STRONG LINK BETWEEN THE ALPHA(1)-ANTITRYPSIN PIZ ALLELE AND WEGENERS GRANULOMATOSIS

Objectives. To ascertain whether a relationship exists between the PiZ alpha(1)-antitrypsin (alpha(1)AT) variant and antineutrophil cytoplas m antibodies (ANCA)-positive vasculitis in a large group of Swedish pa tients, and whether analysis for the presence of the PiZ Variant might be useful for diagnostic or prognostic purposes. Design, Retrospectiv e cross-sectional study. Setting. The Department of Internal Medicine, Malmo General Hospital, and the Department of Nephrology, University of Lund, Sweden. Subjects and main outcome measures, Serum samples fro m 105 proteinase 3-ANCA-positive patients were analysed using an ELISA with a monoclonal antibody specific for the PiZ-gene product. Complet e clinical data were retrieved for 84% (88/105) of the patients, for d iagnosis and survival analysis. Results. We identified 17 heterozygote s and one homozygote (P<0.0001). All 88 patients with available clinic al data were considered to have some form of microscopic vasculitis in cluding 66 (75%) diagnosed as having Wegener's granulomatosis (WG), of whom 15 (23%) were PiZ heterozygotes (odds ratio 6.0, 95% confidence interval 3-10). There were no significant differences between PiZ carr iers and noncarriers in sex distribution, mean age at onset of disease , interval between onset and inclusion in the study, or in median dura tion of follow-up (P > 0.2 for all comparisons). During follow-up, 38% (6/16) of the PiZ heterozygotes died, compared with 17% (11/66) of no ncarriers of the variant (P = 0.02), which suggests that PiZ heterozyg osity may be a marker of poor prognosis. PiZ heterozygotes with system ic vasculitis would not appear to be identifiable by their pretreatmen t plasma alpha(1)AT concentrations, as all such patients in the presen t study had concentrations within or above the normal range. Conclusio n. We conclude that heterozygotes for the PiZ variant of the alpha(1)A T gene are at greater risk of than the general population of developin g WG. Knowledge of such a genetic factor may not only aid our understa nding of the mechanism involved in this illness but may also serve as significant prognostic factor in following the course of the disease.