Alpha1-Antitrypsin Pi-Types in 965 COPD Patients

doi:10.1378/chest.89.3.370

Chest

Volume 89, Issue 3, March 1986, Pages 370-373

https://doi.org/10.1378/chest.89.3.370 Get rights and content

To study further the role of intermediate alpha₁-antitrypsin (AAT) deficiency in chronic obstructive pulmonary disease (COPD), AAT Pi-types and serum-trypsin-inhibitory-capacity (STIC) were measured in 965 patients with COPD. Heterozygosity of the Z variant was the major cause of intermediate AAT deficiency (primarily the MZ phenotype), accounting for 8.0 percent of the patients compared to 2.9 percent of control subjects (p<.0005). ZZ homozygosity was detected in 1.9 percent of the patients, compared to 0.04 percent of control studies performed by others (none was present in our own control group of 1,380 subjects). The mean age for MS or MZ patients did not differ from that of the COPD patients as a whole, whereas the ZZ homozygotes were younger (55.9±9.8 vs 65.3±7.5 years). These results resemble those of a previous study in 66 male veterans with pulmonary emphysema suggesting that the MZ phenotype, or intermediate AAT deficiency in general, probably does predispose to the development of COPD. However, the prevalence of AAT deficiency in COPD patients is small (approximately 10 percent). The number with an MS phenotype was not increased in this group of COPD patients.

Section snippets

Battent Selection

Blood samples were obtained from consecutive patients hospitalized for carotid body surgery by BW; serum was separated and delivered to our laboratory at the Sepulveda VA Medical Center. All patients were Caucasian, ranging in age from 41 to 85 years, with a mean± SD of 65.3±7.5 yrs; 28 percent of the patients were women. All had far-advanced COPD with severe dyspnea as their main complaint. Information such as age of onset of lung disease was not available.

STIC Assay

STIC was assayed essentially as

Prevalence of Abnormal Phenotypes

Two separate formats were used for evaluating the Pi-type of these sera. Initially, for the first 223 specimens, phenotyping was performed only when the STIC value was less than 1.2 units. Subsequently, for the next 742 specimens, phenotyping was performed on all sera, irrespective of the STIC value. Table 1 shows that approximately half of the MS Pi-types were missed initially by not typing all sera; 4.9 percent MS types appeared with STIC values less than 1.2 units, whereas 10.1 percent

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Cited by (208)

A Highly Phenotyped Open Access Repository of Alpha-1 Antitrypsin Deficiency Pluripotent Stem Cells
2020, Stem Cell Reports
Individuals with the genetic disorder alpha-1 antitrypsin deficiency (AATD) are at risk of developing lung and liver disease. Patient induced pluripotent stem cells (iPSCs) have been found to model features of AATD pathogenesis but only a handful of AATD patient iPSC lines have been published. To capture the significant phenotypic diversity of the patient population, we describe here the establishment and characterization of a curated repository of AATD iPSCs with associated disease-relevant clinical data. To highlight the utility of the repository, we selected a subset of iPSC lines for functional characterization. Selected lines were differentiated to generate both hepatic and lung cell lineages and analyzed by RNA sequencing. In addition, two iPSC lines were targeted using CRISPR/Cas9 editing to accomplish scarless repair. Repository iPSCs are available to investigators for studies of disease pathogenesis and therapeutic discovery.
Alpha-1-antitrypsin molecular testing in Canada: A seven year, multi-centre comparison
2020, Clinical Biochemistry
Citation Excerpt :
The outlier is the QC-G protocol in which the homozygous Z variant genotype frequency was 2.6% of iAG. This relatively lower rate is equivalent to that found in an unselected chronic obstructive pulmonary disease population [13,14] as one would expect in a protocol which is not restricted by serum A1AT concentration. A similar inter-laboratory pattern was also observed for the compound heterozygote SZ genotype: the genotype frequency in three of the labs (5.2–8.0%) was higher than the lower rate (2.7%) in the QC-G protocol (Table 1).
Laboratory confirmation of alpha-1-antitrypsin (A1AT) deficiency may be achieved by multiple methods. Here, we compare the relative comprehensiveness and efficiency of pathogenic variant (PV) detection of four different protocols utilized at different diagnostic centres in Canada.
Diagnostic results from 2011 to 2018 at clinical laboratories in British Columbia (BC), Alberta (AB), Ontario (ON), and Québec (QC) were reviewed. The four labs utilize the following protocols: BC-CGID (serum A1AT Concentration/Genotyping/Isoelectric focussing (IEF)/SERPINA1 DNA sequencing), AB-CID (serum A1AT Concentration/IEF/DNA sequencing), ON-CD (serum A1AT Concentration/DNA sequencing), and QC-G (Genotyping). As the respective catchment areas varied in size and ethnic composition, the comprehensiveness of PV detection was assessed by comparing the frequency of individual genotypes to the ZZ genotype, which is clearly identified by all protocols.
Collectively 5399 index patients were tested identifying 396 ZZ genotypes. Serum A1AT concentration as a determinant of further testing efficiently identified PV. ON-CD had the highest detection rate for PV; genotypes with at least one PV, other than S, Z or F, were identified at 0.67/ZZ as compared to <0.2/ZZ (all others). However, ON-CD had the highest rates of undefined molecular variants (UMV) (0.16/ZZ) or likely benign variants (LBV) (0.08/ZZ), compared to all others (<0.12/ZZ and < 0.06/ZZ, respectively). The F variant was identified at 0.10/ZZ, only in the ON-CD and the AB-CID protocols. Collectively, M_Malton was the next most common variant, identified as a compound heterozygous genotype at 0.04/ZZ, only in the ON-CD and BC-CGID protocols.
Strategies which readily detect variants across the full coding sequence of SERPINA1 detect more PV as well as more UMV and LBV.
Pitfalls and caveats in α1-antitrypsin deficiency testing: a guide for clinicians
2019, The Lancet Respiratory Medicine
Citation Excerpt :
This could prompt some clinicians to believe that the rate of detection of clinically significant genotypes would be low. However, the evidence suggests that severe AATD is overrepresented in certain populations, observed in as many as 2% of patients with COPD.13 The clinical motivation to test for AATD should not simply be the detection of severe deficiency of AAT.
α1-antitrypsin deficiency (AATD) remains the only readily identified genetic cause of chronic obstructive pulmonary disease (COPD). Furthermore, there is growing evidence that even a moderate deficiency increases the risk of lung disease among smokers. Despite these facts, the uptake of testing for AATD in at-risk populations remains low for many reasons, and a lack of clarity among clinicians regarding the most appropriate diagnostic techniques presents a major deterrent. This Personal View addresses the benefits of diagnosis, the technical basis of the available diagnostic methods, and possible clinical confounders for each test. We include a series of unusual cases encountered at our National Centre of Expertise to provide context. The topics covered should equip clinicians with the core knowledge required to confidently assess patients for AATD.
Whole-genome methylation profiling from PBMCs in acute-exacerbation COPD patients with good and poor responses to corticosteroid treatment
2019, Genomics
Identifying heterogeneity in chronic obstructive pulmonary disease (COPD) phenotypes is important for the development of personalized medicine. Genome-wide analysis was used to compare the methylation levels of peripheral blood mononuclear cell (PBMC) samples from 24 acute-exacerbation (AE) COPD patients with good/poor response to corticosteroid therapy and 12 non-COPD controls. Pyrosequencing was employed to validate the genome-wide analysis. In the dataset specific to COPD patients with a good response, enrichment was identified for the following: genes in the Ubl conjugation pathway, nicotinamide nucleotide metabolism, the alkaloid metabolic process, and regulation of the glucose metabolic process. Validation results confirmed CpG sites in PRKAG2 with different methylation levels in COPD patients and normal subjects. The CpG sites of ALOX5AP were specifically associated with a good response. The results suggested that a good response to corticosteroid treatment for AE-COPD should be considered a distinct subtype according to the putative epigenetic mechanism.
The new epidemiology of COPD
2024, ERS Monograph
Alpha-1 Antitrypsin Gene Variants in Patients without Severe Deficiency Diagnosed with Pulmonary Emphysema on Chest CT
2024, International Journal of COPD

View all citing articles on Scopus

Supported by the Medical Research Service of the Veterans Administration.

Manuscript received July 15; revision accepted September 12.

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Chest

Clinical InvestigationsAlpha1-Antitrypsin Pi-Types in 965 COPD Patients

Section snippets

Battent Selection

STIC Assay

Prevalence of Abnormal Phenotypes

Alpha1-antitrypsin deficiency and related disorders

Heterozygous and homozygous alpha1-antitrypsin deficiency in patients with pulmonary emphysema

N Engl J Med

Obstructive lung disease and alpha1-antitrypsin deficiency gene heterozygosity

Science

Identification and characteristics of the common alpha1-antitrypsin phenotypes

Chest

Collaborative study to assess risk of lung disease in Pi MZ phenotype subjects

Am Rev Respir Dis

This week's citation classic

Current Contents

Racial distribution of alpha1-antitrypsin variants among junior high school students

Am Rev Respir Dis

Alpha1-antitrypsin deficiency in clinic patients

Ann Clin Res

Emphysema panlobulaire: relations avec le taux d'alpha1-antitrypsin serique le phenotype Pi et le systeme H.L.A

Nouv Presse Med

Variations du taux d'alpha1-antitrypsine chez les sujets atteints de bronchopneumopathies aigues. Roles du phenotype Pi et de la function hepatique

Nouv Presse Med

Pi phenotypes and the prevalence of chest symptoms and lung function abnormalities in workers employed in dusty industries

Am Rev Respir Dis

Clinical Investigations
Alpha₁-Antitrypsin Pi-Types in 965 COPD Patients

Alpha₁-antitrypsin deficiency and related disorders

Heterozygous and homozygous alpha₁-antitrypsin deficiency in patients with pulmonary emphysema

Obstructive lung disease and alpha₁-antitrypsin deficiency gene heterozygosity

Identification and characteristics of the common alpha₁-antitrypsin phenotypes

Racial distribution of alpha₁-antitrypsin variants among junior high school students

Alpha₁-antitrypsin deficiency in clinic patients

Emphysema panlobulaire: relations avec le taux d'alpha₁-antitrypsin serique le phenotype Pi et le systeme H.L.A

Variations du taux d'alpha₁-antitrypsine chez les sujets atteints de bronchopneumopathies aigues. Roles du phenotype Pi et de la function hepatique