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

Abstract

<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.

Genetics in Idiopathic Pulmonary Fibrosis: A Clinical Perspective

“…Elaborate genealogical research studies have shown that a latency period of >300 years may pass before the cumulative effect of telomere shortening eventually leads to familial PF in TRG mutation carriers [ 141 , 155 ]. In addition to personal/familial extra-pulmonary abnormalities suggestive of STS involving the skin, the liver, and the bone marrow, the disease is uniformly progressive, irrespective of its phenotypic heterogeneity, and bears a reduced transplant-free survival time [ 18 , 19 , 32 , 156 , 157 ]. The increased risk for complications and high mortality post-lung-transplantation is due mostly to sepsis, greater than expected bone-marrow suppression and increased rates of chronic allograft dysfunction and airway complications (dehiscence and stenosis) [ 156 , 157 , 158 , 159 , 160 ].…”

“…Therefore, telomeropathy is now recognized in addition to age, frailty, pulmonary hypertension, cardiovascular risk, and lung cancer as a parameter for which careful consideration must be given to pre-operative optimization, surgical technique, pulmonary rehabilitation, and a tailored immunosuppressive treatment protocol to produce the best post-transplantation outcomes [ 127 , 143 , 162 , 163 , 164 , 165 , 166 ]. Bone-marrow failure presenting as myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) may arise at any timepoint in the disease’s course in almost 10% of patients, especially those younger than 65 years old [ 18 , 19 , 32 , 141 , 167 , 168 , 169 , 170 ]. Naturally occurring somatic mutations in telomere maintenance genes observed in some patients with familial-PF potentially might rescue premature age-related clonal hematopoiesis and transformation to MDS/AML [ 139 , 171 ].…”

“…Genome-wide-association studies continue to identify new candidate chromosomal loci to be associated with increased susceptibility to IPF [ 29 , 30 , 31 ]. The discovery in IPF that multiple genetic components, including the rarest variants, may be encountered in the same patient broadens our understanding of clinical heterogeneity [ 32 , 33 , 34 ], suggesting co-responsibility in the pathogenetic mechanisms of the disease instead of a mere cohabitation and necessitating a unifying pathogenetic theory regarding genetic risk. Differences in genomics in IPF patients may drive differences in the disease course (phenotypic unpredictability) through the diversity of pathogenetic mechanisms and in the near future may lead to a personalized approach towards precision in the cure of a currently incurable disease [ 32 , 35 , 36 ].…”

Prognostic Value of Serum Biomarkers in Patients with Idiopathic Pulmonary Fibrosis in Relation to Disease Progression

“…Recent research has suggested that the S100 calcium-binding protein A12 (S100A12) could potentially serve as a prognostic serum biomarker in IPF [ 10 ]. Furthermore, according to studies, genomic approaches may include the identification of microRNAs and the polymorphism in the promoter region of MUC5B, as well as some other rare mutations [ 11 , 12 ]. Regarding novel approaches, recently, the serum proteomic profile has the potential to offer valuable insights into the heterogeneity of IPF and to uncover protein alterations that can aid in its diagnosis and treatment decisions [ 13 ].…”

Genomic Fingerprint Associated with Familial Idiopathic Pulmonary Fibrosis: A Review

“…Previous research has examined genetic associations, common single nucleotide polymorphisms (SNP) and rare gene mutations are associated with their development 25 . Rare mutations in genes telomerase reverse transcriptase ( TERT ) 27 , telomerase RNA component ( TERC ) 28 , dyskeratosis congenita 1 ( DKC1 ) 29 , telomere repeat binding factor 1-interacting nuclear factor 2 ( TINF2 ) 30 , regulator of telomere length 1 ( RTEL1 ), zinc finger CCHC-type containing 8 ( ZCCHC8 ), poly(A)-specific ribonuclease ( PARN ) 31 , surfactant protein C ( SFTPC ) 32 , surfactant protein A2 ( SFTPA2 ) 33 , the ATP-binding cassette-type family A member 3 transporter ( ABCA3 ) 34 ), and common variants of 10 loci (3q26, 4q22, 5p15, 6p24, 7q22, 10q24, 11p15, 13q34, 15q14-15, and 19p13) 25 are associated with f-IPF.…”