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Genetically determined severity of anti-myeloperoxidase glomerulonephritis
Hong Xiao1, Dominic Ciavatta, David L Aylor
1Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Abstract:
Myeloperoxidase (MPO) is a target antigen for antineutrophil cytoplasmic autoantibodies (ANCA). There is evidence that MPO-ANCA cause necrotizing and crescentic glomerulonephritis (NCGN) and vasculitis. NCGN severity varies among patients with ANCA disease, and genetic factors influence disease severity. The role of genetics in MPO-ANCA NCGN severity was investigated using 13 inbred mouse strains, F1 and F2 hybrids, bone marrow chimeras, and neutrophil function assays. Mouse strains include founders of the Collaborative Cross. Intravenous injection of anti-MPO IgG induced glomerular crescents in >60% of glomeruli in 129S6/SvEv and CAST/EiJ mice, but <1% in A/J, DBA/1J, DBA/2J, NOD/LtJ, and PWK/PhJ mice. C57BL6J, 129S1/SvImJ, LP/J, WSB/EiJ, NZO/HILtJ, and C3H mice had intermediate severity. High-density genotypes at 542,190 single nucleotide polymorphisms were used to identify candidate loci for disease severity by identifying genomic regions that are different between 129S6/SvEv and 129S1/SvImJ mice, which are genetically similar but phenotypically distinct. C57BL/6 × 129S6 F2 mice were genotyped at 76 SNPs to capture quantitative trait loci for disease severity. The absence of a dominant quantitative trait locus suggests that differences in severity are the result of multiple gene interactions. In vivo studies using bone marrow chimeric mice and in vitro studies of neutrophil activation by anti-MPO IgG indicated that severity of NCGN is mediated by genetically determined differences in the function of neutrophils.
Insights
Genetic factors significantly influence the severity of myeloperoxidase-antineutrophil cytoplasmic autoantibody-associated necrotizing and crescentic glomerulonephritis. Mouse studies reveal that genetically determined differences in neutrophil function mediate disease severity, likely involving multiple gene interactions.
Area of Science:
- Immunology
- Genetics
- Nephrology
Background:
- Myeloperoxidase (MPO) is a key target antigen for antineutrophil cytoplasmic autoantibodies (ANCA).
- MPO-ANCA are implicated in causing necrotizing and crescentic glomerulonephritis (NCGN) and vasculitis.
- Disease severity in ANCA-associated NCGN exhibits patient-to-patient variability, suggesting a role for genetic factors.
Purpose of the Study:
- To investigate the genetic basis of MPO-ANCA NCGN severity.
- To identify genetic loci associated with NCGN severity using diverse mouse models.
- To elucidate the mechanisms underlying genetically determined differences in disease severity.
Main Methods:
- Utilized 13 inbred mouse strains, F1 and F2 hybrids, and bone marrow chimeras.
- Administered anti-MPO IgG intravenously to induce NCGN and assessed severity across strains.
- Employed high-density genotyping (542,190 SNPs) and quantitative trait loci (QTL) analysis.
- Conducted in vitro neutrophil function assays and in vivo bone marrow chimera studies.
Main Results:
- Significant variation in NCGN severity was observed among mouse strains following anti-MPO IgG induction.
- Genomic analysis identified potential candidate loci for disease severity by comparing phenotypically distinct but genetically similar mouse strains.
- Absence of a dominant QTL suggests that NCGN severity results from complex interactions among multiple genes.
- Neutrophil function assays and chimera studies indicated that genetically determined neutrophil function mediates NCGN severity.
Conclusions:
- Genetic factors play a crucial role in determining the severity of MPO-ANCA-associated NCGN.
- Differences in neutrophil function, influenced by genetics, are central to the pathogenesis of NCGN.
- Multiple gene interactions, rather than a single major gene, likely underlie the observed variations in disease severity.
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