Genetic Variants in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A Bayesian Approach and Systematic Review.

Kwang Lee,Younhee Ko,Jae Shin,Katherine Siminovitch,Christopher Amos,Andreas Kronbichler,Peter Merkel,David Jayne,Chinar Rahmattulla,Michael Eisenhut,Daniel Pereira Vasconcelos,Felipe Pereira Da Silva,Keum Lee,Yeon Oh

doi:10.3390/jcm8020266

Abstract

A number of genome-wide association studies (GWASs) and meta-analyses of genetic variants have been performed in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. We reinterpreted previous studies using false-positive report probability (FPRP) and Bayesian false discovery probability (BFDP). This study searched publications in PubMed and Excerpta Medica Database (EMBASE) up to February 2018. Identification of noteworthy associations were analyzed using FPRP and BFDP, and data (i.e., odds ratio (OR), 95% confidence interval (CI), p-value) related to significant associations were separately extracted. Using filtered gene variants, gene ontology (GO) enrichment analysis and protein–protein interaction (PPI) networks were performed. Overall, 241 articles were identified, and 7 were selected for analysis. Single nucleotide polymorphisms (SNPs) discovered by GWASs were shown to be noteworthy, whereas only 27% of significant results from meta-analyses of observational studies were noteworthy. Eighty-five percent of SNPs with borderline p-values (5.0 × 10−8 < p < 0.05) in GWASs were found to be noteworthy. No overlapping SNPs were found between PR3-ANCA and MPO-ANCA vasculitis. GO analysis revealed immune-related GO terms, including “antigen processing and presentation of peptide or polysaccharide antigen via major histocompatibility complex (MHC) class II”, “interferon-gamma-mediated (IFN-γ) signaling pathway”. By using FPRP and BFDP, network analysis of noteworthy genetic variants discovered genetic risk factors associated with the IFN-γ pathway as novel mechanisms potentially implicated in the complex pathogenesis of ANCA-associated vasculitis.

Highlights

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of autoimmune diseases characterized by the inflammation of small vessels
Significant associations were selected if the reported p-value was
The re-analysis of genetic variants was mainly driven by two categories of studies: one meta-analysis of observational studies and two GWASs with replication cohorts

Summary

Introduction

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of autoimmune diseases characterized by the inflammation of small vessels. Clinical overlap among the different subtypes of AAV, granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA) can result in diagnostic difficulties [1]. The clinical manifestations of the disease types can vary widely; most patients have signs of a lung, kidney, and/or ear, nose, and throat (ENT) involvement. ENT involvement is especially common in patients with GPA and EGPA [1]. A perinuclear ANCA (p-ANCA)—target antigen MPO—is found in 60–80% of MPA patients. Cytoplasmic ANCA (c-ANCA)—target antigen proteinase 3 (PR3)—is frequently found in patients with severe GPA (approximately 90% of patients) and to a lesser degree in those with non-severe disease (approximately 50% of patients) [1]

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