Frequency of alleles and genotypes associated with alpha-1 antitrypsin deficiency in clinical and general populations: Revelations about underdiagnosis

Pérez, José María Hernández; Ramos-Díaz, Ruth; Vaquerizo-Pollino, C; Pérez, Jose Antonio Pérez

doi:10.1016/j.pulmoe.2022.01.017

Cited by 19 publications

(21 citation statements)

References 36 publications

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“…The proportion of patients with both an AATD diagnosis and a Pi*ZZ genotype from the Mayo Clinic cohort (0.07%) is broadly in accordance with previous epidemiological studies that have reported rates below 1%, suggesting that our study cohort is likely to be representative of the general population 5,39,40 . Many patients with a liver disease diagnosis made before AATD diagnosis experienced a considerable delay in reaching a diagnosis of AATD (median [IQR] delay: 1.5 [0.1–6.6] years).…”

Section: Discussionsupporting

confidence: 85%

Liver disease progression in patients with alpha‐1 antitrypsin deficiency and protease inhibitor ZZ genotype with or without lung disease

Wu,

Hagiwara,

Gnass

et al. 2023

Aliment Pharmacol Ther

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SummaryBackgroundAlpha‐1 antitrypsin deficiency (AATD) is caused by mutations in SERPINA1, which encodes alpha‐1 antitrypsin, a protease inhibitor (Pi). Individuals with AATD and the homozygous Pi*ZZ genotype have variable risk of progressive liver disease but the influence of comorbid lung disease is poorly understood.AimsTo characterise patients with AATD Pi*ZZ and liver disease (AATD‐LD‐Pi*ZZ) with or without lung disease and describe liver disease‐related clinical events longitudinally.MethodsThis was an observational cohort study of patients in the Mayo Clinic Healthcare System (January 2000–September 2021). Patients were identified using diagnosis codes and natural language processing. Fibrosis stage (F0–F4) was assessed using a hierarchical approach at baseline (90 days before or after the index date) and follow‐up. Clinical events associated with liver disease progression were assessed.ResultsAATD‐LD‐Pi*ZZ patients with lung disease had a longer median time from AATD diagnosis to liver disease diagnosis versus those without lung disease (2.2 vs. 0.2 years, respectively). Compared to those without lung disease, patients with lung disease had a longer time to liver disease‐related clinical events (8.5 years and not reached, respectively). AATD‐LD‐Pi*ZZ patients without lung disease were more likely to undergo liver transplantation compared with those with lung disease.ConclusionIn patients with AATD and lung disease, there is a delay in the diagnosis of comorbid liver disease. Our findings suggest that liver disease may progress more rapidly in patients without comorbid lung disease.

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Section: Discussionsupporting

confidence: 85%

Liver disease progression in patients with alpha‐1 antitrypsin deficiency and protease inhibitor ZZ genotype with or without lung disease

Wu,

Hagiwara,

Gnass

et al. 2023

Aliment Pharmacol Ther

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“…In this study, patients with Pi*ZZ genotypes and those with rare variants have not been added because rare variants were published in another article in more detail. 19 We also found that the patients with the highest percentage of an obstructive pattern were those with the lowest AAT levels, rendering this association equally statistically significant ( P < .005). Moreover, we detected another genotype, Pi*SS , which has been linked to an increase in prevalence of COPD ( P < .004) ( Figure 2 ).…”

Section: Discussionsupporting

confidence: 50%

Pulmonary Function and Respiratory Diseases in Different Genotypes of Alpha-1 Antitrypsin Deficiency

Pérez¹,

Sánchez²,

Charry³

et al. 2022

Turk Thorac J

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OBJECTIVE: Respiratory disease is the major cause of morbidity and mortality in patients with alpha-1 antitrypsin deficiency, mainly in homozygous PI*ZZ individuals. However, this association is uncertain in subjects with other deficiency genotypes. The objective of this study was to assess, in the context of alpha-1 antitrypsin deficiency, the existence of further risk factors that have been associated with respiratory diseases. MATERIAL AND METHODS: Lung function was assessed by spirometry in a sample of 1334 patients with a known genotype for the SERPINA1 gene whose serum alpha-1 antitrypsin levels had been previously determined. Patients with a normal genotype ( PI*MM ) were compared to 389 patients carrying a deficiency allele. Results: Statistically significant associations were detected between (i) PI*ZZ genotype and abnormal FEV 1 values (χ 2 = 26.45; P < .0002), FEV 1 /FVC (χ 2 = 14.8; P < .02) or forced mid-expiratory flow 25%-75% (χ 2 =22.66; P < .0009); (ii) chronic obstructive pulmonary disease and PI*ZZ odds ratio: 26.5; 95% CI: (2.6-265.9); P < .005 and or PI*SS genotype odds ratio: 9; 95% CI: (2-40.1); P < .004; (iii) prevalence of COPD in PI*MZ subjects and smoking habit ( P < .01), low body weight ( P < .01) or older age ( P < .0001). Conclusion: The PI*ZZ and PI*SS genotypes seem to be associated with the prevalence of chronic obstructive pulmonary disease. Tobacco use, low body weight, and older age are risk factors that increase the probability of prevalence of chronic obstructive pulmonary disease by up to 70% in PI*MZ individuals.

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“…It is known that serum concentrations of A1AT can be influenced by genetics. A small percentage of individuals, ranging from 1/1500 to 1/10,000 depending on ethnicity, exhibit severe A1AT deficiency due to homozygosity or compound heterozygosity for deficiency (most commonly, Z and S alleles, and other rare allelic variants) or Null alleles. , However, it has been generally assumed (so far) that the common subtypes of the M alleles (M1-4) have little influence on A1AT serum concentrations.…”

Section: Introductionmentioning

confidence: 99%

Normal Alpha-1-Antitrypsin Variants Display in Serum Allele-Specific Protein Levels

2023

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Alpha-1-antitrypsin (A1AT or SERPINA1) has been proposed as a putative biomarker distinguishing healthy from diseased donors throughout several proteomics studies. However, the SERPINA1 gene displays high variability of frequent occurring genotypes among the general population. These different genotypes may affect A1AT expression and serum protein concentrations, and this is often not known, ignored, and/or not reported in serum proteomics studies. Here, we address allelespecific protein serum levels of A1AT in donors carrying the normal M variants of A1AT by measuring the proteoform profiles of purified A1AT from 81 serum samples, originating from 52 donors. When focusing on heterozygous donors, our data clearly reveal a statistically relevant difference in allele-specific protein serum levels of A1AT. In donors with genotype PI*M1VM1A, the experimentally observed ratio was approximately 1:1 (M1V/M1A, 1.00:0.96 ± 0.07, n = 17). For individuals with genotype PI*M1VM2, this ratio was 1:1.28 (M1V/M2, 1.00:1.31, ±0.19, n = 7). For genotypes PI*M1VM3 and PI*M1AM3, a significant higher amount of M3 was observed compared to the M1-subtypes (M1V/M3, 1.00:1.84 ± 0.35, n = 8; M1A/M3, 1.00:1.61 ± 0.33, n = 5). We argue that these observations are important and should be considered when analyzing serum A1AT levels before proposing A1AT as a putative serum biomarker.

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Frequency of alleles and genotypes associated with alpha-1 antitrypsin deficiency in clinical and general populations: Revelations about underdiagnosis

Cited by 19 publications

References 36 publications

Liver disease progression in patients with alpha‐1 antitrypsin deficiency and protease inhibitor ZZ genotype with or without lung disease

Liver disease progression in patients with alpha‐1 antitrypsin deficiency and protease inhibitor ZZ genotype with or without lung disease

Pulmonary Function and Respiratory Diseases in Different Genotypes of Alpha-1 Antitrypsin Deficiency

Normal Alpha-1-Antitrypsin Variants Display in Serum Allele-Specific Protein Levels

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