Identification of Functional and Expression Polymorphisms Associated With Risk for Antineutrophil Cytoplasmic Autoantibody–Associated Vasculitis

for the Vasculitis Clinical Research Consortium

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1054-1066
Number of pages13
JournalArthritis and Rheumatology
Volume69
Issue number5
DOIs
StatePublished - May 1 2017

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Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
Vasculitis
Microscopic Polyangiitis
Antineutrophil Cytoplasmic Antibodies
Myeloblastin
Haplotypes
Odds Ratio
Granulomatosis with Polyangiitis
Proteins
Genome-Wide Association Study
Peroxidase
Single Nucleotide Polymorphism
Meta-Analysis
Monocytes
Neutrophils
B-Lymphocytes
Alleles
Genome
T-Lymphocytes
Gene Expression

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology

Cite this

Identification of Functional and Expression Polymorphisms Associated With Risk for Antineutrophil Cytoplasmic Autoantibody–Associated Vasculitis. / for the Vasculitis Clinical Research Consortium.

In: Arthritis and Rheumatology, Vol. 69, No. 5, 01.05.2017, p. 1054-1066.

Research output: Contribution to journalArticle

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title = "Identification of Functional and Expression Polymorphisms Associated With Risk for Antineutrophil Cytoplasmic Autoantibody–Associated Vasculitis",
abstract = "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.",
author = "{for the Vasculitis Clinical Research Consortium} and Merkel, {Peter A.} and Gang Xie and Monach, {Paul A.} and Xuemei Ji and Ciavatta, {Dominic J.} and Jinyoung Byun and Pinder, {Benjamin D.} and Ai Zhao and Jinyi Zhang and Yohannes Tadesse and David Qian and Matthew Weirauch and Rajan Nair and Alex Tsoi and Christian Pagnoux and Simon Carette and Sharon Chung and David Cuthbertson and Davis, {John C.} and Dellaripa, {Paul F.} and Lindsy Forbess and Ora Gewurz-Singer and Hoffman, {Gary S.} and Nader Khalidi and Curry Koening and Langford, {Carol A.} and Mahr, {Alfred D.} and Carol McAlear and Larry Moreland and Seo, {E. Philip} and Ulrich Specks and Spiera, {Robert F.} and Antoine Sreih and St.Clair, {E. William} and Stone, {John H.} and Ytterberg, {Steven R} and Elder, {James T.} and Jia Qu and Toshiki Ochi and Naoto Hirano and Edberg, {Jeffrey C.} and Falk, {Ronald J.} and Amos, {Christopher I.} and Siminovitch, {Katherine A.}",
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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.

PY - 2017/5/1

Y1 - 2017/5/1

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.

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