Idiopathic Pulmonary Fibrosis Genetics in Idiopathic Pulmonary Fibrosis Effrosyni D Manali 2nd Pulmonary Medicine Department Attikon University Hospital National and Kapodistrian University of Athens Greece

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The most incontestable evidence of a genetic signature in pulmonary fibrosis comes from familial clustering of the disease

Familial pulmonary fibrosis is defined by Definitions Familial pulmonary fibrosis is defined by the presence of at least two cases of pulmonary fibrosis in the same family (2-20% IPF cases) Family trees evoke autosomal dominant transmission in 80% of the cases with the presence of cases in several successive generations (vertical transmission) Borie R, et al. Rev Mal Respir. 2014 pii: S0761-8425(14)01143-7

Sporadic and familial disease reflect a spectrum of genetic risk for pulmonary fibrosis MAF<0.1% Telomere maintenance Surfactant metabolism Mucociliary dysfunction MAF>5% Host defense Cell-cell adhesion DNA repair TOLLIP toll interacting protein, SPPL2C signal peptide peptidase like 2c, DSP desmoplakin Kropski JA, et al. Eur Respir J 2015; 45(6): 1717-1727, Mathai SK, et al. Thorax 2016; 71: 1154-1160 Spagnolo P, et al. Lancet Respir Med 2014; 2: 416-428

A breakthrough occurred in 2001… A woman with DIP from the age of 1 year gave birth to a full term baby girl that developed respiratory failure at six weeks of age The histopathology features of the child resembled more to NSIP N Engl J Med 2001; 344: 573

SFTPC and SFTPA2 are expressed exclusively by type II alveolar epithelial cells (AECs) in the lungs, related to lung immunity and host defense suggesting that AEC dysfunction is a feature of IPF ER stress Local dysregulation of immune responses Fibrotic remodeling ATP BINDING CASSETE SUBFAMILY A MEMBER 3 A Thomas, et al. AJRCCM 2002, C van Moorsel et al. AJRCC, 2010, Ono S, et al. ERJ 2011, Wang Y, et al. Am J Hum Gen 2009, Campo I, et al. Res Res 2014; 15:43, Cottin V, et al. Thorax 2011, Epaud R, et al. ERJ 2014, Kroner C et al. ERJ 2015, Nathan N et al. Hum Mol Gen 2016, Kroner C et al. Thorax 2017, Mulugeta S, et al. Am J Physiol Lung cell Mol Physiol 2015

2007… N Engl J Med 2007;356:1317-1326 PNAS 2007 ; 104 : 7552-7557

The telomerase complex maintains telomere integrity by adding sequences to the ends of chromosomes. Defects in telomere maintenance Short dysfunctional telomeres Impaired response to epithelial injury

Genetic variation related to telomerase biology and homeostasis Members of the telomerase complex, TERT telomerase reverse transcriptase, TERC telomerase RNA component, RTEL1 regulator of telomere elongation helicase 1, PARN poly (A) specific ribonuclease, DKC1 dyskerin pseudouridine synthase 1, TINF2 TERF1 interacting nuclear factor 2, NAF1 nuclear assembly factor 1 ribonucleoprotein, TERF1 Telomeric repeat-binding factor 1 Genetic variation related to telomerase biology and homeostasis (TERT, TERC, RTEL1, PARN, DKC1, TINF2, NAF1) is central to the development of FIP Cogan JD, et al. Am J Respir Crit Care Med 2015, Stuart B, et al. Nat Genet 2015, Alder J et al. Chest 2015, Kropsi J, et al Chest 2014, Kropski J et al. Am J Respir Crit Care Med 2017, Kannengiesser C, et al. ERJ 2015

2011… MUC5A and MUC5B are the major gel-forming proteins in human airway secretions. markedly increased MUC5B expression in the lung a 20-fold increased risk of IPF in subjects that were homozygous for the polymorphism and a 7-fold increased risk in heterozygous subjects N Engl J Med. 2011; 364(16): 1503–1512, Yang I, et al. Ann Am Thorac Soc 2015

Recurrent injury at the bronchoalveolar junction, ↑MUC5B, ↓ciliary function, retention of particles and enhanced injury Disrupted repair Impaired response to epithelial injury ER stress Local dysregulation of immune responses Gene-gene Gene -environmental interactions Peljto Al et al. JAMA. 2013, Peljto AL et al. Chest 2015, Roy MG, et al. Nature 2014

Familial forms tend to present at an earlier age and Familial and sporadic pulmonary fibrosis are clinically indistinguishable Familial forms tend to present at an earlier age and might show some differences in radiological patterns Fernandez BA, et al. Respiratory Research 2012, 13:64 Ravaglia C, et al. Sarcoid Vasc Dif Lung Dis 2014; 31(1): 28-36

Heritable interstitial lung disease related to surfactant proteins mutations large spectrum of phenotypic pulmonary manifestations ranging from severe respiratory insufficiency occurring early in life leading to death to lung fibrosis and cancer in adult patients 69/69yo 50yo 45/50yo 40yo 52/54yo 31yo 6 mo 33yo Hum Mol Genet 2016; 25: 1457-1467

Heritable interstitial lung disease related to telomerase complex mutations Among FPF patients, the proportion with mutation was 18.2%. The highest proportion with mutation was for those with FPF and extra-pulmonary signs (42%) Eur Respir J 2016; 48 (6): 1721-1731

Eur Respir J 2016; 48 (6): 1710-1720

2.75 years (1.65-4.61) 2.56 years (2.56-4.82)

Adapt immunosuppression for selected patients J Heart Lung Transplant. 2015 Apr;34(4):538-46

Heritable interstitial lung disease related to MUC5B mutation the presence of the variant allele of the single-nucleotide polymorphism (SNP) rs35705950, located 3 kb upstream of the MUC5B gene transcription start site, increases the risk of IPF but is associated with better survival JAMA. 2013 ; 309(21): 2232–2239

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No significant decrease in lung function during the study Treatment … No significant decrease in lung function during the study N Engl J Med 2016; 374:1922-1931

Need for an international Consensus Signed informed consent Genetic testing before Lung Tx ? Eur Respir Rev 2017; 26: 160122

Genetic and somatic evaluation for asymptomatic relatives The therapeutic impact of diagnosis of asymptomatic ILD in mutation carriers unknown The psychological impact of ILD diagnosis in relatives of patients with PF should not be minimized

Missing knowledge about… Heritability Borie R, et al. Eur Respir Rev 2017; 26: 160122

The Greek Cohort of pulmonary fibrosis patients undergoing genetic testing (n=116) Patients FPF FPF +personal extrapulmonary signs FPF+ personal + familial extrapulmonary signs FPF+ familial extrapulmonary signs Young age alone “sans famille” No (%) 78 (67.25) 11 (9.5) 3 (2.6) 8 (6.9) 16 (13.8) Age (years) Median IQR 66 (62-69) 79 (66-80) 70 (64-70) 67 (61.5-75.5) 52 (47-53.5) Mutation 3 (TERC, TERT, ABC3A) 1 TERT 5/71 tested=7.05% Mutated age (years) 51 (42.25-62) vs non mutated 69 (62-76) (p=0.009)

Similar or different defects in pathogenetic pathways ?

To conclude The ultimate challenge that lies ahead is To develop an integrated understanding of the role of genetic variants (rare and common) 2. To identify genetic signatures that predict disease behavior and response to treatment and permit a personalized and successful approach for each patient

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