01_Faner_Condicionantes genéticos en el desarrollo de EPOC: "Young COPD"
1. 28/09/2023
www.brn.cat
BRN Trustees:
Investigando en EPOC: desde la
genética a la clínica
Chairs: Dra. Salud Santos (H. Bellvitge), Dr. Sergi Pascual (H. del Mar)
Speakers: Dra. Rosa Faner (H. Clínic), Dra. Sara Martí (H. Bellvitge), Dr. Dr. César Jessé Enríquez
(H. del Mar), Dra. Marina Galdeano (H. Germans Trias i Pujol), Dr. César Maquilón (Clínica Dávila,
Santiago de Chile)
With the sponsorship of:
2. PARTE I:
Condicionantes genéticos en el desarrollo de EPOC:
"Young COPD"
Mª Rosa Faner Canet, PhD
Universitat de Barcelona,
FCRB-IDIBAPS, CIBER.
rfaner@ub.edu
BRN Trustees:
Investigando en EPOC: desde la genética a la clínica
With the sponsorship of:
28/09/2023
www.brn.cat
4. Ian A Yang et al. Lancet Resp Med 2022
COPD smoking and beyond
• One-tenth of the population
• 3rd leading cause of mortality
• FEV1/FVC < 0.7
• Mean age @diagnostic 65 yrs.
• Clinical heterogeneity
• 20-40% of COPD patients worldwide are never
smokers.
5. The many faces of COPD….
Smoking, infections, genetics, environment
Mahmoud O et al. ERJ 2023
50% of COPD without evidence of accelerated decline
History of early childhood LRTIs/pneumonia
• 8/14 reduction FEV1 values,
• 6/12 reductions in FVC
Restrictive spirometry pattern.
Andrew J Collaro, et al. Lancet Child Adolesc Health 2023
Allinson JP et al. Lancet 2023
And … earlier all cause mortality
Agusti, Faner. Lancet Respir Med. 2019
Schiffers C, Respirology 2023
Beckman H, AJRCCM 2023
Agusti, Faner. Lancet Respir Med. 2017
COPD
Mortality
Multimorbidity
6. Wang G, Mélen E AJRCCM 2022
Agusti, Faner. Lancet Respir Med. 2017
Wang G et al. AJRCCM 2023
Schiffers C, Respirology 2023
Beckman H, AJRCCM 2023
The way(s) to low peak lung function….
7. • Chronic respiratory symptoms
• No airflow limitation
Pre-COPD
• <50 years old
• >10 packs/year
• FEV1/FVC<LLN or Lung
abnormality or Accelerated FEV1
decline
Early COPD
Young COPD
• <50 years old
• FEV1/FVC<0.7
Martinez et al. AJRCCM 2018 ,
Han M et al. AJRCCM 2021,
Martinez et al. AJRCCM 2022
• FEV1/FVC<0.7
COPD
Towards an earlier diagnosis?
8. Agusti, Faner. Lancet Respir Med. 2017
Wang G et al. AJRCCM 2023
Schiffers C, Respirology 2023
Beckman H, AJRCCM 2023
Olvera et al. AJRCCM. 2023
Odds ratio (95% C.I. and p-value) for FEV1 < LLN
Abnormal peak lung function…. Towards COPD?
9. Biological domain
Conception Time (age) Death
Low birthweight Pollution
Exercise
Maternal smoking
Vaccinations
Infections
Smoking
Allergens Socioeconomic status
Diet
Lifestyle
Alcohol
Breastfeeding Microbiome
Sunlight
Occupational exposure
Prematurity
Accidents
Exposome
Genome
Health and disease
Phenotypes and treatable traits
Health and disease
Phenotypes and treatable traits
Health and disease
Phenotypes and treatable traits
Endotypes and biomarkers
Epigenetics
Immune
response
Development and
repair
Endotypes and biomarkers
Epigenetics
Immune
response
Repair and ageing
Endotypes and biomarkers
Epigenetics
Immune
response
Repair and ageing
GETomics: COPD as Gene x Enviroment and Time disease
Clinical domain
Agusti, Faner, Lancet Respiratory Medicine 2022
11. • Chronic respiratory symptoms
• No airflow limitation
Pre-COPD
• <50 years old
• >10 packs/year
• FEV1/FVC<LLN or Lung
abnormality or Accelerated FEV1
decline
Early COPD
Young COPD
• <50 years old
• FEV1/FVC<0.7
Martinez et al. AJRCCM 2018 ,
Han M et al. AJRCCM 2021,
Martinez et al. AJRCCM 2022
• FEV1/FVC<0.7
COPD
Towards an earlier diagnosis?
12. 35-50 years
FEV1/FVC<0.7 >10 PY
Young COPD
FEV1/FVC %
FEV1 (% ref.)
DLCO (% ref.)
Cosio B, Faner R et al. ERJ Open
17. 82 GWAS loci for COPD
35 New
Sakornsakolpat P et al. 2019
SNPs associated to
lung development
Supporting a role of early life events in the risk of COPD
Genetics of old COPD
18. Eur Respir J 2022; 60: 2101954
Polygenic risk score and age of diagnosis of COPD
19. Nissen G. et al. NEJM evidence 2023
• COPD PRS
• lung function at 5 years
Pulakka A et al. Eur Respir J 2023
Pre-term birth and obstructive disease Cohort of Pre-term birth children
The genetics view
20. Epigenetics of Pre-COPD, Young COPD?
Age acceleration in cases vs. controls (40.2 vs. 38.7), p=0.03
Martino D. et al. AJRCCM 2023
Controls
Cases
THAS
22. Conclusions
• A life course perspective is need for COPD.
• Young and old COPD from the same “setting” share phenotypic characteristics.
• COPD biomarkers are present in young adults with abnormal peak lung function.
• Accelerated aging has a role in the severity of the disease, independent of the
patient’s age.
• The genetics of COPD are related to its early onset.
23. Thank you for your attention
FUNDING
Grup: Inflamació i reparació a les malalties respiratòries
24. Martinu T. et al, Annu. Rev. Med. 2023. 74:427–41
CC-16 (CCSP) and lung disease
• Secretory protein mainly expressed by airways club cells
• Role regulating pulmonary inflammation
Editor's Notes
To do so, this is the outline that I will follow, first introducing the concept of the different types of COPD, then confronting the evidences from abnormal growth vs accelerated aging in this three levels, and finally concluding.
The traditional paradigm postulated an accelerated lung function decline associated to tobaco smoke and an abnormal immune response.
And is associatet to Tobacco smoking, enviromental factors, has a genetic susceptibility and is asociated to an abnormal immune response. however COPD it is still mainly diagnosed at older ages,
The traditional paradigm postulated an accelerated lung function decline associated to tobaco smoke and an abnormal immune response.
And is associatet to Tobacco smoking, enviromental factors, has a genetic susceptibility and is asociated to an abnormal immune response. however COPD it is still mainly diagnosed at older ages,
So to move towards an early diagnosis some clinical terms have been defined
Specifically:
the term pre-COPD which refers to individuals of any age who have respiratory symptoms without airflow limitation
and the term EARLY COPD, which was defined by Martinez et al. in 2018, to refer to individuals younger than 50 years, with a smoking history of 10 or more pack-years, and evidence of fev1 declline or obstruction.
however since COPD can start in the utero we don't know if these patients are at an early phase, meaning the beggining of the disease.
Therefore
The term Young COPD was proposed
to identify patients with COPD (defined by the GOLD standards) that are younger than 50 years old
Additionally COPD patients can also be stratified by the severity of the airflow limitation into mild, moderate, severe or very severe, based on their FEV1 measure.
What it is not known is whether accelerated aging has similar effects in both young and old COPD patients, and also depending on the severity of airflow limitation.
The traditional paradigm postulated an accelerated lung function decline associated to tobaco smoke and an abnormal immune response.
And is associatet to Tobacco smoking, enviromental factors, has a genetic susceptibility and is asociated to an abnormal immune response. however COPD it is still mainly diagnosed at older ages,
To do so, this is the outline that I will follow, first introducing the concept of the different types of COPD, then confronting the evidences from abnormal growth vs accelerated aging in this three levels, and finally concluding.
So to move towards an early diagnosis some clinical terms have been defined
Specifically:
the term pre-COPD which refers to individuals of any age who have respiratory symptoms without airflow limitation
and the term EARLY COPD, which was defined by Martinez et al. in 2018, to refer to individuals younger than 50 years, with a smoking history of 10 or more pack-years, and evidence of fev1 declline or obstruction.
however since COPD can start in the utero we don't know if these patients are at an early phase, meaning the beggining of the disease.
Therefore
The term Young COPD was proposed
to identify patients with COPD (defined by the GOLD standards) that are younger than 50 years old
Additionally COPD patients can also be stratified by the severity of the airflow limitation into mild, moderate, severe or very severe, based on their FEV1 measure.
What it is not known is whether accelerated aging has similar effects in both young and old COPD patients, and also depending on the severity of airflow limitation.
Evidence of CT emphysema
63% cases
32% controls
Dimension Reduction,
One of the novel key aspects is including the age of interactions as a mechanism leading to different biology
Determinants of onset and progression of COPD in Young adults.
Destruction of terminal bronchioles before lung function decline or emphysema (Koo HK, Lancet Resp Med 2018)
. Exclusion criteria were: alpha-1 antitrypsin (A1AT) deficiency, conditions that can potentially limit follow-up (foreseen changes of residence, psychiatric diseases), chronic inflammatory or autoimmune diseases, severe bronchiectasis, active tuberculosis, active cancer or other severe pulmonary diseases 10. Exclusion criteria for controls also included a previous diagnosis of asthma .
Wnt receptor56,57 and MAPK–ERK
55DMRs
To do so, this is the outline that I will follow, first introducing the concept of the different types of COPD, then confronting the evidences from abnormal growth vs accelerated aging in this three levels, and finally concluding.