1. 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

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. 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 pii: S (14)

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
TOLLIP toll interacting protein, SPPL2C signal peptide peptidase like 2c, DSP desmoplakin
Kropski JA, et al. Eur Respir J 2015; 45(6): , Mathai SK, et al. Thorax 2016; 71:
Spagnolo P, et al. Lancet Respir Med 2014; 2:

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
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

9. 2007…
N Engl J Med 2007;356:
PNAS 2007 ; 104 :

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
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

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 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

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
31yo
6 mo
33yo
Hum Mol Genet 2016; 25:

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):

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

23. 2.75 years ( )
2.56 years ( )

24. Adapt immunosuppression for selected patients
J Heart Lung Transplant 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) rs , located 3 kb upstream of the MUC5B gene transcription start site,
increases the risk of IPF but is associated with better survival
JAMA ; 309(21): 2232–2239

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

27. 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:

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

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:

32. 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 ( )
52 ( )
Mutation
3 (TERC, TERT, ABC3A)
1 TERT
5/71 tested=7.05%
Mutated age (years) 51 ( )
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
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