Genomic approaches to understand the pathogenesis of the acute respiratory distress syndrome

  1. Beatriz Guillén Guío
Supervised by:
  1. Carlos Alberto Flores Infante Director

Defence university: Universidad de La Laguna

Year of defence: 2020

Committee:
  1. Ángel Carracedo Álvarez Chair
  2. Agustin Valenzuela Fernandez Secretary
  3. Tilman Eike Klassert Committee member

Type: Thesis

Teseo: 614135 DIALNET

Abstract

The acute respiratory distress syndrome (ARDS) is an acute lung inflammatory process that commonly develops as a consequence of severe infections, being sepsis its main cause of development. Despite the fatality of the syndrome, there is a lack of specific therapeutic options and effective prognostic methods for patients. Since many studies support the influence of genetic factors and microbiome shifts in the origin and evolution of ARDS, here we have aimed to address its pathophysiology using different genomic approaches. We have performed a genome-wide association study in European patients with sepsis, revealing a novel gene associated with ARDS susceptibility. Additionally, we have sequenced the bacterial DNA extracted from lung aspirates from a subset of the individuals with sepsis, reporting the association of the reduction of bacterial diversity with intensive care unit mortality during the first 8 h of sepsis diagnosis. Finally, the exploration of the genomic variation of a recently admixed population has pointed out genomic regions related to the ethnicity and harboring novel genes associated with response to infections and with the severe acute respiratory syndrome, among many other traits. All these findings have allowed us to further understand the pathogenesis of the syndrome and of main risk factors, as well as i) to propose VEGFR-1 as a potential therapeutic target, ii) to suggest the bacterial diversity as an early prognostic biomarker in critical patients, and iii) to lay the foundations for designing fine and admixture mapping studies in Canary Islanders to identify novel risk genes for complex traits such as sepsis and ARDS.