title: Replication study confirms the association between UBAC2 and Behçet's disease in two independent Chinese sets of patients and controls.
abstract: BACKGROUND
  The purpose of this study was to replicate genetic factors associated with the susceptibility to Behçet's disease (BD). We conducted a two-stage candidate genes association and functional study, involving 477 BD patients and 1,334 normal controls of Chinese Han descent.
  
  
  METHODS
  The genotyping of five candidate genes/loci, including LOC100129342, KIAA1529, CPVL, UBASH3B and UBAC2, were performed using TaqMan single nucleotide polymorphism (SNP) assays. Real-time PCR and luciferase reporter assay were performed to test the function of the identified promoter polymorphism. The main outcome measures were genotype frequencies and expression levels in BD patients.
  
  
  RESULTS
  The first-stage study results showed that UBAC2 (rs9513584, Pc = 0.018, OR = 1.4), but not LOC100129342, KIAA1529, CPVL, UBASH3B was associated with the susceptibility to BD in Chinese Han. The fine-mapping association study of UBAC2 identified six risk SNPs for BD in the Chinese cohort; three of them were verified in validation study (rs3825427, first-stage Pc = 2.2 × 10-3, second-stage Pc = 9.3 × 10-3, combined Pc = 6.9 × 10-6; rs9517668, first-stage Pc = 1.7 × 10-3, second-stage Pc = 0.03, combined Pc = 3.3 × 10-4; rs9517701, first-stage Pc = 5.1 × 10-3, second-stage Pc = 9.0 × 10-3, combined Pc = 2.9 × 10-5; respectively). Functional analysis showed that the risk T allele of the promoter polymorphism rs3825427 had a significantly lower promoter activity than the non-risk G allele (P = 0.002) and a decreased expression of UBAC2 transcript variant 1 in peripheral blood mononuclear cells (PBMCs) and skin of normal controls carrying the risk T allele than that in individuals with the G allele (P = 0.045, P = 0.025; respectively). The mRNA expression of UBAC2 transcript variant 1 was significantly decreased in PBMCs and skin of BD patients as compared with controls (P = 0.025; P = 0.047, respectively). The mRNA expression of UBAC2 transcript variant 2 was significantly increased in skin of BD patients as compared with controls (P = 0.004).
  
  
  CONCLUSIONS
  This study replicates a predisposition gene to BD, UBAC2, and suggests that UBAC2 may be involved in the development of BD through its transcriptional modulation.
authors.affiliation: The First Affiliated Hospital of Chongqing Medical University, Youyi Road 1, Chongqing, 400016, P, R, China.
authors.forename: Shengping
authors.initials: S
authors.lastname: Hou
authors.forename: Qinmeng
authors.initials: Q
authors.lastname: Shu
authors.forename: Zhengxuan
authors.initials: Z
authors.lastname: Jiang
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Chen
authors.forename: Fuzhen
authors.initials: F
authors.lastname: Li
authors.forename: Feilan
authors.initials: F
authors.lastname: Chen
authors.forename: Aize
authors.initials: A
authors.lastname: Kijlstra
authors.forename: Peizeng
authors.initials: P
authors.lastname: Yang
mesh_terms: D000328:Adult; D044466:Asian People / Q000208:ethnology / Q000235:genetics*; D001528:Behcet Syndrome / Q000201:enzymology / Q000208:ethnology / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D056726:Genetic Association Studies / Q000379:methods; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017027:Protein Tyrosine Phosphatases / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics; D044764:Ubiquitin-Activating Enzymes / Q000235:genetics*
chemical_list: C470301:UBA2 protein, human; D017027:Protein Tyrosine Phosphatases; C489397:UBASH3B protein, human; D044764:Ubiquitin-Activating Enzymes