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

<b><i>Background:</i></b> 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 <i>MUC5B</i> 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. <b><i>Patients and Methods:</i></b> 150 patients with familial PF, personal-family extrapulmonary disease suggesting short telomere syndrome, and/or young age IPF were analyzed. <b><i>Results:</i></b> <i>MUC5B</i> 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 <i>TERT</i>, 5 <i>TERC</i>, 2 <i>RTEL1</i>, 2 <i>PARN</i>, 1 <i>NOP10</i>, and 1 <i>NHP2</i>), and biallelic <i>ABCA3</i> pathogenic variations in 3. Overlapping <i>MUC5B rs35705950</i> T risk allele and TRG pathogenic variations were shown in 11 patients (5 <i>TERT</i>, 3 <i>TERC</i>, 1 <i>PARN</i>, 1 <i>NOP10</i>, and 1 <i>NHP2</i>), <i>MUC5B</i> rs35705950 T risk allele, and biallelic <i>ABCA3</i> pathogenic variations in 2. In 38 patients, neither <i>MUC5B</i> rs35705950 T risk allele nor TRG pathogenic variations were detectable. Kaplan-Meier curves showed differences in time-to-death (<i>p</i> = 0.025) where patients with <i>MUC5B</i> rs35705950 T risk allele alone or in combination with TRG pathogenic variations presented better prognosis. <b><i>Conclusion:</i></b> 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.