INVESTIGAÇÃO DE VARIANTES GENÉTICAS DO SISTEMA COMPLEMENTO POTENCIALMENTE ASSOCIADAS À COVID-19

Abstract

The severity of clinical manifestations in patients with coronavirus disease 2019 (COVID-19) has raised interest in identifying genetic factors that may be associated with these outcomes. Recent studies have expanded the understanding of various aspects related to the pathophysiology of the disease, among them, COVID-19 triggers a complex immune response characterized by different patterns of inflammatory mediators, intrinsically related to the complement system (CS). Studies on CS polymorphisms are essential to elucidate its role in disease severity. Objective: To identify genetic variations of complement system components in the human genome that are potentially associated with the severity of COVID-19 infection. Methodology: A prospective multicenter cohort study that included whole-genome sequencing of samples collected from the SARS-CoV-2 virus and exome sequencing of peripheral blood samples from infected patients. The data were analyzed using bioinformatics, and associations between genotypes and clinical groups of severe and non-severe cases were examined. Multiple logistic regression, adjusted for variables such as dyspnea, cardiovascular diseases, and obesity, was conducted between cases and controls. Haplotype analysis and linkage disequilibrium (LD) were performed with all significant polymorphisms for the clinical condition. Results: In the entire analysis, a significance level of 0.05 (5%) was adopted, resulting in 28 single nucleotide polymorphisms (SNPs) in the genes CR1, CFH, C4BPA, C8A, C8B, CR2, CD55, and MBL2. MBL2 SNPs rs930507G and rs930508G were more frequent in severe patients under additive and dominant genetic models. Linkage disequilibrium was observed between the haplotypes AA (rs646817/rs41274768), GG (rs140275089/rs114995634), AA (rs646817/rs17617), and AA (rs41274768/rs17617), suggesting that these SNPs are possibly inherited together. Missense SNPs rs534399 (G-T) and rs515299 (G-T) of the CFH gene were significant for the severity of COVID-19. Discussion: Haplotype blocks differed significantly (p < 0.01) between clinical groups with an odds ratio of 10.71 for this genotype to be associated with severe COVID-19, in both additive and dominant models. The presence of allele T for SNPs rs515299 and rs534399 was associated with severe cases, suggesting that genetic variants rs515299 and rs534399 may be related to the evaluated phenotype. Conclusion: These findings suggest that genetic variations in the complement system may influence the immune response to SARS-CoV-2, leading to variable clinical outcomes.