PMID- 31511551
OWN - NLM
STAT- MEDLINE
DCOM- 20201028
LR  - 20221207
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 9
IP  - 1
DP  - 2019 Sep 11
TI  - Exome Sequencing Reveals Immune Genes as Susceptibility Modifiers in Individuals 
      with alpha(1)-Antitrypsin Deficiency.
PG  - 13088
LID - 10.1038/s41598-019-49409-1 [doi]
LID - 13088
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.
FAU - Rigobello, Chiara
AU  - Rigobello C
AD  - Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University 
      of Padova, Padova, Italy.
FAU - Baraldo, Simonetta
AU  - Baraldo S
AUID- ORCID: 0000-0001-8923-7511
AD  - Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University 
      of Padova, Padova, Italy.
FAU - Tine, Mariaenrica
AU  - Tine M
AD  - Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University 
      of Padova, Padova, Italy.
FAU - Ferrarotti, Ilaria
AU  - Ferrarotti I
AD  - Center for Diagnosis of Inherited Alpha 1-antitrypsin Deficiency, Department of 
      Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy.
FAU - Corsico, Angelo Guido
AU  - Corsico AG
AD  - Center for Diagnosis of Inherited Alpha 1-antitrypsin Deficiency, Department of 
      Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy.
AD  - Division of Respiratory Diseases, IRCCS Policlinico San Matteo Foundation, Pavia, 
      Italy.
FAU - Bazzan, Erica
AU  - Bazzan E
AUID- ORCID: 0000-0003-2956-0880
AD  - Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University 
      of Padova, Padova, Italy.
FAU - Turato, Graziella
AU  - Turato G
AUID- ORCID: 0000-0003-1895-6388
AD  - Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University 
      of Padova, Padova, Italy.
FAU - Balestro, Elisabetta
AU  - Balestro E
AD  - Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University 
      of Padova, Padova, Italy.
FAU - Biondini, Davide
AU  - Biondini D
AD  - Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University 
      of Padova, Padova, Italy.
FAU - Valle, Giorgio
AU  - Valle G
AD  - CRIBI Biotechnology Center, University of Padova, Padova, Italy.
FAU - Saetta, Marina
AU  - Saetta M
AD  - Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University 
      of Padova, Padova, Italy. marina.saetta@unipd.it.
FAU - Cosio, Manuel G
AU  - Cosio MG
AD  - Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University 
      of Padova, Padova, Italy.
AD  - Meakins-Christie Laboratories, Respiratory Division, McGill University, Montreal, 
      Canada.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190911
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
SB  - IM
MH  - Adult
MH  - Aged
MH  - Female
MH  - Genetic Predisposition to Disease/*genetics
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Molecular Sequence Annotation
MH  - *Exome Sequencing
MH  - alpha 1-Antitrypsin Deficiency/*genetics/*immunology
PMC - PMC6739380
COIS- M.S. has received unrestricted research grants from Takeda Ltd, Chiesi 
      Farmaceutici, Laboratori Guidotti Spa, outside this specific study.
EDAT- 2019/09/13 06:00
MHDA- 2020/10/29 06:00
PMCR- 2019/09/11
CRDT- 2019/09/13 06:00
PHST- 2019/05/24 00:00 [received]
PHST- 2019/08/23 00:00 [accepted]
PHST- 2019/09/13 06:00 [entrez]
PHST- 2019/09/13 06:00 [pubmed]
PHST- 2020/10/29 06:00 [medline]
PHST- 2019/09/11 00:00 [pmc-release]
AID - 10.1038/s41598-019-49409-1 [pii]
AID - 49409 [pii]
AID - 10.1038/s41598-019-49409-1 [doi]
PST - epublish
SO  - Sci Rep. 2019 Sep 11;9(1):13088. doi: 10.1038/s41598-019-49409-1.