Alpha1-antitrypsin deficiency-related alleles Z and S and the risk of Wegener's granulomatosis

Alfred D. Mahr, Jeffrey C. Edberg, John H. Stone, Gary S. Hoffman, E. William St.clair, Ulrich Specks, Paul F. Dellaripa, Philip Seo, Robert F. Spiera, Farshid N. Rouhani, Mark L. Brantly, Peter A. Merkel

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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.

Original languageEnglish (US)
Pages (from-to)3760-3767
Number of pages8
JournalArthritis and Rheumatism
Volume62
Issue number12
DOIs
StatePublished - Dec 2010

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Granulomatosis with Polyangiitis
Alleles
Genotype
Odds Ratio
Confidence Intervals
Gene Frequency
Case-Control Studies

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Rheumatology
  • Pharmacology (medical)

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Mahr, A. D., Edberg, J. C., Stone, J. H., Hoffman, G. S., St.clair, E. W., Specks, U., ... Merkel, P. A. (2010). Alpha1-antitrypsin deficiency-related alleles Z and S and the risk of Wegener's granulomatosis. Arthritis and Rheumatism, 62(12), 3760-3767. https://doi.org/10.1002/art.27742

Alpha1-antitrypsin deficiency-related alleles Z and S and the risk of Wegener's granulomatosis. / Mahr, Alfred D.; Edberg, Jeffrey C.; Stone, John H.; Hoffman, Gary S.; St.clair, E. William; Specks, Ulrich; Dellaripa, Paul F.; Seo, Philip; Spiera, Robert F.; Rouhani, Farshid N.; Brantly, Mark L.; Merkel, Peter A.

In: Arthritis and Rheumatism, Vol. 62, No. 12, 12.2010, p. 3760-3767.

Research output: Contribution to journalArticle

Mahr, AD, Edberg, JC, Stone, JH, Hoffman, GS, St.clair, EW, Specks, U, Dellaripa, PF, Seo, P, Spiera, RF, Rouhani, FN, Brantly, ML & Merkel, PA 2010, 'Alpha1-antitrypsin deficiency-related alleles Z and S and the risk of Wegener's granulomatosis', Arthritis and Rheumatism, vol. 62, no. 12, pp. 3760-3767. https://doi.org/10.1002/art.27742
Mahr, Alfred D. ; Edberg, Jeffrey C. ; Stone, John H. ; Hoffman, Gary S. ; St.clair, E. William ; Specks, Ulrich ; Dellaripa, Paul F. ; Seo, Philip ; Spiera, Robert F. ; Rouhani, Farshid N. ; Brantly, Mark L. ; Merkel, Peter A. / Alpha1-antitrypsin deficiency-related alleles Z and S and the risk of Wegener's granulomatosis. In: Arthritis and Rheumatism. 2010 ; Vol. 62, No. 12. pp. 3760-3767.
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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.",
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T1 - Alpha1-antitrypsin deficiency-related alleles Z and S and the risk of Wegener's granulomatosis

AU - Mahr, Alfred D.

AU - Edberg, Jeffrey C.

AU - Stone, John H.

AU - Hoffman, Gary S.

AU - St.clair, E. William

AU - Specks, Ulrich

AU - Dellaripa, Paul F.

AU - Seo, Philip

AU - Spiera, Robert F.

AU - Rouhani, Farshid N.

AU - Brantly, Mark L.

AU - Merkel, Peter A.

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N2 - 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.

AB - 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.

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