Chest
Volume 143, Issue 4, April 2013, Pages 1000-1008
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Original Research
COPD
α1-Antitrypsin Phenotypes and Associated Serum Protein Concentrations in a Large Clinical Population

https://doi.org/10.1378/chest.12-0564Get rights and content

Background

α1-Antitrypsin (AAT) deficiency variants reduce the concentration of serum AAT protease inhibitor and can lead to the development of pulmonary and hepatic disease. Relative frequencies of rare AAT variant phenotypes (non-M, Z, and S) and associated serum concentrations in the clinical population have not been thoroughly described.

Methods

Protein phenotypes were determined by isoelectric focusing electrophoresis for 72,229 consecutive samples. Phenotype frequencies, median serum concentrations, and central 95% concentration intervals were determined for observed phenotypes. Concurrent AAT phenotype and concentration data were used to evaluate the efficacy of using serum AAT concentration alone to detect AAT deficiency.

Results

Age, race, and sex had only slight effects on the median 95% serum protein concentration intervals of the 58,087 PiMM (wild type) phenotype specimens. Positive predictive values were calculated for the detection of potential deficiency phenotypes at different serum cutoff concentrations, aiding potential screening effort design. For example, the PiZZ deficiency phenotype (n = 814) could be detected at 99.5% sensitivity and 96.5% specificity using a cutoff of ≤ 85 mg/dL. However, at-risk specimens with two putative deleterious variants (Z, S, I, F, P, T, and Null variants) were detected with only 85.9% sensitivity at this cutoff (n = 1,661). Rare phenotype variants were observed in 2.5% of samples.

Conclusions

This analysis provides novel information on serum AAT concentrations associated with different AAT phenotypes and provides insight into the severity of depression of AAT concentration in the presence of rare deficiency variants. Additionally, it allows for evaluation of efficacy of testing algorithms incorporating AAT serum concentration determination.

Section snippets

Materials and Methods

A retrospective database was generated consisting of patient age in years, sex, patient race (when available), reported AAT phenotypes, and measured AAT concentrations for patient serum samples consecutively submitted for AAT phenotyping by IEF electrophoresis and concurrent AAT serum concentration determination to ARUP Laboratories. All samples were treated in accordance with procedures approved by the institutional review board of the University of Utah (IRB 7275).

Pi protein phenotypes were

Results

The observed protein phenotypes and associated serum concentrations are summarized in Table 1. A total of 1,664 patient samples had two apparent deficiency phenotype alleles and were classified as at-risk phenotypes. Of these, 99 samples contained a rare deficiency allele paired with an S or Z deficiency allele, and nine samples harbored two rare deficiency alleles (Pi FF, PP, II, TT). Three Null phenotype samples exhibiting no apparent AAT variant were classified at risk. Additionally, 16,893

Discussion

The large number of native PiMM individuals in this study allowed for investigation of differences in normal populations.35 As expected, the M1, M2, and M3 variants had no significant effect on serum AAT concentrations.11 Median AAT concentrations were slightly lower in males (P ≤ .01), although the magnitude of this effect is likely not clinically significant. Interestingly, PiMM individuals broadly designated as Asian exhibited significantly (P ≤ .05) lower AAT concentrations when compared

Acknowledgments

Author contributions: Dr Bornhorst had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Dr Bornhorst: contributed to the study design, data collection, data analyses, and manuscript writing.

Dr Greene: contributed to the study design, data analyses, and manuscript writing.

Dr Ashwood: contributed to the study design, data collection, data analyses, and manuscript writing.

Dr Grenache: contributed to the study

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    Funding/Support: This work was supported by the ARUP Institute for Clinical and Experimental Pathology.

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