastname: Sawalha
authors.forename: Travis
authors.initials: T
authors.lastname: Hughes
authors.forename: Ajay
authors.initials: A
authors.lastname: Nadig
authors.forename: Vuslat
authors.initials: V
authors.lastname: Yılmaz
authors.forename: Kenan
authors.initials: K
authors.lastname: Aksu
authors.forename: Gokhan
authors.initials: G
authors.lastname: Keser
authors.forename: Ayse
authors.initials: A
authors.lastname: Cefle
authors.forename: Ayten
authors.initials: A
authors.lastname: Yazıcı
authors.forename: Andaç
authors.initials: A
authors.lastname: Ergen
authors.forename: Marta E
authors.initials: ME
authors.lastname: Alarcón-Riquelme
authors.forename: Carlo
authors.initials: C
authors.lastname: Salvarani
authors.forename: Bruno
authors.initials: B
authors.lastname: Casali
authors.forename: Haner
authors.initials: H
authors.lastname: Direskeneli
authors.forename: Güher
authors.initials: G
authors.lastname: Saruhan-Direskeneli
mesh_terms: D000328:Adult; D000483:Alleles; D001528:Behcet Syndrome / Q000235:genetics*; D016022:Case-Control Studies; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: D047908:Intracellular Signaling Peptides and Proteins