Alpha1‐antitrypsin deficiency–related alleles Z and S and the risk of Wegener's granulomatosis
Open Access
- 8 September 2010
- journal article
- vasculitis
- Published by Wiley in Arthritis & Rheumatism
- Vol. 62 (12), 3760-3767
- https://doi.org/10.1002/art.27742
Abstract
Objective Deficiency of α1‐antitrypsin (α1AT) may be a determinant of susceptibility to Wegener's granulomatosis (WG). Several previous, mainly small, case–control studies have shown that 5–27% of patients with WG carried the α1AT deficiency Z allele. It is not clear whether the S allele, the other major α1AT deficiency variant, is associated with WG. This study investigated the relationship of the α1AT deficiency Z and S alleles with the risk of developing WG in a large cohort. Methods We studied the distribution of the α1AT deficiency alleles Z and S in 433 unrelated Caucasian patients with WG and 421 ethnically matched controls. Genotyping was performed using an allele discrimination assay. Results were compared between cases and controls using exact statistical methods. Results Among the patients with WG, the allele carriage frequencies of Z and S were 7.4% and 11.5%, respectively. The frequencies of the 6 possible genotypes differed in a statistically significant manner between cases and controls (P = 0.01). The general genetic 2‐parameter codominant model provided the best fit to the data. Compared with the normal MM genotype, the odds ratio (OR) for MZ or MS genotypes was 1.47 (95% confidence interval [95% CI] 0.98–2.22), and the OR for ZZ, SS, or SZ genotypes was 14.58 (95% CI 2.33–∞). ORs of similar direction and magnitude were observed within the restricted cohorts that excluded cases and controls carrying ≥1 Z or ≥1 S allele. Conclusion Both Z and S alleles display associations with risk of WG in a codominant genetic pattern. These findings strengthen the evidence of a causal link between α1AT deficiency and susceptibility to WG.Keywords
Funding Information
- Vasculitis Clinical Research Consortium funded by the NIH/National Center for Research Resources (U54-RR-019497)
- NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases (P60-AR-047785, R01-AR-047799)
- Société Nationale Française de Médicine Interne
- NIH/National Heart, Lung, and Blood Institute Mid-Career Development Award in Clinical Investigation (K24-HL-004456)
- NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases Mid-Career Development Award in Clinical Investigation (K24-AR-02224)
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