title: Identification of Functional and Expression Polymorphisms Associated With Risk for Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis.
abstract: To identify risk alleles relevant to the causal and biologic mechanisms of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV).
  
  
  
  A genome-wide association study and subsequent replication study were conducted in a total cohort of 1,986 cases of AAV (patients with granulomatosis with polyangiitis [Wegener's] [GPA] or microscopic polyangiitis [MPA]) and 4,723 healthy controls. Meta-analysis of these data sets and functional annotation of identified risk loci were performed, and candidate disease variants with unknown functional effects were investigated for their impact on gene expression and/or protein function.
  
  
  
  Among the genome-wide significant associations identified, the largest effect on risk of AAV came from the single-nucleotide polymorphism variants rs141530233 and rs1042169 at the HLA-DPB1 locus (odds ratio [OR] 2.99 and OR 2.82, respectively) which, together with a third variant, rs386699872, constitute a triallelic risk haplotype associated with reduced expression of the HLA-DPB1 gene and HLA-DP protein in B cells and monocytes and with increased frequency of complementary proteinase 3 (PR3)-reactive T cells relative to that in carriers of the protective haplotype. Significant associations were also observed at the SERPINA1 and PTPN22 loci, the peak signals arising from functionally relevant missense variants, and at PRTN3, in which the top-scoring variant correlated with increased PRTN3 expression in neutrophils. Effects of individual loci on AAV risk differed between patients with GPA and those with MPA or between patients with PR3-ANCAs and those with myeloperoxidase-ANCAs, but the collective population attributable fraction for these variants was substantive, at 77%.
  
  
  
  This study reveals the association of susceptibility to GPA and MPA with functional gene variants that explain much of the genetic etiology of AAV, could influence and possibly be predictors of the clinical presentation, and appear to alter immune cell proteins and responses likely to be key factors in the pathogenesis of AAV.
authors.affiliation: University of Pennsylvania, Philadelphia.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Merkel
authors.affiliation: Mount Sinai Hospital, Lunenfeld-Tanenbaum Research Institute and Toronto General Research Institute, Toronto, Ontario, Canada.
authors.forename: Gang
authors.initials: G
authors.lastname: Xie
authors.affiliation: Boston University and VA Boston Healthcare System, Boston, Massachusetts.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Monach
authors.affiliation: Dartmouth College, Lebanon, New Hampshire.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Ji
authors.affiliation: University of North Carolina, Chapel Hill.
authors.forename: Dominic J
authors.initials: DJ
authors.lastname: Ciavatta
authors.affiliation: Dartmouth College, Lebanon, New Hampshire.
authors.forename: Jinyoung
authors.initials: J
authors.lastname: Byun
authors.affiliation: Mount Sinai Hospital, Lunenfeld-Tanenbaum Research Institute and Toronto General Research Institute, Toronto, Ontario, Canada.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Pinder
authors.affiliation: Mount Sinai Hospital, Lunenfeld-Tanenbaum Research Institute and Toronto General Research Institute, Toronto, Ontario, Canada.
authors.forename: Ai
authors.initials: A
authors.lastname: Zhao
authors.affiliation: Mount Sinai Hospital, Lunenfeld-Tanenbaum Research Institute, Toronto General Research Institute and University of Toronto, Toronto, Ontario, Canada.
authors.forename: Jinyi
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Mount Sinai Hospital, Lunenfeld-Tanenbaum Research Institute and Toronto General Research Institute, Toronto, Ontario, Canada.
authors.forename: Yohannes
authors.initials: Y
authors.lastname: Tadesse
authors.affiliation: Dartmouth College, Lebanon, New Hampshire.
authors.forename: David
authors.initials: D
authors.lastname: Qian
authors.affiliation: Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Matthew
authors.initials: M
authors.lastname: Weirauch
authors.affiliation: University of Michigan, Ann Arbor.
authors.forename: Rajan
authors.initials: R
authors.lastname: Nair
authors.affiliation: University of Michigan, Ann Arbor.
authors.forename: Alex
authors.initials: A
authors.lastname: Tsoi
authors.affiliation: Mount Sinai Hospital and University of Toronto, Toronto, Ontario, Canada.
authors.forename: Christian
authors.initials: C
authors.lastname: Pagnoux
authors.affiliation: Mount Sinai Hospital and University of Toronto, Toronto, Ontario, Canada.
authors.forename: Simon
authors.initials: S
authors.lastname: Carette
authors.affiliation: University of California, San Francisco.
authors.forename: Sharon
authors.initials: S
authors.lastname: Chung
authors.affiliation: University of South Florida, Tampa.
authors.forename: David
authors.initials: D
authors.lastname: Cuthbertson
authors.affiliation: University of California, San Francisco.
authors.forename: John C
authors.initials: JC
authors.lastname: Davis
authors.affiliation: Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Dellaripa
authors.affiliation: Cedars-Sinai Medical Center, West Hollywood, California.
authors.forename: Lindsy
authors.initials: L
authors.lastname: Forbess
authors.affiliation: University of Michigan, Ann Arbor.
authors.forename: Ora
authors.initials: O
authors.lastname: Gewurz-Singer
authors.affiliation: Cleveland Clinic, Cleveland, Ohio.
authors.forename: Gary S
authors.initials: GS
authors.lastname: Hoffman
authors.affiliation: McMaster University, Hamilton, Ontario, Canada.
authors.forename: Nader
authors.initials: N
authors.lastname: Khalidi
authors.affiliation: University of Utah, Salt Lake City.
authors.forename: Curry
authors.initials: C
authors.lastname: Koening
authors.affiliation: Cleveland Clinic, Cleveland, Ohio.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Langford
authors.affiliation: Hôpital Saint-Louis, Paris, France.
authors.forename: Alfred D
authors.initials: AD
authors.lastname: Mahr
authors.affiliation: University of Pennsylvania, Philadelphia.
authors.forename: Carol
authors.initials: C
authors.lastname: McAlear
authors.affiliation: University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Larry
authors.initials: L
authors.lastname: Moreland
authors.affiliation: Johns Hopkins University, Baltimore, Maryland.
authors.forename: E Philip
authors.initials: EP
authors.lastname: Seo
authors.affiliation: Mayo Clinic, Rochester, Minnesota.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Specks
authors.affiliation: Hospital for Special Surgery, New York, New York.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Spiera
authors.affiliation: University of Pennsylvania, Philadelphia.
authors.forename: Antoine
authors.initials: A
authors.lastname: Sreih
authors.affiliation: Duke University Medical Center, Durham, North Carolina.
authors.forename: E William
authors.initials: EW
authors.lastname: St Clair
authors.affiliation: Massachusetts General Hospital, Boston.
authors.forename: John H
authors.initials: JH
authors.lastname: Stone
authors.affiliation: Mayo Clinic, Rochester, Minnesota.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Ytterberg
authors.affiliation: University of Michigan and Ann Arbor VA Hospital, Ann Arbor, Michigan.
authors.forename: James T
authors.initials: JT
authors.lastname: Elder
authors.affiliation: Wenzhou Medical University, Wenzhou, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Qu
authors.affiliation: University of Toronto and Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Ochi
authors.affiliation: University of Toronto and Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors.forename: Naoto
authors.initials: N
authors.lastname: Hirano
authors.affiliation: University of Alabama at Birmingham.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Edberg
authors.affiliation: University of North Carolina, Chapel Hill.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Falk
authors.affiliation: Dartmouth College, Lebanon, New Hampshire.
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Amos
authors.affiliation: Mount Sinai Hospital, Lunenfeld-Tanenbaum Research Institute, Toronto General Research Institute and University of Toronto, Toronto, Ontario, Canada.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Siminovitch
mesh_terms: D000328:Adult; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / Q000235:genetics; D001324:Autoantigens / Q000276:immunology; D001402:B-Lymphocytes / Q000378:metabolism; D016022:Case-Control Studies; D005260:Female; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D014890:Granulomatosis with Polyangiitis / Q000235:genetics*; D006682:HLA-DP Antigens / Q000378:metabolism; D059868:HLA-DP beta-Chains / Q000235:genetics* / Q000378:metabolism; D006239:Haplotypes; D006801:Humans; D008297:Male; D055953:Microscopic Polyangiitis / Q000235:genetics*; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D053146:Myeloblastin / Q000235:genetics* / Q000276:immunology; D009504:Neutrophils / Q000378:metabolism; D016017:Odds Ratio; D009195:Peroxidase / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D000515:alpha 1-Antitrypsin / Q000235:genetics*
chemical_list: D001324:Autoantigens; D006682:HLA-DP Antigens; D059868:HLA-DP beta-Chains; C071170:HLA-DPB1 antigen; C043392:SERPINA1 protein, human; D000515:alpha 1-Antitrypsin; D009195:Peroxidase; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; D053146:Myeloblastin