Effrosyni D Manali 2 nd Pulmonary Medicine Department Attikon University Hospital

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

2. The wedding of King Cadmus and Armonia

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

5. 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

6. 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 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

7. 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

8. 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 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

9. 2007… N Engl J Med 2007;356:1317-1326 PNAS 2007 ; 104 : 7552-7557

10. 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

11. 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

12. 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

13. 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

14. 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

16. 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 6 mo 31yo 33yo Hum Mol Genet 2016; 25: 1457-1467

17. 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

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

23. 2.75 years (1.65-4.61) 2.56 years (2.56-4.82)

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

25. 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 bettersurvival JAMA. 2013 ; 309(21): 2232–2239

26. Challenges… Cadmus fighting the dragon Le Louvre 340-350 BC

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

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

29. 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

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

32. The Greek Cohort of pulmonary fibrosis patients undergoing genetic testing (n=116) • 5/71 tested=7.05% • Mutated age (years) 51 (42.25-62) • vs non mutated 69 (62-76) (p=0.009)

33. Similar or different defects in pathogenetic pathways ?

34. 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

35. Thank you very much çok teşekkür ederim