ABSTRACT
Although advanced age, male sex, and some comorbidities impact the clinical course of COVID-19, these factors only partially explain the inter-individual variability in disease severity. Some studies have shown that genetic polymorphisms contribute to COVID-19 severity; however, the results are inconclusive. Thus, we investigated the association between polymorphisms in ACE1, ACE2, DPP9, IFIH1, IFNAR2, IFNL4, TLR3, TMPRSS2, and TYK2 and the clinical course of COVID-19. A total of 694 patients with COVID-19 were categorized as: (1) ward inpatients (moderate symptoms) or patients admitted at the intensive care unit (ICU; severe symptoms); and (2) survivors or non-survivors. In females, the rs1990760/IFIH1 T/T genotype was associated with risk of ICU admission and death. Moreover, the rs1799752/ACE1 Ins and rs12329760/TMPRSS2 T alleles were associated with risk of ICU admission. In non-white patients, the rs2236757/IFNAR2 A/A genotype was associated with risk of ICU admission, while the rs1799752/ACE1 Ins/Ins genotype, rs2236757/IFNAR2 A/A genotype, and rs12329760/TMPRSS2 T allele were associated with risk of death. Moreover, some of the analyzed polymorphisms interact in the risk of worse COVID-19 outcomes. In conclusion, this study shows an association of rs1799752/ACE1, rs1990760/IFIH1, rs2236757/IFNAR2, rs12329760/TMPRSS2, and rs2304256/TYK2 polymorphisms with worse COVID-19 outcomes, especially among female and non-white patients.
Subject(s)
COVID-19 , Humans , Male , Female , COVID-19/genetics , Interferon-Induced Helicase, IFIH1/genetics , Polymorphism, Genetic , Genotype , Disease Progression , TYK2 Kinase/genetics , Receptor, Interferon alpha-beta/genetics , Serine Endopeptidases/genetics , Interleukins/geneticsABSTRACT
AIMS: We hypothesized that critically ill patients with SARS-CoV-2 infection and insulin resistance would present a reduced Heat Shock Response (HSR), which is a pathway involved in proteostasis and anti-inflammation, subsequently leading to worse outcomes and higher inflammation. In this work we aimed: (i) to measure the concentration of extracellular HSP72 (eHSP72) in patients with severe COVID-19 and in comparison with noninfected patients; (ii) to compare the HSR between critically ill patients with COVID-19 (with and without diabetes); and (iii) to compare the HSR in these patients with noninfected individuals. METHODS: Sixty critically ill adults with acute respiratory failure with SARS-CoV-2, with or without diabetes, were selected. Noninfected subjects were included for comparison (healthy, n = 19 and patients with diabetes, n = 22). Blood samples were collected to measure metabolism (glucose and HbA1c); oxidative stress (lypoperoxidation and carbonyls); cytokine profile (IL-10 and TNF); eHSP72; and the HSR (in vitro). RESULTS: Patients with severe COVID-19 presented higher plasma eHSP72 compared with healthy individuals and noninfected patients with diabetes. Despite the high level of plasma cytokines, no differences were found between critically ill patients with COVID-19 with or without diabetes. Critically ill patients, when compared to noninfected, presented a blunted HSR. Oxidative stress markers followed the same pattern. No differences in the HSR (extracellular/intracellular level) were found between critically ill patients, with or without diabetes. CONCLUSIONS: We demonstrated that patients with severe COVID-19 have elevated plasma eHSP72 and that their HSR is blunted, regardless of the presence of diabetes. These results might explain the uncontrolled inflammation and also provide insights on the increased risk in developing type 2 diabetes after SARS-CoV-2 infection.
Subject(s)
COVID-19 , Diabetes Mellitus, Type 2 , Adult , Humans , Interleukin-10 , SARS-CoV-2 , Critical Illness , HSP72 Heat-Shock Proteins/metabolism , Glycated Hemoglobin , Heat-Shock Response , Cytokines , Inflammation , Molecular Chaperones , GlucoseABSTRACT
Although advanced age and presence of comorbidities significantly impact the variation observed in the clinical symptoms of COVID-19, it has been suggested that genetic variants may also be involved in the disease. Thus, the aim of this study was to perform a systematic review with meta-analysis of the literature to identify genetic polymorphisms that are likely to contribute to COVID-19 pathogenesis. Pubmed, Embase and GWAS Catalog repositories were systematically searched to retrieve articles that investigated associations between polymorphisms and COVID-19. For polymorphisms analyzed in 3 or more studies, pooled OR with 95% CI were calculated using random or fixed effect models in the Stata Software. Sixty-four eligible articles were included in this review. In total, 8 polymorphisms in 7 candidate genes and 74 alleles of the HLA loci were analyzed in 3 or more studies. The HLA-A*30 and CCR5 rs333Del alleles were associated with protection against COVID-19 infection, while the APOE rs429358C allele was associated with risk for this disease. Regarding COVID-19 severity, the HLA-A*33, ACE1 Ins, and TMPRSS2 rs12329760T alleles were associated with protection against severe forms, while the HLA-B*38, HLA-C*6, and ApoE rs429358C alleles were associated with risk for severe forms of COVID-19. In conclusion, polymorphisms in the ApoE, ACE1, TMPRSS2, CCR5, and HLA loci appear to be involved in the susceptibility to and/or severity of COVID-19.