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

Autor: Katherine A. Siminovitch, Toshiki Ochi, Gary S. Hoffman, Paul A. Monach, Paul F. Dellaripa, Sharon A. Chung, Ai Zhao, E. William St. Clair, Robert Spiera, Steven R. Ytterberg, Lindsy J. Forbess, Christopher I. Amos, Matthew T. Weirauch, Ulrich Specks, Simon Carette, Naoto Hirano, Jinyoung Byun, A. Tsoi, Ronald J. Falk, Alfred Mahr, Gang Xie, Rajan P. Nair, John C. Davis, David Cuthbertson, Christian Pagnoux, Larry W. Moreland, Dominic Ciavatta, Carol A. McAlear, Benjamin D. Pinder, Peter A. Merkel, Antoine G. Sreih, Yohannes Tadesse, James T. Elder, Jeffrey C. Edberg, Jinyi Zhang, John H. Stone, Ora Gewurz-Singer, Xuemei Ji, Jia Qu, Carol A. Langford, E. Philip Seo, David C. Qian, Curry L. Koening, Nader Khalidi
Rok vydání: 2017
Předmět:
Vasculitis
Adult
Male
0301 basic medicine
HLA-DP Antigens
Neutrophils
Myeloblastin
T-Lymphocytes
Immunology
Gene Expression
Microscopic Polyangiitis
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
Genome-wide association study
Biology
Autoantigens
Polymorphism
Single Nucleotide
Monocytes
PTPN22
03 medical and health sciences
0302 clinical medicine
Rheumatology
Proteinase 3
Odds Ratio
medicine
Humans
Immunology and Allergy
Genetic Predisposition to Disease
HLA-DP beta-Chains
Peroxidase
Anti-neutrophil cytoplasmic antibody
030203 arthritis & rheumatology
Genetics
B-Lymphocytes
Haplotype
Granulomatosis with Polyangiitis
Autoantibody
Protein Tyrosine Phosphatase
Non-Receptor Type 22
Middle Aged
medicine.disease
3. Good health
030104 developmental biology
Haplotypes
Case-Control Studies
alpha 1-Antitrypsin
Female
Microscopic polyangiitis
Granulomatosis with polyangiitis
Genome-Wide Association Study
Zdroj: Arthritis & Rheumatology (Hoboken, N.j.)
ISSN: 2326-5205
2326-5191
Popis: 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.
Databáze: OpenAIRE
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