Associação de biomarcadores genéticos no hospedeiros com o prognóstico e a susceptibilidade da Covid-19

Abstract

Coronavirus disease 2019 (COVID-19) is caused by a virus in the family Coronaviridae, known as the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The clinical manifestation is quite heterogeneous, and those infected can range from asymptomatic to severe respiratory symptoms and may even die. In this work, we explore genetic biomarkers that may be associated with variability in clinical outcomes of COVID-19, as well as susceptibility to SARS-CoV-2 infection. In the first chapter, we performed a systematic review involving genetic association studies and the prognosis and susceptibility of COVID-19 published during the year 2020. 20 studies were included, 14 on susceptibility and 11 on prognosis, with 5 addressing both outcomes. In Chapter 2, we performed a systematic review followed by a meta-analysis to explore the contribution of IFITM3, TNF-alpha, ACE1 and FURIN genes to the COVID-19 prognosis. We found 5 studies for IFITM3, 3 for TNF-alpha, 17 for ACE1 and 2 for FURIN. Meta-analysis was possible for the rs12252 polymorphism in IFITM3, rs4646994 polymorphism in ACE1 and rs1800629 polymorphism in the TNF-alpha gene. No effect was observed for the rs12252 polymorphism in IFITM3 on severity and for the rs1800629 polymorphism in TNF-alpha on mortality. However, an allelic risk effect for the deleterious allele (D allele) of the rs4646994 polymorphism in ACE1 was observed (OR: 1.45; 95% CI: 1.26 – 1.66), in addition to a genotypic effect of genotype D /D for severity (OR: 1.49, 95% CI:1.22 – 1.83), with the homozygous genotype for insertion (I/I) promoting a protective effect (OR: 0.57, 95% CI: 0.45 – 0.74). In chapter 3, we investigated the influence of age, sex and the ACE1, ACE2 and TMPRSS2 genes expression levels, in addition to the rs4646994 polymorphism, on the increased chance of using mechanical ventilation and the chance of death from COVID-19. We observed an association between age and the chance of hospitalization (p<0.001) in the Rio de Janeiro cohort. No change in ACE1, ACE2 and TMPRSS2 gene expression was associated with severity or mortality. The rs4646994 polymorphism in the ACE1 gene also did not influence any of the results. No association was observed in the Rio de Janeiro cohort for hospitalization either, although an effect was observed in a meta-analysis combined with the literature: dominant D allele (OR:1.39; 95%CI: 1.12-1.72) and dominant I allele (OR:0.76; 95%CI: 0.61-0.95). In chapter 4 we attempted to replicate the 3p21.31 locus reported to be associated with severe COVID-19 with polymorphisms in the CXCR6 and LZTFL1 genes. No association was observed for the CXCR6 (rs2234358) and LZTFL1 (rs10490770) polymorphisms for either respiratory support or mortality. However, an association was observed for the CXCR6 polymorphism (rs2234355) for mortality (p=0.022) in a codominance model, and the AG genotype showed a decreased chance of death (OR: 0.09; 95% CI: 0.011 -0.576). In chapter 5, we report in a letter the results found in an association analysis involving the rs12252 polymorphism in the IFITM3 gene in respiratory distress and chance of death. No association was observed for any of the outcomes. These results reinforce the importance of replicating genetic association studies in COVID-19. The use of meta-analyses to increase the reliability of results is extremely important, as is care for the quality of published original studies. It is essential that more prognostic biomarkers are explored so that we can come ever closer to understanding the heterogeneity of symptoms in COVID-19. Considering the multifactorial symptomatology of infectious diseases, understanding the dynamics of biomarkers in clinical outcomes is essential for safe disease interventions, and studies involving the influence of multiple genetic markers become extremely important in this context.