Proteinase 3 gene polymorphisms and Wegener's granulomatosis.
BACKGROUND
Wegener's granulomatosis (WG) is a rare systemic autoimmune disease characterized by small-vessel vasculitis leading to organ damage and the presence of antineutrophil cytoplasmic autoantibodies (ANCAs). ANCAs were shown to be involved in the pathogenesis of the disease by increasing adhesion of polymorphonuclear cells (PMNs) to endothelial cells and through activation of primed PMN. The main autoantigen of ANCA in WG is proteinase 3 (PR3), a neutrophil- and monocyte-derived neutral serine protease. The association of WG with individuals continuously expressing a high level of PR3 on the surface of PMNs suggests that PR3 variants or altered regulation of PR3 expression might be directly involved in the pathogenesis of the disease.


METHODS
We screened the entire coding and promoter sequences of the PR3 gene for polymorphisms by means of polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP). Allelic, genotypic, and haplotype frequencies were compared between 79 WG patients and a cohort of 129 healthy controls.


RESULTS
Seven single-nucleotide polymorphisms (SNPs), one amino acid change (Val119Ile), one 84 bp insertion/deletion, and a microsatellite were identified. An association with WG could be demonstrated for the A-564G polymorphism in the PR3 promoter affecting a putative transcription factor-binding site.


CONCLUSIONS
This study excludes certain PR3 epitope variants as autoantigenic stimuli in WG, since the Val119Ile polymorphism showed no differences between patients and controls. Overexpression of PR3, however, might predispose the patient to the development of autoimmune ANCA-associated vasculitis.
Gencik
M
M
Molecular Human Genetics, Ruhr-University Bochum, and Medizinische Klinik, Klinikum Innenstadt, Universität München, München, Germany. martin.gencik@ruhr-uni-bochum.de
Meller
S
S
Borgmann
S
S
Fricke
H
H
D000483:Alleles; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D017931:DNA Primers; D005787:Gene Frequency; D014890:Granulomatosis with Polyangiitis / Q000201:enzymology / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D007438:Introns; D008969:Molecular Sequence Data; D053146:Myeloblastin; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000502:physiology; D012697:Serine Endopeptidases / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D017931:DNA Primers; D014157:Transcription Factors; D012697:Serine Endopeptidases; D053146:Myeloblastin