Presentation: Prevalence of Alpha 1-Antitrypsin (AAT) Deficiency in Wegener’s Granulomatosis (WG) (2007)

2014 Prevalence of Alpha 1-Antitrypsin (AAT) Deficiency in Wegener’s Granulomatosis (WG)

Background: AAT plays a major role in inactivating neutrophil proteinase 3 and elastase and has other important anti-inflammatory properties. It has been reported that AAT deficiency may be a determinant of genetic susceptibility to WG. Several small studies demonstrated an increased prevalence of the AAT-deficiency Z allele in WG (7-27% of patients) with both homozygosity and heterozygosity of Z being overrepresented. It is unclear if the other major AAT-deficiency allele S also contributes to WG risk and whether AAT-deficiency allele carriage impacts on clinical phenotype in WG. We undertook a study to estimate the prevalence of the AAT-deficiency alleles Z and S in a large WG cohort and to identify genotype-phenotype correlations.
Methods: This study was conducted using the ‘Wegener's Granulomatosis GEnetic Repository’ and included 345 unrelated patients with WG (93% Caucasian). Genotyping was performed by ABI TaqMan allelic discrimination. The observed frequencies were compared to those expected from the US population (de Serres FJ, et al. Clin Genet 2003) using exact one-way goodness-of-fit χ² tests. AAT-deficiency allele carriers and non-carriers were compared for WG features using χ², Fisher’s exact, and Student’s t tests.
Results: Allele, allele carriage and genotype frequencies of Z and S in WG patients were all significantly higher than expected (Table 1). The observed genotype distribution deviated from Hardy-Weinberg equilibrium (P=0.02), mainly because of an excess in Z or S homozygosity. Z or S allele carriage was associated with a lower frequency of lung nodules (P=0.004) and a higher frequency of gangrene (P=0.047); no other between-group differences were detected in demographics, 19 other clinical variables, peak serum creatinine, PR3-ANCA positivity, and disease extent (limited/severe).
Conclusion: Homozygosity and heterozygosity for the AAT-deficient Z and S alleles are associated with WG, although in a smaller proportion of cases than previously reported. The departure from Hardy-Weinberg equilibrium could indicate that the homozygous genotypes confer a higher risk for WG than heterozygosity. The role of AAT deficiency in the overall pathogenesis of WG requires further consideration.

 A.D. Mahr, None; J.C. Edberg, None; J.H. Stone, None; P.F. Dellaripa, None; G.S. Hoffman, None; U. Specks, None; R.F. Spiera, None; E. St. Clair, None; F.N. Rouhani, None; M.L. Brantly, None; P.A. Merkel, None.