Bases genéticas de la enfermedad pulmonar obstructiva crónica

  1. David Blanquer Escribano
Supervised by:
  1. Daniel Bachiller Pérez Director
  2. Josep Antoni Tur Marí Tutor

Defence university: Universitat de les Illes Balears

Year of defence: 2016

  1. Jaume Ferrer Sancho Chair
  2. Antonio Oliver Palomo Secretary
  3. E. Fernández Fabrellas Committee member

Type: Thesis


COPD consists on a “persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases, usually secondary to tobacco smoke, pollution, coal or biomass fuels combustion exposure”. Its pathogenesis is not well known. Complete sequencing of human genome, genomic techniques of differential gene expression and the development of biobancs, biobanc networks and nanotechnology are steps forward towards a progressive increase in its comprehension. A genome-wide association pilot study (GWAS) of differential gene expression of COPD (and emphysema and combined tobacco and spirometry phenotypes) vs non-COPD patients using Agillent is reported, from lung tissue samples piled in 2005 and 2006 at our begginings of Son Dureta University Hospital Lung Tissue Biobank. General features of the COPD and non-COPD patients included in clinic-radiologic-funcional data-bases were assessed for the detection of biases and limitations for further interpretation of differential gene expression, and representativity of its consecutive patients compared to the bulk of usual patients’ COPD population visited ambulatorily at our daily pneumonological praxis at a comarcal hospital external consultation. It might worth to be highlighted the importance of some “groups of genes” according to their differential gene expression in the COPD group (p<0.05) which are involved in several molecular pathways common to different key cells which are being already targeted for research on new medications for COPD: receptors such as CXCR3 and CCR4, or G-protein coupled; intracellular signal transduction systems such as MAP kinases or PYK2; IFN-a, TNF-a and TGF-b. The role of some interleukines such as IL-2, IL-3 and IL-5 is discussed, as alternatives in COPD to usual IL-1b and IL-8 increase and growth factors modelling inbalances between repair-apoptosis-fibrosis and angiogenesis: EGF, VEGF, PDGF and TGF-b, eritropoietin (EPO), thrombopoietin (TPO), etc. Furthermore, some molecular pathways of cytoskeleton (TIGH and GAP junctions), extracellular matrix (INTEGRIN, M-CALPAIN, MPR) and surfactant, affected by proteases-antiproteases and oxydants-antioxydants inbalances, and other pathways involved in systemic manifestations of COPD. Our results suggest that most of COPD patients might have multiple polymorphisms which might be mildly affected, but could altogether imply signifficant functional alterations when grouped in especific molecular pathways. At secondary analyses comparing differential gene expression of the different COPD phenotypes: emphysema, chronic bronchitis, asthmatiform COPD and subgroups according to tobacco smoke consume, it is discussed why no signifficant differential results could be obtained. This might be attributed to small sample size, and supports further needs of lung tissue biobank networks which could supply bigger numbers of samples for further increasing sample size, and the importance of scrupulous phenotyping in much purer phenotypes, with definitions, markers and diagnostic tests the most objective, consensed and unified possible. A more foccussed preoperatory approach on especific study of these COPD phenotypes for the biobank might be recommended. Among limitations and biases of the study with consecutive patients from biobank lung tissue samples, sex, age and oncologic co-diagnoses might be taken in mind as could represent potencial interactions or confounding factors (non signifficant in our case) when interpreting differential gene expression, and should be taken in consideration for further studies on differential gene expression from lung tissue biobank networks. Our COPD patients with biobank resected lung tissue represent milder stages of mild-to-moderate COPD according to GOLD severity of obstruction, and are less advanced in age, compared to usual ambulatory patients visited at our external pneumonology consultations, which make them difficult to compare with other studies on COPD gene expression involving more severe COPD or emphysema or of an early onset. Restrictions to access to more samples made it not possible to increase sample size or confirm our results with replication studies, which should be further performed in the future.