Proteinase 3 gene polymorphisms and Wegener's granulomatosis

Background. Wegener's granulomatosis (WG) is a rare systemic autoimmune dis ease characterized by small-vessel vasculitis leading to organ damage and t he presence of antineutrophil cytoplasmic autoantibodies (ANCAs). ANCAs wer e shown to be involved in the pathogenesis of the disease by increasing adh esion of polymorphonuclear cells (PMNs) to endothelial cells and through ac tivation of primed PMN. The main autoantigen of ANCA in WG is proteinase 3 (PR3), a neutrophil and monocyte-derived neutral serine protease. The assoc iation of WG with individuals continuously expressing a high level of PR3 o n the surface of PMNs suggests that PR3 variants or altered regulation of P R3 expression might be directly involved in the pathogenesis of the disease . Methods. We screened the entire coding and promoter sequences of the PR3 ge ne for polymorphisms by means of polymerase chain reaction single-strand co nformation polymorphism (PCR-SSCP). Allelic, genotypic, and haplotype frequ encies were compared between 79 WG patients and a cohort of 129 healthy con trols. Results. Seven single-nucleotide polymorphisms (SNPs), one amino acid chang e (Val19Ile), one 84 bp insertion/deletion, and a microsatellite were ident ified. An association with WG could be demonstrated for the A-564G polymorp hism in the PR3 promoter affecting a putative transcription factor-binding site. Conclusions. This study excludes certain PR3 epitope variants as autoantige nic stimuli in WG, since the Val119IIe poly morphism showed no differences between patients and controls. Overexpression of PR3, however, might predis pose the patient to the development of autoimmune ANCA-associated vasculiti s.