Transcript Diapositiva 1

Genetics of IPF/fibrosing ILDs
Paolo Spagnolo
Clinica di Malattie dell’Apparato Respiratorio
Università degli Studi di Padova
Evidence for a genetic basis
 Pulmonary fibrosis associated with pleiotropic genetic disorders
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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
What do we expect from genetics?
 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
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
8-month old girl
At the age of 18 months
At the age of 5 years
Spagnolo P, Bush A. Pediatrics 2016 [in press]
Courtesy Maurizio Zompatori
Telomere structure
Calado TR et al. N Engl J Med 2009; 361: 2353-65
Consequences of telomere erosion
Calado TR et al. N Engl J Med 2009; 361: 2353-65
The telomerase complex and its components
Calado TR et al. N Engl J Med 2009; 361: 2353-65
N Engl J Med 2007; 356: 1317-26
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*
TERT
8-15%
TERC
<1%
RTEL1
5%
DKC1
<1%
TINF2
<1%
SFTPC
2-25%
SFTPA2
<1%
ABCA3
<1%
*FIP: familial pulmonary fibrosis
MUC5B polymorphism and pulmonary fibrosis
SNP
rs35705950
Nucleotide
change
G→T
Minor Allele frequency
FIP
(n=83)
Sporadic IPF
(n=492)
Controls
(n=322)
33.8%
37.5%
9.1%
Seibold MA et al. N Engl J Med 2011; 364: 1503-12
OR for
FIP
6.2
P value
OR for
sporadic
IPF
P value
3.7 x 10-12
8.3
4.6 x 10-31
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
Hunninghake GM et al. N Engl J Med 2013; 368: 2192-200
Progression of subclinical ILD
Sverzellati N et al. Eur Respir J 2011; 38: 392-400
% 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]
MUC5B is (also) a genetic determinant of survival in IPF
Peljto AL et al. JAMA 2013; 309: 2232-2239
MUC5B and development of pulmonary fibrosis
Spagnolo P et al. Lancet Respir Med 2014; 2: 416-28
Survival analysis by TOLLIP rs5743890 genotype
Noth I et al. Lancet Respir Med 2013; 1: 309-17
TLR3 L412F polymorphism and IPF disease progression
O’Dwyer DN et al. Am J Respir Crit Care Med 2013; 188: 1442-1450
PANTHER study (part B): results
NAC alone showed no difference in FVC decline or any secondary
endpoints compared to placebo
0
FVC (liters)
−0.05
−0.10
Acetylcysteine
−0.15
Placebo
−0.20
Baseline
15
30
Week
Martinez FJ et al. N Engl J Med 2014; 370: 2093-2101
45
60
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
The genetic basis of IPF
Mathai SK et al. BMC Medicine 2015; 13: 191
Gene-environment interaction model in pulmonary fibrosis
Kropski JA et al. Eur Respir J 2015; 45: 1717-27
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