Genotype-Phenotype Relationships in Inheritable Idiopathic Pulmonary Fibrosis: A Greek National Cohort Study

Effrosyni D Manali; Caroline Kannengiesser; Raphael Borie; Ibrahima Ba; Demosthenes Bouros; Aikaterini Markopoulou; Katerina Antoniou; Lykourgos Kolilekas; Andriana I Papaioannou; Vasileios Tzilas; Argyrios Tzouvelekis; Zoe Daniil; Evangelia Fouka; Despoina Papakosta; Areti Xyfteri; Anna Karakatsani; Stylianos Loukides; Ioanna Korbila; Ioannis P Tomos; Athanasios K Konstantinidis; Athina Gogali; Paschalis Steiropoulos; Ilias C Papanikolaou; Chrysa Bazaka; Aggeliki Haritou; Theodoros Vassilakopoulos; Maria Maniati; Konstantinos Kagouridis; Evangelos Markozannes; Evangelos Bouros; Christina Rampiadou; Georgia Kounti; Athina Trachalaki; Ilias Dimeas; Theodoros Karampitsakos; Panagiotis Lyberopoulos; Nikolaos Malamadakis; Sofia Spyropoulou; Patrick Revy; Elodie Lainey; Philippe Dieudé; Khedidja Rebah; Christelle Ménard; Claire Oudin; Cécile Masson; Aurélie Plessier; Marie Legendre; Nadia Nathan; Aurore Coulomb-L'Hermine; Annick Clement; Serge Amselem; Catherine Boileau; Bruno Crestani; Spyros Papiris; Greek Group of ILD Investigators

doi:10.1159/000520657

Genotype-Phenotype Relationships in Inheritable Idiopathic Pulmonary Fibrosis: A Greek National Cohort Study

Respiration. 2022;101(6):531-543. doi: 10.1159/000520657. Epub 2022 Jan 25.

Authors

Effrosyni D Manali¹, Caroline Kannengiesser^{2

3

4}, Raphael Borie^{4

5}, Ibrahima Ba^{2

3

4}, Demosthenes Bouros^{6

7}, Aikaterini Markopoulou⁸, Katerina Antoniou⁹, Lykourgos Kolilekas¹⁰, Andriana I Papaioannou¹, Vasileios Tzilas^{6

7}, Argyrios Tzouvelekis¹¹, Zoe Daniil¹², Evangelia Fouka¹³, Despoina Papakosta¹³, Areti Xyfteri¹⁴, Anna Karakatsani¹, Stylianos Loukides¹, Ioanna Korbila¹, Ioannis P Tomos¹, Athanasios K Konstantinidis¹⁵, Athina Gogali¹⁵, Paschalis Steiropoulos¹⁶, Ilias C Papanikolaou¹⁷, Chrysa Bazaka¹⁸, Aggeliki Haritou¹⁹, Theodoros Vassilakopoulos²⁰, Maria Maniati¹, Konstantinos Kagouridis¹, Evangelos Markozannes⁶, Evangelos Bouros⁶, Christina Rampiadou⁸, Georgia Kounti⁸, Athina Trachalaki⁹, Ilias Dimeas¹², Theodoros Karampitsakos¹¹, Panagiotis Lyberopoulos¹, Nikolaos Malamadakis¹, Sofia Spyropoulou²¹, Patrick Revy²², Elodie Lainey²³, Philippe Dieudé²⁴, Khedidja Rebah^{2

3}, Christelle Ménard^{2

3}, Claire Oudin^{2

3}, Cécile Masson²⁵, Aurélie Plessier²⁶, Marie Legendre²⁷, Nadia Nathan²⁸, Aurore Coulomb-L'Hermine²⁹, Annick Clement²⁸, Serge Amselem²⁷, Catherine Boileau^{2

3}, Bruno Crestani^{4

5}, Spyros Papiris¹; Greek Group of ILD Investigators

Affiliations

¹ 2nd Pulmonary Medicine Department, General University Hospital "Attikon," Medical School, National and Kapodistrian University of Athens, Athens, Greece.
² Département de Génétique, APHP Hôpital Bichat, Paris, France.
³ Université de Paris, Paris, France.
⁴ INSERM UMR 1152, Université de Paris, Paris, France.
⁵ APHP, Service de Pneumologie A, Centre de Référence des Maladies Pulmonaires Rares, FHU APOLLO, Hôpital Bichat, Paris, France.
⁶ First Academic Department of Pneumonology, Hospital for Diseases of the Chest "Sotiria," Medical School, National and Kapodistrian University of Athens, Athens, Greece.
⁷ Iatriko Medical Center, Athens, Greece.
⁸ Pulmonary Department, "G Papanikolaou" General Hospital, Thessaloniki, Greece.
⁹ Laboratory of Molecular & Cellular Pneumonology, Department of Respiratory Medicine, School of Medicine, University of Crete, Heraklion, Greece.
¹⁰ 7th Pulmonary Department, Athens Chest Hospital "Sotiria,", Athens, Greece.
¹¹ Department of Respiratory Medicine, General Hospital of Patras, University of Patras, Patras, Greece.
¹² Department of Respiratory Medicine, Medical School, University of Thessaly, Larissa, Greece.
¹³ A Department of Pulmonary Medicine, Aristotle University of Thessaloniki, "G. Papanikolaou" Hospital, Thessaloniki, Greece.
¹⁴ Private Clinic, Messini, Greece.
¹⁵ Department of Pneumonology, Medical School, University of Ioannina, Ioannina, Greece.
¹⁶ Department of Respiratory Medicine, University General Hospital Alexandroupolis, Medical School, Democritus University of Thrace, Thrace, Greece.
¹⁷ Pulmonary Department, Corfu General Hospital, Corfu, Greece.
¹⁸ Private Clinic, Agrinio, Greece.
¹⁹ Private Clinic, Ioannina, Greece.
²⁰ 3rd Department of Critical Care Medicine, Evgenideio Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
²¹ Private Clinic, Chalkis, Greece.
²² Laboratory of Genome Dynamics in the Immune System, Imagine Institute, INSERM UMR 1163, Labellisé Ligue Contre Le Cancer, Université de Paris, Paris, France.
²³ Service d'Hématologie Biologique, Hôpital Robert Debré, APHP, UMRS 1131, Institut Universitaire d'Hématologie, Paris, France.
²⁴ Department of Rheumatology, Hôpital Bichat-Claude Bernard, APHP, INSERM U1152, Université de Paris, Paris, France.
²⁵ Imagine Institute, Bioinformatics Platform, INSERM UMR 1163, Université de Paris, Paris, France.
²⁶ APHP, Service d'Hépatologie, Hôpital Beaujon, Clichy, France.
²⁷ Sorbonne Université, INSERM UMR S933 Maladies Génétiques d'Expression Pédiatrique, and Assistance Publique Hôpitaux de Paris, U.F. de Génétique Moléculaire, Hôpital Armand Trousseau, Paris, France.
²⁸ Sorbonne Université, INSERM UMR S933, France, Assistance Publique Hôpitaux de Paris, Service de Pneumologie Pédiatrique, Hôpital Armand Trousseau, Centre National de Référence des Maladies Respiratoires Rares RespiRare, Paris, France.
²⁹ Service d'Anatomie et de Cytologie Pathologiques, Sorbonne Université, Hôpital d'Enfants Armand Trousseau, Paris, France.

PMID: 35078193
DOI: 10.1159/000520657

Abstract

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.

Keywords: Inheritable pulmonary fibrosis; MUC5B rs35705950 T risk allele; Pathogenic variations; Prognosis; Surfactant protein-related genes; Telomere-related genes.

MeSH terms

Cohort Studies
Genetic Predisposition to Disease
Genotype
Greece
Humans
Idiopathic Pulmonary Fibrosis* / genetics
Phenotype