ObjectivesUncontrolled thromboinflammation plays an important role in the pathogenesis of coronavirus disease (COVID-19) caused by SARS-CoV-2 virus. Complement was implicated as key contributor to this process, therefore we hypothesized that markers of the complement profile, indicative for the activation state of the system, may be related to the severity and mortality of COVID-19.MethodsIn this prospective cohort study samples of 102 hospitalized and 26 outpatients with PCR-confirmed COVID-19 were analyzed. Primary outcome was in-hospital, COVID-19 related mortality, and secondary outcome was COVID-19 severity as assessed by the WHO ordinal scale. Complement activity of alternative and classical pathways, its factors, regulators, and activation products were measured by hemolytic titration, turbidimetry, or enzyme-immunoassays. Clinical covariates and markers of inflammation were extracted from hospital records.ResultsIncreased complement activation was characteristic for hospitalized COVID-19 patients. Complement activation was significantly associated with markers of inflammation, such as interleukin-6, C-reactive protein, and ferritin. Twenty-five patients died during hospital stay due to COVID-19 related illness. Patients with uncontrolled complement activation leading to consumption of C3 and decrease of complement activity were more likely to die, than those who had complement activation without consumption. Cox models identified anaphylatoxin C3a, and C3 overactivation and consumption (ratio of C3a/C3) as predictors of in-hospital mortality [HR of 3.63 (1.55–8.45, 95% CI) and 6.1 (2.1–17.8), respectively].ConclusionIncreased complement activation is associated with advanced disease severity of COVID-19. Patients with SARS-CoV-2 infection are more likely to die when the disease is accompanied by overactivation and consumption of C3. These results may provide observational evidence and further support to studies on complement inhibitory drugs for the treatment of COVID-19.
Abbreviations: ABCC1, ATP-binding cassette, sub-family C, member 1; ALL, acute lymphoblastic leukemia; BFM, Berlin-Frankfurt-Münster; ECHO, echocardiography; LV, left ventricular; LVEDD, left ventricular end-diastolic-dimension; LVESD, left ventricular endsystolic dimension; LVFS, left ventricular fractional shortening; MRP1: multidrug resistanceassociated protein 1. 2 AbstractAnthracyclines are potent cytostatic drugs the correct dosage of which is critical to aviod possible cardiac side effects. ABCC1 (MRP1) is expressed in the heart and takes part in the detoxification and protection of the cells from toxic effects of xenobiotics, including anthracyclines. Our objective was to search for associations between left ventricular function and single nucleotide polymorphisms of the ABCC1 gene in children who received anthracycline chemotherapy. We analyzed data of 235 pediatric patients with acute lymphoblastic leukemia. Patients were followed up by echocardiography (median follow up 6.3 years). Nine polymorphisms in the ABCC1 gene were genotyped. The ABCC1 rs3743527TT genotype and rs3743527TT-rs246221TC/TT genotype combination were found to be associated with lower left ventricular fractional shortening (LVFS) after chemotherapy. Our results suggest that genetic variants in the ABCC1 gene could influence anthracycline induced left ventricular dysfunction.
Genetic studies indicate high number of potential factors related to asthma. Based on earlier linkage analyses we selected the 11q13 and 14q22 asthma susceptibility regions, for which we designed a partial genome screening study using 145 SNPs in 1201 individuals (436 asthmatic children and 765 controls). The results were evaluated with traditional frequentist methods and we applied a new statistical method, called Bayesian network based Bayesian multilevel analysis of relevance (BN-BMLA). This method uses Bayesian network representation to provide detailed characterization of the relevance of factors, such as joint significance, the type of dependency, and multi-target aspects. We estimated posteriors for these relations within the Bayesian statistical framework, in order to estimate the posteriors whether a variable is directly relevant or its association is only mediated. With frequentist methods one SNP (rs3751464 in the FRMD6 gene) provided evidence for an association with asthma (OR = 1.43(1.2–1.8); p = 3×10 −4 ). The possible role of the FRMD6 gene in asthma was also confirmed in an animal model and human asthmatics. In the BN-BMLA analysis altogether 5 SNPs in 4 genes were found relevant in connection with asthma phenotype: PRPF19 on chromosome 11, and FRMD6 , PTGER2 and PTGDR on chromosome 14. In a subsequent step a partial dataset containing rhinitis and further clinical parameters was used, which allowed the analysis of relevance of SNPs for asthma and multiple targets. These analyses suggested that SNPs in the AHNAK and MS4A2 genes were indirectly associated with asthma. This paper indicates that BN-BMLA explores the relevant factors more comprehensively than traditional statistical methods and extends the scope of strong relevance based methods to include partial relevance, global characterization of relevance and multi-target relevance.
In this study, we aimed to identify novel genes involved in experimental and human asthma, importance of which has not yet been recognized. In an ovalbumin-induced murine model of asthma, we applied microarray gene expression analysis at different time points after allergen challenges. Advanced statistical methods were used to relate gene expression changes to cellular processes and to integrate our results into multiple levels of information available in public databases. At 4 h after the first allergen challenge, gene expression pattern reflected mainly an acute, but non-atopic, inflammatory response and strong chemotactic activity. At 24 h after the third allergen challenge, gene set enrichment analysis revealed significant over-representation of gene sets corresponding to T(h)2-type inflammation models. Among the top down-regulated transcripts, an anti-oxidant enzyme, paraoxonase-1 (PON1), was identified. In human asthmatic patients, we found that serum PON1 activity was reduced at exacerbation, but increased parallel with improving asthma symptoms. PON1 gene polymorphisms did not influence the susceptibility to the disease. Our observations suggest that an altered PON1 activity might be involved in the pathogenesis of asthma, and serum PON1 level might be used for following up the effect of therapy.
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