title: Association of granulomatosis with polyangiitis (Wegener's) with HLA-DPB1*04 and SEMA6A gene variants: evidence from genome-wide analysis.
abstract: OBJECTIVE
  To identify genetic determinants of granulomatosis with polyangiitis (Wegener's) (GPA).
  
  
  METHODS
  We carried out a genome-wide association study (GWAS) of 492 GPA cases and 1,506 healthy controls (white subjects of European descent), followed by replication analysis of the most strongly associated signals in an independent cohort of 528 GPA cases and 1,228 controls.
  
  
  RESULTS
  Genome-wide significant associations were identified in 32 single-nucleotide polymorphic (SNP) markers across the HLA region, the majority of which were located in the HLA-DPB1 and HLA-DPA1 genes encoding the class II major histocompatibility complex (MHC) DPβ chain 1 and DPα chain 1 proteins, respectively. Peak association signals in these 2 genes, emanating from SNPs rs9277554 (for DPβ chain 1) and rs9277341 (DPα chain 1) were strongly replicated in an independent cohort (in the combined analysis of the initial cohort and the replication cohort, P = 1.92 × 10(-50) and 2.18 × 10(-39) , respectively). Imputation of classic HLA alleles and conditional analyses revealed that the SNP association signal was fully accounted for by the classic HLA-DPB1*04 allele. An independent single SNP, rs26595, near SEMA6A (the gene for semaphorin 6A) on chromosome 5, was also associated with GPA, reaching genome-wide significance in a combined analysis of the GWAS and replication cohorts (P = 2.09 × 10(-8) ).
  
  
  CONCLUSIONS
  We identified the SEMA6A and HLA-DP loci as significant contributors to risk for GPA, with the HLA-DPB1*04 allele almost completely accounting for the MHC association. These two associations confirm the critical role of immunogenetic factors in the development of GPA.
authors.affiliation: Mount Sinai Hospital and University of Toronto, Toronto, Ontario, Canada.
authors.forename: Gang
authors.initials: G
authors.lastname: Xie
authors.forename: Delnaz
authors.initials: D
authors.lastname: Roshandel
authors.forename: Richard
authors.initials: R
authors.lastname: Sherva
authors.forename: Paul A
authors.initials: PA
authors.lastname: Monach
authors.forename: Emily Yue
authors.initials: EY
authors.lastname: Lu
authors.forename: Tabitha
authors.initials: T
authors.lastname: Kung
authors.forename: Keisha
authors.initials: K
authors.lastname: Carrington
authors.forename: Steven S
authors.initials: SS
authors.lastname: Zhang
authors.forename: Sara L
authors.initials: SL
authors.lastname: Pulit
authors.forename: Stephan
authors.initials: S
authors.lastname: Ripke
authors.forename: Simon
authors.initials: S
authors.lastname: Carette
authors.forename: Paul F
authors.initials: PF
authors.lastname: Dellaripa
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Edberg
authors.forename: Gary S
authors.initials: GS
authors.lastname: Hoffman
authors.forename: Nader
authors.initials: N
authors.lastname: Khalidi
authors.forename: Carol A
authors.initials: CA
authors.lastname: Langford
authors.forename: Alfred D
authors.initials: AD
authors.lastname: Mahr
authors.forename: E William
authors.initials: EW
authors.lastname: St Clair
authors.forename: Philip
authors.initials: P
authors.lastname: Seo
authors.forename: Ulrich
authors.initials: U
authors.lastname: Specks
authors.forename: Robert F
authors.initials: RF
authors.lastname: Spiera
authors.forename: John H
authors.initials: JH
authors.lastname: Stone
authors.forename: Steven R
authors.initials: SR
authors.lastname: Ytterberg
authors.forename: Soumya
authors.initials: S
authors.lastname: Raychaudhuri
authors.forename: Paul I W
authors.initials: PI
authors.lastname: de Bakker
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Farrer
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Amos
authors.forename: Peter A
authors.initials: PA
authors.lastname: Merkel
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Siminovitch
mesh_terms: D000328:Adult; D000483:Alleles; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D014890:Granulomatosis with Polyangiitis / Q000235:genetics* / Q000276:immunology; D059868:HLA-DP beta-Chains / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D008285:Major Histocompatibility Complex; D008297:Male; D020641:Polymorphism, Single Nucleotide; D039961:Semaphorins / Q000235:genetics*
chemical_list: D059868:HLA-DP beta-Chains; C505113:HLA-DPB1*04:01 antigen; C504201:SEMA6A protein, human; D039961:Semaphorins