TY - JOUR
T1 - Exome Sequencing Reveals Immune Genes as Susceptibility Modifiers in Individuals with α1-Antitrypsin Deficiency
AU - Rigobello, Chiara
AU - Baraldo, Simonetta
AU - Tinè, Mariaenrica
AU - Ferrarotti, Ilaria
AU - Corsico, Angelo Guido
AU - Bazzan, Erica
AU - Turato, Graziella
AU - Balestro, Elisabetta
AU - Biondini, Davide
AU - Valle, Giorgio
AU - Saetta, Marina
AU - Cosio, Manuel G.
PY - 2019/9/11
Y1 - 2019/9/11
N2 - 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.
AB - 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.
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U2 - 10.1038/s41598-019-49409-1
DO - 10.1038/s41598-019-49409-1
M3 - Article
C2 - 31511551
AN - SCOPUS:85072101221
VL - 9
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
ER -