1. Genetics of IPF/fibrosing ILDs Paolo Spagnolo Clinica di Malattie dell’Apparato Respiratorio Università degli Studi di Padova

2. Evidence for a genetic basis Pulmonary fibrosis associated with pleiotropic genetic disorders  Hermansky-Pudlak syndrome  Neurofibromatosis (7-20%)  Tuberous sclerosis (0.1-1.0%)  Neimann-Pick disease (unknown)  Gaucher’s disease (frequent in the infantile form, rare in the adult form)  Hypocalciuric hypercalcemia  Dyskeratosis congenita Variable individual susceptibility to fibrogenic dusts (asbestos) Inbred strains of mice differ in their susceptibility to fibrogenic agents Familial IPF (but this is quite different from sporadic disease) Spagnolo P et al, Orphanet J Rare Dis 2012; 7: 79

7. Inherited risk of developing the disease Improve our knowledge and understanding of disease pathobiology Make and early diagnosis/prevent disease Predict disease behaviour/course Predict response to treatment Develop better drugs What do we expect from genetics?

8. Surfactant protein C (SP-C) gene mutations Full term infant diagnosed with NSIP at 6/52 Mother diagnosed with DIP at 1 year Heterozygous G/A substitution at genomic base 1728 in child and mother Low/absent SP-C in both individuals’ lungs Nogee LM et al, N Engl J Med 2001; 344: 573-9

9. 8-month old girlAt the age of 18 months At the age of 5 years Courtesy Maurizio Zompatori Spagnolo P, Bush A. Pediatrics 2016 [in press]

10. Telomere structure Calado TR et al. N Engl J Med 2009; 361: 2353-65

11. Consequences of telomere erosion Calado TR et al. N Engl J Med 2009; 361: 2353-65

12. The telomerase complex and its components

13. N Engl J Med 2007; 356: 1317-26

14. Genes mutated in familial pulmonary fibrosis Modified from Stanley SE et al. Am J Respir Crit Care Med 2015; 191: 608-10 Gene% of FIP * TERT8-15% TERC<1% RTEL15% DKC1<1% TINF2<1% SFTPC2-25% SFTPA2<1% ABCA3<1% *FIP: familial pulmonary fibrosis

15. MUC5B polymorphism and pulmonary fibrosis SNP Nucleotide change Minor Allele frequency OR for FIP P value OR for sporadic IPF P value FIP (n=83) Sporadic IPF (n=492) Controls (n=322) rs35705950G → T33.8%37.5%9.1%6.23.7 x 10 -12 8.34.6 x 10 -31 Seibold MA et al. N Engl J Med 2011; 364: 1503-12

16. Hunninghake GM et al. N Engl J Med 2013; 368: 2192-200 A variant within MUC5B is associated with both familial and idiopathic pulmonary fibrosis Blinded assessment of interstitial lung abnormalities (ILA) in 2633 participants in the Framingham Heart Study 177 (7%) of the 2633 CT scans showed SILA * *SILA: subclinical interstitial lung abnormalities

18. Progression of subclinical ILD Sverzellati N et al. Eur Respir J 2011; 38: 392-400

19. % of UIP diagnoses on chest CT relative to MUC5B Chung JH et al. Chest 2016 Jan 13. pii: S0012-3692(15)00170-1. DOI:10.1016/J.CHEST.2015.11.009. [Epub ahead of print]

20. MUC5B is (also) a genetic determinant of survival in IPF Peljto AL et al. JAMA 2013; 309: 2232-2239

21. MUC5B and development of pulmonary fibrosis Spagnolo P et al. Lancet Respir Med 2014; 2: 416-28

22. Survival analysis by TOLLIP rs5743890 genotype Noth I et al. Lancet Respir Med 2013; 1: 309-17

23. O’Dwyer DN et al. Am J Respir Crit Care Med 2013; 188: 1442-1450 TLR3 L412F polymorphism and IPF disease progression

24. NAC alone showed no difference in FVC decline or any secondary endpoints compared to placebo Baseline −0.20 FVC (liters) 0 −0.10 Week 3060 Acetylcysteine Placebo 1545 −0.05 −0.15 PANTHER study (part B): results Martinez FJ et al. N Engl J Med 2014; 370: 2093-2101

25. NAC effectiveness by TOLLIP genotype Composite endpoint of FVC decline, hospitalization, death or transplant Oldham JM et al. Am J Respir Crit Care Med 2015; 192: 1475-1482

26. The genetic basis of IPF Mathai SK et al. BMC Medicine 2015; 13: 191

27. Gene-environment interaction model in pulmonary fibrosis Kropski JA et al. Eur Respir J 2015; 45: 1717-27

28. Conclusions Genetic risk plays a central role in IPF Both common and rare variants are associated with increased disease risk Genotypes significantly affects disease outcomes Potential for early diagnosis and personalized/genotype-based treatments