Genotype-Phenotype Relationships in Inheritable Idiopathic Pulmonary Fibrosis: A Greek National Cohort Study
Effrosyni D Manali
(1)
,
Caroline Kannengiesser
(2, 3)
,
Raphael Borie
(3, 4)
,
Ibrahima Ba
(2, 3)
,
Demosthenes Bouros
(1, 5)
,
Aikaterini Markopoulou
(6)
,
Katerina Antoniou
(7)
,
Lykourgos Kolilekas
(8)
,
Andriana I Papaioannou
(1)
,
Vasileios Tzilas
(1, 5)
,
Argyrios Tzouvelekis
(9)
,
Zoe Daniil
(10)
,
Evangelia Fouka
(11, 6)
,
Despoina Papakosta
(11, 6)
,
Areti Xyfteri
(12)
,
Anna Karakatsani
(1)
,
Stylianos Loukides
(1)
,
Ioanna Korbila
(1)
,
Ioannis P Tomos
(1)
,
Athanasios K Konstantinidis
(13)
,
Athina Gogali
(13)
,
Paschalis Steiropoulos
(14)
,
Ilias C Papanikolaou
(15)
,
Chrysa Bazaka
(16)
,
Aggeliki Haritou
(17)
,
Theodoros Vassilakopoulos
(1)
,
Maria Maniati
(1)
,
Konstantinos Kagouridis
(1)
,
Evangelos Markozannes
(1)
,
Evangelos Bouros
(1)
,
Christina Rampiadou
(6)
,
Georgia Kounti
(6)
,
Athina Trachalaki
(7)
,
Ilias Dimeas
(10)
,
Theodoros Karampitsakos
(9)
,
Panagiotis Lyberopoulos
(1)
,
Nikolaos Malamadakis
(1)
,
Sofia Spyropoulou
(18)
,
Patrick Revy
(19)
,
Elodie Lainey
(3)
,
Philippe Dieudé
(3)
,
Khedidja Rebah
(2, 20)
,
Christelle Ménard
(2, 20)
,
Claire Oudin
(2, 20)
,
Cécile Masson
(21)
,
Aurélie Plessier
(22)
,
Marie Legendre
(23, 24)
,
Nadia Nathan
(23, 24, 24)
,
Aurore Coulomb-L’hermine
(24)
,
Annick Clement
(23, 24)
,
Serge Amselem
(23, 24)
,
Catherine Boileau
(2, 20)
,
Bruno Crestani
(3, 4)
,
Spyros Papiris
(1)
1
NKUA -
National and Kapodistrian University of Athens
2 AP-HP - Hôpital Bichat - Claude Bernard [Paris]
3 PHERE (UMR_S_1152 / U1152) - Physiopathologie et Epidémiologie des Maladies Respiratoires
4 Centre de Référence des Maladies Pulmonaires Rares [AP-HP Hôpital Bichat]
5 Iatriko Medical Center [Athens]
6 General Hospital of Thessaloniki George Papanikolaou
7 UOC - University of Crete [Heraklion]
8 Sotiria Thoracic Diseases Hospital of Athens
9 University of Patras
10 University of Thessaly [Larissa]
11 Aristotle University of Thessaloniki
12 Private Clinic, Messini
13 University of Ioannina
14 DUTH - Democritus University of Thrace
15 Corfu General Hospital [Corfu]
16 Private Clinic, Agrinio
17 Private Clinic, Ioannina
18 Private Clinic, Chalkis
19 Equipe Inserm U1163 - Genome dynamics in the immune system
20 UPCité - Université Paris Cité
21 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)
22 Hôpital Beaujon [AP-HP]
23 U933 - Maladies génétiques d'expression pédiatrique
24 CHU Trousseau [APHP]
2 AP-HP - Hôpital Bichat - Claude Bernard [Paris]
3 PHERE (UMR_S_1152 / U1152) - Physiopathologie et Epidémiologie des Maladies Respiratoires
4 Centre de Référence des Maladies Pulmonaires Rares [AP-HP Hôpital Bichat]
5 Iatriko Medical Center [Athens]
6 General Hospital of Thessaloniki George Papanikolaou
7 UOC - University of Crete [Heraklion]
8 Sotiria Thoracic Diseases Hospital of Athens
9 University of Patras
10 University of Thessaly [Larissa]
11 Aristotle University of Thessaloniki
12 Private Clinic, Messini
13 University of Ioannina
14 DUTH - Democritus University of Thrace
15 Corfu General Hospital [Corfu]
16 Private Clinic, Agrinio
17 Private Clinic, Ioannina
18 Private Clinic, Chalkis
19 Equipe Inserm U1163 - Genome dynamics in the immune system
20 UPCité - Université Paris Cité
21 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)
22 Hôpital Beaujon [AP-HP]
23 U933 - Maladies génétiques d'expression pédiatrique
24 CHU Trousseau [APHP]
Raphael Borie
- Fonction : Auteur
- PersonId : 770718
- ORCID : 0000-0002-9906-0024
- IdRef : 081295626
Aikaterini Markopoulou
- Fonction : Auteur
- PersonId : 1170900
- ORCID : 0000-0002-0836-594X
Andriana I Papaioannou
- Fonction : Auteur
- PersonId : 1170901
- ORCID : 0000-0001-9708-3241
Stylianos Loukides
- Fonction : Auteur
- PersonId : 1170902
- ORCID : 0000-0002-4278-9922
Paschalis Steiropoulos
- Fonction : Auteur
- PersonId : 1170903
- ORCID : 0000-0001-7121-6253
Ilias C Papanikolaou
- Fonction : Auteur
- PersonId : 1170904
- ORCID : 0000-0003-1391-2925
Claire Oudin
- Fonction : Auteur
Marie Legendre
- Fonction : Auteur
- PersonId : 1147534
- IdHAL : marie-legendre
- ORCID : 0000-0003-2178-0846
Nadia Nathan
- Fonction : Auteur
- PersonId : 1029287
- IdHAL : nadianathan
- ORCID : 0000-0001-5149-7975
Serge Amselem
- Fonction : Auteur
- PersonId : 936326
- IdHAL : serge-amselem
- ORCID : 0000-0001-9506-3968
- IdRef : 066957761
Résumé
Background: Monogenic and polygenic inheritances are evidenced for idiopathic pulmonary fibrosis (IPF). Pathogenic variations in surfactant protein-related genes, telomere-related genes (TRGs), and a single-nucleotide polymorphism in the promoter of MUC5B gene encoding mucin 5B (rs35705950 T risk allele) are reported. This French-Greek collaborative study, Gen-Phen-Re-GreekS in inheritable IPF (iIPF), aimed to investigate genetic components and patients' characteristics in the Greek national IPF cohort with suspected heritability.
Patients and methods: 150 patients with familial PF, personal-family extrapulmonary disease suggesting short telomere syndrome, and/or young age IPF were analyzed.
Results: MUC5B rs35705950 T risk allele was detected in 103 patients (90 heterozygous, 13 homozygous, allelic frequency of 39%), monoallelic TRG pathogenic variations in 19 patients (8 TERT, 5 TERC, 2 RTEL1, 2 PARN, 1 NOP10, and 1 NHP2), and biallelic ABCA3 pathogenic variations in 3. Overlapping MUC5B rs35705950 T risk allele and TRG pathogenic variations were shown in 11 patients (5 TERT, 3 TERC, 1 PARN, 1 NOP10, and 1 NHP2), MUC5B rs35705950 T risk allele, and biallelic ABCA3 pathogenic variations in 2. In 38 patients, neither MUC5B rs35705950 T risk allele nor TRG pathogenic variations were detectable. Kaplan-Meier curves showed differences in time-to-death (p = 0.025) where patients with MUC5B rs35705950 T risk allele alone or in combination with TRG pathogenic variations presented better prognosis.
Conclusion: The Gen-Phen-Re-GreekS in iIPF identified multiple and overlapping genetic components including the rarest, underlying disease's genetic "richesse," complexity and heterogeneity. Time-to-death differences may relate to diverse IPF pathogenetic mechanisms implicating "personalized" medical care driven by genotypes in the near future
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