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.
Highlights
Alpha-1 antitrypsin (AAT) deficiency is a hereditary disorder first reported in the early 1960s when emphysema was described in patients with low plasma levels of AAT protein [1]
Our study describes the prevalence of Alpha-1 antitrypsin deficiency (AATD) in a randomly selected sample of 1,100 individuals from the Irish population and in a targeted population, with regard to the two most common alleles associated with AATD, the Z and S mutations
Other more rare SERPINA1 mutations could be present in the Biobank cohort, for example, we identified 22 rare non-Z, non-S mutations in the Irish National Targeted Detection Programme (INTDP) cohort which would be missed by our genotyping method
Summary
Alpha-1 antitrypsin (AAT) deficiency is a hereditary disorder first reported in the early 1960s when emphysema was described in patients with low plasma levels of AAT protein [1]. AAT deficiency is characterised by misfolding of the AAT protein and belongs to a class of genetic diseases termed conformational disorders [8]. Mutations which confer an increased risk of developing pulmonary emphysema and/or liver disease are those in which deficiency alleles are combined in homozygous or heterozygous states, yielding AAT serum levels below a putative protective threshold of 11 μM. The class of SERPINA1 variants termed “null” mutations lead to a complete absence of AAT production and while extremely rare, confer a high risk of emphysema [10]. Alpha-1 antitrypsin deficiency (AATD) results from mutations in the SERPINA1 gene and classically presents with early-onset emphysema and liver disease. AATD is an underdiagnosed 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
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
