title: Alpha₁-antitrypsin deficiency-related alleles Z and S and the risk of Wegener's granulomatosis.
abstract: OBJECTIVE
  Deficiency of α(1) -antitrypsin (α(1) AT) 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 α(1) AT deficiency Z allele. It is not clear whether the S allele, the other major α(1) AT deficiency variant, is associated with WG. This study investigated the relationship of the α(1) AT deficiency Z and S alleles with the risk of developing WG in a large cohort.
  
  
  METHODS
  We studied the distribution of the α(1) AT 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.
  
  
  CONCLUSIONS
  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 α(1) AT deficiency and susceptibility to WG.
authors.affiliation: Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Alfred D
authors.initials: AD
authors.lastname: Mahr
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Edberg
authors.forename: John H
authors.initials: JH
authors.lastname: Stone
authors.forename: Gary S
authors.initials: GS
authors.lastname: Hoffman
authors.forename: E William
authors.initials: EW
authors.lastname: St Clair
authors.forename: Ulrich
authors.initials: U
authors.lastname: Specks
authors.forename: Paul F
authors.initials: PF
authors.lastname: Dellaripa
authors.forename: Philip
authors.initials: P
authors.lastname: Seo
authors.forename: Robert F
authors.initials: RF
authors.lastname: Spiera
authors.forename: Farshid N
authors.initials: FN
authors.lastname: Rouhani
authors.forename: Mark L
authors.initials: ML
authors.lastname: Brantly
authors.forename: Peter A
authors.initials: PA
authors.lastname: Merkel
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D014890:Granulomatosis with Polyangiitis / Q000208:ethnology / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D044465:White People / Q000208:ethnology / Q000235:genetics; D000515:alpha 1-Antitrypsin / Q000235:genetics*
chemical_list: C043392:SERPINA1 protein, human; D000515:alpha 1-Antitrypsin
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