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Correspondence |

α1-Antitrypsin Level and Pheno/GenotypesAlpha1-antitrypsin Concentration in Blood FREE TO VIEW

Ilaria Ferrarotti, PhD; Gian Andri Thun, MSc; Nicole M. Probst-Hensch, PhD; Maurizio Luisetti, MD, FCCP
Author and Funding Information

From the Centre for the Diagnosis of Hereditary Deficiency of a1-antitrypsin (Drs Ferrarotti and Luisetti), Department of Molecular Medicine, Pneumology Section, University of Pavia; Swiss Tropical and Public Health Institute (Mr Thun and Dr Probst-Hensch); and the University of Basel (Mr Thun and Dr Probst-Hensch).

Correspondence to: Ilaria Ferrarotti, PhD, Centre for the Diagnosis of Hereditary Deficiency of α1-antitrypsin, Department of Molecular Medicine, Pneumology Section, University of Pavia, Pavia, Italy; e-mail: i.ferrarotti@smatteo.pv.it


Financial/nonfinancial disclosures: The authors have reported to CHEST 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):1732-1733. doi:10.1378/chest.13-1464
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Published online
To the Editor:

We read with great interest the recently published article by Bornhorst et al1 in CHEST (April 2013), dealing with laboratory evaluation of α1-antitrypsin (AAT) deficiency. The authors investigated the relative frequencies and associated serum concentrations corresponding to the presence of common and rare AAT variants in a large database of patients; moreover, they established 95th percentile ranges for various AAT phenotype groups. We appreciate the goal of the article because ranges of plasma proteins are a much-discussed topic but are seldom investigated for AAT. Together with another recently published article of similar scope,2 this work, therefore, fills an important gap. Nevertheless, we would like to comment on a few aspects regarding the interpretation of the reference values given in these articles.

We recently published ranges of serum AAT according to the main genotype classes in a population-based study with 6,057 participants,3 which showed noteworthy differences from Bornhorst et al’s1 and Donato et al’s2 data (Table 1). The adults, who were randomly selected from eight population registries in Switzerland, had comparable lower limits, but the upper limits of 95% reference values were much lower. The age and sex dependency findings of the AAT reference values as described in Bornhorst et al’s article were very similar to our data,4 but should be regarded in combination with an inflammatory condition measured by C-reactive protein. Namely, when we stratified subjects according to the presence of an inflammatory condition, the genotype strata without an inflammatory condition showed significantly narrower ranges of serum AAT.3 The ranges suggested in the articles by Donato et al and Bornhorst et al would be expected to be influenced even more by the fact that AAT is an acute-phase reactant showing increased levels in inflammatory conditions as shown in data derived from clinical populations.

Table Graphic Jump Location
Table 1 —Comparison of 95% Reference Ranges of AAT in Adults Based on Three Different Studies

AAT = α1-antitrypsin.

a 

Calculated if sample size was large enough (PI*MM, PI*MS, PI*MZ). For the other three genotypes, minima and maxima are depicted.

An indication that the suggested reference values may not be representative of the general population also comes from the genotype distribution for the S and Z alleles. Unlike in our data, the reported frequencies of these alleles are far beyond the Hardy-Weinberg equilibrium (P < .0001).

A final relevant point is related to the use of phenotyping instead of genotyping to characterize AAT genetic polymorphisms. Discrepancies are well known because of the limits of isoelectric focusing (IEF) and immunofixation.5 In particular, phenotyping is not able to detect Mlike and null variants. From our data, we calculated that the allele frequencies of rare detectable (I, E, F, N, P, V, X) and undetectable (Mlike, null) variants by IEF are 0.21% and 0.12%, respectively. The allelic frequencies of variants other than M, S, and Z in Donato et al’s2 and Bornhorst et al’s1 data were higher (> 1.0%). We can, therefore, speculate that the inclusion of undetectable variants such as Mlike and null resulted in a slight decrease in the lower limits of the reported reference values.

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]
 
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]
 
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]
 
Senn O, Russi EW, Schindler C, et al; SAPALDIA Team. Circulating alpha1-antitrypsin in the general population: determinants and association with lung function. Respir Res. 2008;9:35. [CrossRef] [PubMed]
 
Miravitlles M, Herr C, Ferrarotti I, et al. Laboratory testing of individuals with severe alpha1-antitrypsin deficiency in three European centres. Eur Respir J. 2010;35(5):960-968. [CrossRef] [PubMed]
 

Figures

Tables

Table Graphic Jump Location
Table 1 —Comparison of 95% Reference Ranges of AAT in Adults Based on Three Different Studies

AAT = α1-antitrypsin.

a 

Calculated if sample size was large enough (PI*MM, PI*MS, PI*MZ). For the other three genotypes, minima and maxima are depicted.

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]
 
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]
 
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]
 
Senn O, Russi EW, Schindler C, et al; SAPALDIA Team. Circulating alpha1-antitrypsin in the general population: determinants and association with lung function. Respir Res. 2008;9:35. [CrossRef] [PubMed]
 
Miravitlles M, Herr C, Ferrarotti I, et al. Laboratory testing of individuals with severe alpha1-antitrypsin deficiency in three European centres. Eur Respir J. 2010;35(5):960-968. [CrossRef] [PubMed]
 
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