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... Show moreA 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 x 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-gamma) signaling pathway". By using FPRP and BFDP, network analysis of noteworthy genetic variants discovered genetic risk factors associated with the IFN-gamma pathway as novel mechanisms potentially implicated in the complex pathogenesis of ANCA-associated vasculitis. Show less
Zee, P.M. van der; Biro, E.; Trouw, L.A.; Ko, Y.; Winter, R.J. de; Hack, C.E.; ... ; Nieuwland, R. 2010
Background: C-reactive protein (CRP) is elevated in patients with acute myocardial infarction (AMI). When CRP binds to membrane phospholipids or Fc receptors, it activates the complement system.... Show moreBackground: C-reactive protein (CRP) is elevated in patients with acute myocardial infarction (AMI). When CRP binds to membrane phospholipids or Fc receptors, it activates the complement system. Recent studies show that CRP can be exposed on cell-derived microparticles (MP) and is associated complement activation. Objectives. We studied complement activation on circulating MP in AMI patients and healthy controls. Methods. MP were isolated from plasma of AMI patients (n=21) and sex- and age-matched healthy individuals (n=10), and analyzed by flow cytometry for bound complement components (C1q, C4, C3) and complement inhibitor and activator molecules (C4bp, CRP, serum amyloid P component, immunoglobulins IgM and IgG). Concurrently, the levels of fluid phase complement activation products and inhibitor and activator molecules were determined Results: Fluid phase CRP, MP with bound CRP (CRP + MP), and C3 activation products were elevated in AMI patients compared to controls (P=0.032, P=0.031 and P=0.023, respectively), and fluid phase CRP correlated with CRP+ MP (r=0.84, P<0.001). Although CRP+ MP were elevated, they were not associated with C1q+ MP (r=0.32, P=0.174). In contrast, IgG+ MP were associated with C1q+ MP (r=0.73, P<0.001), C4+ MP and C3+ MP (r=0.78 and r=0.87, respectively, both P<0 001), and C4bp (r=0.63, P=0.004). In healthy individuals, CRP+ MP were strongly associated with C1q+ MP (r=0 82, P=0.007), which in turn were associated with C4+ MP and C3+ MP (r=0.68, P=0.032 and r=0.68, P=0.031, respectively). Conclusions: Despite CRP-associated complement activation on the surface of MP in healthy individuals and a strong correlation between MP-bound CRP and fluid phase CRP in AMI patients, the MP-associated complement activation is IgG- but not CRP-dependent in AMP patients (C) 2010 Elsevier Inc. All rights reserved. Show less
