title: Association of -27T>C and its haplotype at the putative promoter for IgA-specific receptor gene with IgA nephropathy among the Chinese Han population.
abstract: BACKGROUND
  One-third to half of IgA nephropathy (IgAN) patients have raised serum IgA levels. Decreased clearance of IgA/IgA complex has been observed in IgAN patients. FCAR codes for IgA-specific receptor and plays an important role in IgA metabolism. Previous small sample-sized studies reported controversial findings in its association with IgAN.
  
  
  METHODS
  We re-sequenced the FCAR in 107 IgAN patients and 112 controls. Association of -27T/C and their haplotypes were performed in 606 patients versus 606 controls, its two independent subsets: 293 single patients with family members and 313 cases versus 606 controls. Functional impact of -27T>C and their haplotypes were analyzed by bioinformatics, allelic differential expression and luciferase activity assays. Cell surface FCAR density between -27T/C heterozygous patients and -27T/T homozygous controls was assessed by flow cytometry.
  
  
  RESULTS
  -27T>C, on the consensus TATA box of transcription factor-binding motif in the putative promoter of the gene was the only variation identified in all coding, splice-site and known protein-binding sequence in re-sequencing. -27C and its haplotype were associated with IgAN (P = 0.0034/0.0013, 0.0099/0.0054, 0.0129/0.0076 and 0.00039/0.00014 in 606 cases versus 606 controls, family-based study, 313 cases versus 606 controls and meta-analysis, respectively). Bioinformatics predicted 2 bp binding changes by -27C. Allelic differential expression and luciferase activity assays showed a reduced expression/activity by the associated haplotype/allele (P < 0.001). -27T/C heterozygous patients had a lower receptor density on cell surface compared to -27T/T homozygous controls (P < 0.001).
  
  
  CONCLUSIONS
  Our results provide evidence for genetic variation at the putative promoter region of FCAR conferring susceptibility to IgAN, suggesting -27C and its haplotype may be causative for the susceptibility among the Chinese Han population.
authors.affiliation: Department of Medical Genetics and Center for Genome Research, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Weijun
authors.initials: W
authors.lastname: Huang
authors.forename: Hongbiao
authors.initials: H
authors.lastname: Gu
authors.forename: Ru
authors.initials: R
authors.lastname: Li
authors.forename: Tanqi
authors.initials: T
authors.lastname: Lou
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Ye
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.forename: Caixia
authors.initials: C
authors.lastname: Li
authors.forename: Shiyi
authors.initials: S
authors.lastname: Xiong
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Changyou
authors.initials: C
authors.lastname: Wu
authors.forename: Joseph C K
authors.initials: JC
authors.lastname: Leung
authors.forename: Man F
authors.initials: MF
authors.lastname: Lam
authors.forename: Kar N
authors.initials: KN
authors.lastname: Lai
authors.forename: Yiming
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000328:Adult; D044466:Asian People / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D005434:Flow Cytometry; D020022:Genetic Predisposition to Disease; D005922:Glomerulonephritis, IGA / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011961:Receptors, Fc / Q000235:genetics*
chemical_list: C045281:IgA receptor; D011961:Receptors, Fc; D008156:Luciferases