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