Estratificação molecular e avaliação da influência de polimorfismos de ACE2 e TMPRSS2 no prognóstico da COVID-19

• Ano de defesa: 2023
• Autor(a) principal: Silva, Jean Breno Silveira da
• Tipo de documento: Dissertação
• Tipo de acesso: Acesso aberto
• Idioma: por
• Palavras-chave em Português: COVID-19; SARS-CoV-2; Variação Genética; Polimorfismo de Nucleotídeo Único; CNPQ::CIENCIAS DA SAUDE
• Link de acesso: http://repositorio.ufc.br/handle/riufc/74165

In the first months of the COVID-19 pandemic, scientific studies showed differences in the allele frequencies of variants of the TMPRSS2 gene (rs2070788) between Asians and Italians, revealing that higher levels of TMPRSS2 are more frequent in the population of Italy, a country hit hard by the pandemic, than in the East Asian population. In addition, it was reported that the SNP rs35803318 (ACE2) was more frequent in the Italian population, when compared to the frequencies of the African continent and South Asia. It is noteworthy that both genes originate proteins that are essential for binding the SARS-CoV-2 virus to the host cell membrane and, therefore, polymorphisms in different populations can influence the virulence and severity of the disease. Furthermore, the TMPRSS2 gene product (a transmembrane serine protease) is a potential pharmacological target in COVID-19. Therefore, the objective of this work was the characterization and genetic stratification of the variant allele frequencies of the TMPRSS2 and ACE2 gene of patients with different clinical presentations of COVID-19. For this, molecular diagnosis of SARS-CoV-2 infection was carried out by RT-qPCR. A total of 148 patients with a positive result underwent Real Time PCR (qPCR) genotyping analysis. All genotyping results were analyzed against 3,115 samples from 26 different populations concentrated in five continental groups: Africa, Americas, East Asia, Europe, and South Asia. For ACE2 (rs35803318) the results found were 92.6% for the CC genotype, 3.4% for the CT genotype and 4.0% of TT genotype carriers. For TMPRSS2 (rs2070788), the genotype frequencies were 22.3% of the GG genotype, 50.7% of the AG genotype and 27% of AA genotype carriers. The distribution of genotypes and allele frequencies for the human TMPRSS2 (rs2070788) and ACE2 (rs35803318) polymorphisms varied significantly between world populations and the Fortaleza (Ceará, Brazil) cohort. It was shown that the ACE2 and TMPRSS2 polymorphisms were in Hardy-Weinberg equilibrium (HWE) in most populations (p-value>0.05), except for the SNP rs35803318 (ACE2) in the population of Fortaleza (p-value< 0.05). A quantitative expression trait locus (eQTL) analysis revealed that the SNP rs35803318 is associated with an altered expression of the PIR gene, while for the SNP rs2070788 only association of eQTLs with lung tissue was found. The joint analysis of the genotyping results with the clinical data of critically ill patients due to COVID-19 also revealed that there was no association between the distribution of ACE2 and TMPRSS2 alleles and genotypes with the categorical variables (outcome, occurrence of sepsis and need for mechanical ventilation) and intervals (Glasgow scale, respiratory rate, heart rate, diastolic and systolic pressure, white blood cell and platelet count and creatinine levels) available.