Approches en génomique et bio-informatique afin de comprendre les bases moléculaires de la maladie pulmonaire obstructive chronique

Authors: Lamontagne, Maxime
Advisor: Bossé, Yohan
Abstract: Chronic obstructive pulmonary disease (COPD) is a complex disease characterized by airflow obstruction that is not fully reversible. Currently, no treatment existsto reverse COPD, which is predicted to be the third leading cause of mortality in the world by the year 2030. Important discoveries were made in the last decade, but the pathophysiology of the disease remains largely unknown. The aim of this thesis is to study the genetic component of COPD and more specifically 1) identify genes involved in the development of airflow obstruction, 2) identify lung eQTL in the major histocompatibility complex and find causal genes for lung function and respiratory diseases in this region, 3) find new susceptibility loci for COPD, and 4) evaluate the feasibility and effectiveness of DNA sequencing of the SERPINA1 gene as a single test to diagnose alpha-1 antitrypsin deficiency (AATD) and test the frequencies of AATD alleles in a Canadian COPD population. In the first study, we identified genes (CST3 and CD22) and signalling pathways (xenobiotic metabolism, apoptosis, protease–antiprotease and oxidant–antioxidant balance) involved in the development of airflow obstruction. We combined lung gene expression, whole genotyping data and clinical information’s from 1,111 subjects to identify potential causal genesand pathways. This study has identified underlying mechanisms implicated in the development of airflow obstruction. In the second study, westudied a critical genomic region for the immune system, the major histocompatibility complex (MHC). Previous studies have associated single nucleotide polymorphisms (SNPs) located inside this locus with lung diseases and phenotypes (asthma, cystic fibrosis, idiopathic interstitial pneumonia, lung cancer and lung function). We have identified new susceptibility genes for lung cancer (BTN3A2 and ZFP57), asthma (AGPAT1 and CDSN), lung function (MICB) and idiopathic interstitial pneumonia (AGPAT1). Results from this study provide important biological insights about previously associated SNPsin the MHC. We were also involved in the largest genome-wide association study (GWAS) on COPD. This GWAS was performed by the International COPD Genetics Consortium (ICGC) and identified 22 loci associated at genome-wide significance. Genotypes of 63,192 subjects (15,256 cases and 47,936 controls) from 26 studies were used in the meta-analysis. Results were further replicated in 9,498 cases and 9,748 controls from the UK Biobank. Among the 22 associated loci, 9 were previously associated with COPD, 15 with lung function and 4 (EEFSEC, DSP, MTCL1and SFTPD) werenovel loci. Our findings highlight new loci associated with COPD and demonstrate the genetic overlap between lung function and COPD. Finally, the frequencies of deficient SERPINA1 alleles were evaluated in Canadian patients with COPD and DNA sequencing was evaluated as a single test strategy to detect AATD. DNA sequencing of the coding regions of SERPINA1 was performed in 400 individuals from the CanCOLD study (Canadian Cohort of Obstructive Lung Disease). Nineteen genetic variants were identified, including 15 missense mutations and one new mutation. DNA sequencing of SERPINA1 revealed the true genetic nature of AATD and was demonstrated has an effective, fast, and inexpensive single test strategy to detect AATD. Studies presented in this thesis have identified genes and pathways involved in the development of COPD, which are new targetsfor future studies.
Document Type: Thèse de doctorat
Issue Date: 2017
Open Access Date: 11 July 2019
Permalink: http://hdl.handle.net/20.500.11794/35445
Grantor: Université Laval
Collection:Thèses et mémoires

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