Abstract
Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder associated to early onset emphysema, mainly imputable to Pi*ZZ genotype. In spite of the serious potential effects, many AATD individuals do not develop emphysema. To identify genes/variants potentially involved in emphysema development we studied 4 AATD families. Each family had at least one affected sibling with emphysema and one non-affected. Whole Exome Sequencing (WES) was performed on genomic DNA isolated from 9 individuals with AATD (4 affected/5 non-affected). Genetic variants confirmed at least in three families were prioritized using QueryOR and network analysis was used to verify enriched pathways. In affected subjects: 14 genes (57% immune-related) segregated in a recessive model and 21 (29% immune-related) in a dominant model. In non-affected subjects: 21 genes (43% immune-related) segregated in a recessive model and 50 (24% immune-related) in a dominant model. In affected siblings immune genes had an activating function, while where immune-suppressing in non-affected siblings involving antigen processing, MHC-I presentation, TCR and PD-1 signalling. This study describes possible genetic susceptibility factors for emphysema development in AATD, and suggests that gene variants involved in regulation of immune homeostasis and maintenance of self-tolerance contribute to the development or suppression of the disease.
Highlights
The wild type form of SERPINA1, corresponding to the “M” allele (PI*M), produces normal levels of serum protein
Even when cigarette smoking is considered, there is a substantial variability on the severity of pulmonary disease: lung function can be well preserved in some PI*ZZ smokers, but severely impaired in some non-smokers[14]
In this study we used Whole Exome Sequencing (WES) technology[17] to identify variants that might potentially account for the variability in penetrance and expressivity of the disease induced by the Alpha-1 antitrypsin deficiency (AATD) genetic disorder
Summary
The wild type form of SERPINA1, corresponding to the “M” allele (PI*M), produces normal levels of serum protein. Most of the severe α1-antitrypsin deficiency (AATD) cases are associated with PI*ZZ genotype, a result of a missense mutation (p.E366K-c.1096G > A rs28929474) causing an aminoacidic substitution from a negatively charged Glutamate (GAG) to a positively charged Lysine (AAG) This mutation induces a conformational change favouring abnormal protein folding and polymerization, resulting in AAT retention within the endoplasmic reticulum of the liver and, very low serum AAT levels. Even when cigarette smoking (an important risk factor for the development of emphysema in PI*ZZ individuals) is considered, there is a substantial variability on the severity of pulmonary disease: lung function can be well preserved in some PI*ZZ smokers, but severely impaired in some non-smokers[14] Such evidences strongly suggest that the phenotypic expression of the disease could be influenced by an incomplete penetrance and/or variable expressivity of the PI* Z allele. Some of the results of this study have been reported in the form of an abstract[19]
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