Clarifying the Risk of Lung Disease in SZ Alpha-1 Antitrypsin Deficiency
Alpha-1 antitrypsin deficiency (AATD) is characterised by deficiency of AAT, the primary inhibitor of serine proteases, resulting in an increased risk of COPD. The wild-type allele which encodes for normal AAT is the Pi*M variant, most commonly inherited in homozygosity (genotype MM). The most prevalent deficiency-causing AAT mutations are the Pi*S and Pi*Z alleles which can be inherited in co-dominance with Pi*M or other deficient alleles. The severe form ZZ-AATD, is associated with COPD regardless of smoking and is characterised by very low AAT levels in serum. Moreover, inheritance of a single deficient Pi*Z allele for AAT (MZ-AATD) has also been shown to increase the risk of COPD in smokers but not non-smokers.
The SZ genotype is considered a high-risk genotype despite a lack of conclusive evidence. The aim of this study was to clarify the effect of the SZ genotype on lung health.
Clinical data from MZ, SZ and ZZ participants in the National AATD Registry was compared, demonstrating that SZ-AATD is more akin to the moderately deficient MZ-AATD than severe ZZ-AATD.
Subsequently, a family study was performed, comparing lung function and symptoms between SZ individuals and controls. SZ-AATD demonstrated significantly worse lung function among ever-smokers but not never smokers. Furthermore, within the SZ cohort AAT levels were not found to predict outcomes. The effect of smoking cessation in SZ-AATD was quantified by comparing never- and former-smokers, demonstrating no significant difference in lung function decline or anti-protease capacity.
Finally, AAT deficient individuals on the National AATD Registry were surveyed to determine the factors affecting their smoking habits. Parental smoking was found to significantly increase the risk of being an ever-smoker and that severity of AATD affects disease-insight and the likelihood of being a former-smoker, suggesting that AATD individuals are at risk of inheriting both a genetic substrate for lung disease and an environmental catalyst (smoking) from their parents.
Collectively these results indicate that SZ-AATD is not an independent driver of COPD and that AAT levels should not be used as an indication for treatment, strongly suggesting AAT augmentation is not indicated in this genotype. Summarily, these findings represent a paradigm shift in the field of AATD.
First SupervisorProf. Noel G. McElvaney
Second SupervisorDr. Tomás Carroll
CommentsSubmitted for the Award of Doctor of Philosophy to the Royal College of Surgeons in Ireland, 2020
Published CitationFranciosi A,. Clarifying the Risk of Lung Disease in SZ Alpha-1 Antitrypsin Deficiency. [PhD Thesis] Dublin: Royal College of Surgeons in Ireland; 2020
Degree NameDoctor of Philosophy (PhD)
Date of award31/05/2020
- Doctor of Philosophy (PhD)