Genotype-Phenotype Relationships in Inheritable Idiopathic Pulmonary Fibrosis: A Greek National Cohort Study
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Raphael Borie
- Function : Author
- PersonId : 770718
- ORCID : 0000-0002-9906-0024
- IdRef : 081295626
Aikaterini Markopoulou
- Function : Author
- PersonId : 1170900
- ORCID : 0000-0002-0836-594X
Andriana I Papaioannou
- Function : Author
- PersonId : 1170901
- ORCID : 0000-0001-9708-3241
Stylianos Loukides
- Function : Author
- PersonId : 1170902
- ORCID : 0000-0002-4278-9922
Paschalis Steiropoulos
- Function : Author
- PersonId : 1170903
- ORCID : 0000-0001-7121-6253
Ilias C Papanikolaou
- Function : Author
- PersonId : 1170904
- ORCID : 0000-0003-1391-2925
Claire Oudin
- Function : Author
Marie Legendre
- Function : Author
- PersonId : 1147534
- IdHAL : marie-legendre
- ORCID : 0000-0003-2178-0846
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