TY - JOUR
T1 - Identification of Functional and Expression Polymorphisms Associated With Risk for Antineutrophil Cytoplasmic Autoantibody–Associated Vasculitis
AU - for the Vasculitis Clinical Research Consortium
AU - Merkel, Peter A.
AU - Xie, Gang
AU - Monach, Paul A.
AU - Ji, Xuemei
AU - Ciavatta, Dominic J.
AU - Byun, Jinyoung
AU - Pinder, Benjamin D.
AU - Zhao, Ai
AU - Zhang, Jinyi
AU - Tadesse, Yohannes
AU - Qian, David
AU - Weirauch, Matthew
AU - Nair, Rajan
AU - Tsoi, Alex
AU - Pagnoux, Christian
AU - Carette, Simon
AU - Chung, Sharon
AU - Cuthbertson, David
AU - Davis, John C.
AU - Dellaripa, Paul F.
AU - Forbess, Lindsy
AU - Gewurz-Singer, Ora
AU - Hoffman, Gary S.
AU - Khalidi, Nader
AU - Koening, Curry
AU - Langford, Carol A.
AU - Mahr, Alfred D.
AU - McAlear, Carol
AU - Moreland, Larry
AU - Seo, E. Philip
AU - Specks, Ulrich
AU - Spiera, Robert F.
AU - Sreih, Antoine
AU - St.Clair, E. William
AU - Stone, John H.
AU - Ytterberg, Steven R.
AU - Elder, James T.
AU - Qu, Jia
AU - Ochi, Toshiki
AU - Hirano, Naoto
AU - Edberg, Jeffrey C.
AU - Falk, Ronald J.
AU - Amos, Christopher I.
AU - Siminovitch, Katherine A.
N1 - Publisher Copyright:
© 2016 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.
PY - 2017/5
Y1 - 2017/5
N2 - Objective: To identify risk alleles relevant to the causal and biologic mechanisms of antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV). Methods: 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. Results: 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%. Conclusion: 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.
AB - Objective: To identify risk alleles relevant to the causal and biologic mechanisms of antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV). Methods: 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. Results: 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%. Conclusion: 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.
UR - http://www.scopus.com/inward/record.url?scp=85017470718&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85017470718&partnerID=8YFLogxK
U2 - 10.1002/art.40034
DO - 10.1002/art.40034
M3 - Article
C2 - 28029757
AN - SCOPUS:85017470718
SN - 2326-5191
VL - 69
SP - 1054
EP - 1066
JO - Arthritis and Rheumatology
JF - Arthritis and Rheumatology
IS - 5
ER -