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Joshua A. Bornhorst, PhD; Dina N. Greene, PhD; Edward R. Ashwood, MD; David G. Grenache, PhD
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From the Department of Pathology (Dr Bornhorst), University of Arkansas for Medical Sciences; The Permanente Medical Group Regional Laboratories (Dr Greene), Kaiser Permanente Northern California; Department of Pathology (Drs Ashwood and Grenache), University of Utah School of Medicine; and ARUP Laboratories Institute of Clinical and Experimental Pathology (Drs Ashwood and Grenache).

Correspondence to: Joshua A. Bornhorst, PhD, University of Arkansas for Medical Sciences, 4301 W Markham St 502, Little Rock, AR 72205; e-mail: jabornhorst@uams.edu


Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Bornhorst has received speaking honorarium from CSL Behring. Drs Greene, Ashwood, and Grenache have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2013;144(5):1733-1734. doi:10.1378/chest.13-1974
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To the Editor:

The letter by Dr Ferrarotti and colleagues raises important discussion points regarding the interpretation of three articles, including ours recently published in CHEST,1 investigating serum concentrations for α1-antitrypsin (AAT) variants.1-3 Differences in these studies include the use of genotyping and a randomly selected Swiss population registry2 vs larger cohorts of clinical specimens submitted for AAT phenotyping at national reference laboratories within the United States.1,3 It is known that potential underlying genetic variation may not be captured in phenotypic analysis.4 However, not all samples in the genotype study were submitted for full sequencing, possibly overlooking the presence of rare variant alleles.2,5

The two clinical reference laboratory studies generated remarkably similar upper and lower serum AAT concentration median 95% intervals for major AAT phenotypes.1,3 The lower concentration limits showed agreement with the corresponding genotype reference interval determinations for M/M, M/S, and M/Z groups in all three studies.1-3 This agreement is reassuring, as it is the lower limit of AAT concentration that may be used in screening for AAT deficiency and that has implications for variant-associated risk of disease progression.1-3

The upper limit of the central 95% interval for these three variants was lower in the Swiss population registry study than the other two studies. The presence of elevated C-reactive protein levels was not investigated in the two clinical population studies, and it is possible that significant numbers of the clinical study subjects had inflammation present, potentially elevating observed AAT variant upper reference-interval limits. However, intervals derived from the large and potentially more racially and geographically diverse clinical reference laboratory studies might be considered to more closely resemble some patient populations. Additionally, these large reference laboratory studies are able to provide central 95% intervals for less common phenotype/genotype variants, such as SS, SZ, and ZZ, rather than minima and maxima in the registry study.

The two reference-laboratory clinical population studies were not intended to provide variant gene frequency information for the general population, as presumably the submitted clinical samples are enriched for patients for whom there is clinical suspicion of AAT deficiency. Thus, deficiency variants (S, Z, and rare) would likely be overrepresented relative to the general population in these studies.1,3 Nevertheless, determinations of serum concentration reference intervals within each phenotype/genotype and the relative frequency distribution of different deficiency alleles within these studies can be considered valid.

References

Bornhorst JA, Greene DN, Ashwood ER, Grenache DG. α1-Antitrypsin phenotypes and associated serum protein concentrations in a large clinical population. Chest. 2013;143(4):1000-1008. [CrossRef] [PubMed]
 
Ferrarotti I, Thun GA, Zorzetto M, et al. Serum levels and genotype distribution of α1-antitrypsin in the general population. Thorax. 2012;67(8):669-674. [CrossRef] [PubMed]
 
Donato LJ, Jenkins SM, Smith C, Katzmann JA, Snyder MR. Reference and interpretive ranges for α(1)-antitrypsin quantitation by phenotype in adult and pediatric populations. Am J Clin Pathol. 2012;138(3):398-405. [CrossRef] [PubMed]
 
Bornhorst JA, Calderon FR, Procter M, Tang W, Ashwood ER, Mao R. Genotypes and serum concentrations of human alpha-1-antitrypsin “P” protein variants in a clinical population. J Clin Pathol. 2007;60(10):1124-1128. [CrossRef] [PubMed]
 
Zorzetto M, Russi E, Senn O, et al; SAPALDIA Team. SERPINA1 gene variants in individuals from the general population with reduced alpha1-antitrypsin concentrations. Clin Chem. 2008;54(8):1331-1338. [CrossRef] [PubMed]
 

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Tables

References

Bornhorst JA, Greene DN, Ashwood ER, Grenache DG. α1-Antitrypsin phenotypes and associated serum protein concentrations in a large clinical population. Chest. 2013;143(4):1000-1008. [CrossRef] [PubMed]
 
Ferrarotti I, Thun GA, Zorzetto M, et al. Serum levels and genotype distribution of α1-antitrypsin in the general population. Thorax. 2012;67(8):669-674. [CrossRef] [PubMed]
 
Donato LJ, Jenkins SM, Smith C, Katzmann JA, Snyder MR. Reference and interpretive ranges for α(1)-antitrypsin quantitation by phenotype in adult and pediatric populations. Am J Clin Pathol. 2012;138(3):398-405. [CrossRef] [PubMed]
 
Bornhorst JA, Calderon FR, Procter M, Tang W, Ashwood ER, Mao R. Genotypes and serum concentrations of human alpha-1-antitrypsin “P” protein variants in a clinical population. J Clin Pathol. 2007;60(10):1124-1128. [CrossRef] [PubMed]
 
Zorzetto M, Russi E, Senn O, et al; SAPALDIA Team. SERPINA1 gene variants in individuals from the general population with reduced alpha1-antitrypsin concentrations. Clin Chem. 2008;54(8):1331-1338. [CrossRef] [PubMed]
 
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