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. 2020 Nov 6:15:2827-2836.
doi: 10.2147/COPD.S271810. eCollection 2020.

The Distribution of Alpha-1 Antitrypsin Genotypes Between Patients with COPD/Emphysema, Asthma and Bronchiectasis

Martina Veith  1 , Julia Tüffers  1 , Erika Peychev  1 , Andreas Klemmer  1 , Viktor Kotke  1 , Sabina Janciauskiene  2 , Susanne Wilhelm  1 , Robert Bals  3 , Andreas Rembert Koczulla  4 , Claus Franz Vogelmeier  1 , Timm Greulich  1
Affiliations

The Distribution of Alpha-1 Antitrypsin Genotypes Between Patients with COPD/Emphysema, Asthma and Bronchiectasis

Martina Veith et al. Int J Chron Obstruct Pulmon Dis. .

Abstract

Purpose: Alpha-1-antitrypsin deficiency (AATD) is a rare hereditary condition characterized by low circulating levels of alpha-1antitrypsin (AAT). While the association between AATD and COPD/emphysema is undisputed, the association between AATD and asthma or bronchiectasis is still a matter of debate.

Aims and objectives: Our study aimed to investigate the distribution of AAT genotypes between patients with COPD/emphysema, asthma and bronchiectasis. To back up the diagnostic labels, we described symptoms associated with the diagnosis.

Methods: Between September 2003 and March 2020, 29,465 testing kits (AlphaKit®) were analyzed in the AAT laboratory, University of Marburg, Germany. The diagnosis of AATD has been made based on the measurements of AAT serum levels, followed by genotyping, phenotyping or whole gene sequencing depending on the availability and/or the need for more detailed interpretation of the results. The respiratory symptoms were recorded as well.

Results: Regarding the distribution of the wild type allele M and the most frequent mutations S (E264V) and Z (E342K), no significant differences could be found between COPD/emphysema [Pi*MM (58.24%); Pi*SZ (2.49%); Pi*ZZ (9.12%)] and bronchiectasis [Pi*MM (59.30%) Pi*SZ (2.81%); Pi*ZZ (7.02%)]. When COPD/emphysema and bronchiectasis were recorded in the same patient, the rate of Pi* ZZ (14.78%) mutations was even higher. Asthma patients exhibited significantly less deficient genotypes [Pi*MM (54.81%); Pi*SZ (2%); Pi*ZZ (2.77%)] than two other groups. Associated respiratory symptoms confirmed the diagnosis.

Conclusion: COPD/emphysema and bronchiectasis, but not asthma patients, exhibit higher frequency of AATD genotypes. Our data suggest that AATD testing should be offered to patients with COPD/emphysema and bronchiectasis.

Keywords: SERPINA1; alpha-1-antitrypsin deficiency; asthma; bronchiectasis; diagnosis.

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Conflict of interest statement

Martina Veith reports grants from Grifols. Prof. Dr. Robert Bals reports grants from BMBF, during the conduct of the study; grants from Schwiete Stiftung, Novartis, and Mukoviszidose e.V. and personal fees from AstraZeneca and CSL Behring, outside the submitted work. Prof. Dr. Claus Franz Vogelmeier reports grants, personal fees from AstraZeneca, Boehringer Ingelheim, Grifols, GlaxoSmithKline, and Novartis; personal fees from CSL Behring, Chiesi, Menarini, Nuvaira, MedUpdate, outside the submitted work. Dr Timm Greulich reports grants from Grifols, during the conduct of the study; personal fees from AstraZeneca, serves as a lecturer and part of the advisory board for Berlin Chemie, Boehringer Ingelheim, Chiesi, CSL Behring, Grifols, GSK, Novartis, received grants from German Centre for Lung Research, outside the submitted work. The authors report no other conflicts of interest in this work.

Figures

Figure 1
Figure 1
Frequency of 18,736 patients among chronic respiratory disorders without consideration on AATD. A three-way Venn diagram was plotted to investigate the relationship between patients of COPD/Emphysema, asthma and bronchiectasis and their overlaps. COPD/Emphysema only: 12,283 (65.56%); asthma only: 4,041 (21.57%); bronchiectasis only: 285 (1.52%); COPD/Emphysema and asthma overlap: 1,592 (8.50%); COPD/Emphysema and bronchiectasis overlap: 345 (1.84%); asthma and bronchiectasis overlap: 92 (0.49%); COPD/Emphysema and asthma and bronchiectasis overlap: 98 (0.52%). BioVenn – a web application for the comparison and visualization of biological lists using area-proportional Venn diagrams. T. Hulsen, J. de Vlieg and W. Alkema, BMC Genomics 2008, 9 (1): 488.
Figure 2
Figure 2
Frequency of symptoms among the chronic respiratory diseases: COPD/emphysema, asthma and bronchiectasis. Figure 2 displays the frequency of clinical symptoms (dyspnea, dyspnea attacks, cough, phlegm, wheezing, acute bronchitis and chronic bronchitis) among the chronic respiratory diseases (COPD/emphysema, asthma and bronchiectasis). Chi-square test was used for statistical analyses. This information has been evaluated on the basis of the information on the AlphaKits®. Dyspnea appeared most frequently in patients with COPD/emphysema, whereas dyspnea attacks were more often in patients with asthma. Cough and phlegm could be observed most frequently in patients with bronchiectasis. Acute and chronic bronchitis occurred more often in patients with asthma or bronchiectasis than in patients with COPD/emphysema. ###p<0.001 significant between bronchiectasis and asthma; §§§p<0.001, §p<0.05 significant between bronchiectasis and COPD/emphysema; ***p<0.001, **p<0.01 significant between asthma and COPD/emphysema.
Figure 3
Figure 3
Distribution of the AAT alleles.
Figure 4
Figure 4
Distribution of AAT alleles among the chronic respiratory diseases: COPD/emphysema, asthma and bronchiectasis. Figure 4 displays the distribution of AAT alleles among the chronic respiratory diseases bronchiectasis, asthma and COPD/emphysema. The distribution of the wild type (Pi*MM) was roughly comparable between the three groups (significant only between asthma and COPD/emphysema). The same applied to the distribution of the genotypes Pi*MS, Pi*M/rare and Pi*Z/rare, while the genotypes Pi*SS, Pi*SZ and Pi*S/rare were not distributed significantly different. A higher percentage of asthma patients exhibited the Pi*MZ genotype, whereas more COPD/emphysema and bronchiectasis patients exhibited the Pi*ZZ genotype when compared to asthma patients. ###p<0.001, ##p<0.01 significant between bronchiectasis and asthma; ***p<0.001, *p<0.05 significant between asthma and COPD/emphysema.
Figure 5
Figure 5
Detection rate of patients with COPD/emphysema, bronchiectasis, asthma.
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