The prevalence of alpha-1 antitrypsin deficiency in Ireland

Abstract

BackgroundAlpha-1 antitrypsin deficiency (AATD) results from mutations in the SERPINA1 gene and classically presents with early-onset emphysema and liver disease. The most common mutation presenting with clinical evidence is the Z mutation, while the S mutation is associated with a milder plasma deficiency. AATD is an under-diagnosed condition and the World Health Organisation recommends targeted detection programmes for AATD in patients with chronic obstructive pulmonary disease (COPD), non-responsive asthma, cryptogenic liver disease and first degree relatives of known AATD patients.MethodsWe present data from the first 3,000 individuals screened following ATS/ERS guidelines as part of the Irish National Targeted Detection Programme (INTDP). We also investigated a DNA collection of 1,100 individuals randomly sampled from the general population. Serum and DNA was collected from both groups and mutations in the SERPINA1 gene detected by phenotyping or genotyping.ResultsThe Irish National Targeted Detection Programme identified 42 ZZ, 44 SZ, 14 SS, 430 MZ, 263 MS, 20 IX and 2 rare mutations. Analysis of 1,100 randomly selected individuals identified 113 MS, 46 MZ, 2 SS and 2 SZ genotypes.ConclusionOur findings demonstrate that AATD in Ireland is more prevalent than previously estimated with Z and S allele frequencies among the highest in the world. Furthermore, our targeted detection programme enriched the population of those carrying the Z but not the S allele, suggesting the Z allele is more important in the pathogenesis of those conditions targeted by the detection programme.

Alpha-1 Antitrypsin Deficiency – A Genetic Risk Factor for COPD

“…We subsequently carried out a larger analysis of 1,100 individuals randomly selected from the national electoral register and genotyped this group for Z and S mutations. In contrast to the 1983 data, we found allele frequencies for Z and S to be 0.022 and 0.054, respectively (Carroll et al 2011). The reason for this disparity is most probably due to the small sample size of the original cohort.…”

“…Another US study investigated 969 patients with diagnosed with emphysema, asthma, or chronic bronchitis and found 1 ZZ case in every 31 samples, which is a case detection rate of over 3% (Brantly M 2003). Moreover, the contribution of SERPINA1 heterozygosity to COPD, while controversial, may account for over 10% of COPD cases if one includes ZZ, SZ and MZ phenotypes (Carroll et al 2011). The classic pulmonary presentation of lung disease in AATD is severe, early onset panacinar emphysema with a basilar predominance in adults (Gishen et al 1982).…”

Diagnosing α1-antitrypsin deficiency: how to improve the current algorithm

“…Moreover, the available data may not be as accurate as we would like. For example, LUISETTI and SEERSHOLM [6] presented allele frequencies for PI*S and PI*Z of 0.02-0.04 and 0.005-0.015, respectively, in Ireland, whereas much higher rates were recorded in a study of 1100 randomly sampled individuals from the Trinity College Biobank (Dublin, Ireland) with frequencies for PI*S and PI*Z of 0.054 and 0.022, respectively [7]. Excluding newborn screening studies, this is one of the few truly representative investigations of AAT allele frequencies in a general population as the subjects were randomly selected from the electoral register.…”

“…To address a lack of data relating to AATD in Ireland a study was undertaken to analyse 1100 individuals from the general population (from the Trinity College Biobank collection) and a targeted group as described by the ATS/ERS guidelines [7]. It was intended to compare whether targeted investigation increased the level of diagnosis across all AATD allele groups.…”

The Impact of Smoke Exposure on the Clinical Phenotype of Alpha-1 Antitrypsin Deficiency in Ireland: Exploiting a National Registry to Understand a Rare Disease

“…The WHO, ATS and ERS advocate targeted testing for AATD in all individuals with COPD, non--responsive asthma, cryptogenic liver disease and first degree relatives of individuals with AATD (4). This approach has led to higher rates of detection in the populations most at risk of lung disease, though widespread under recognition of the condition remains (5,6).…”