Influence of complement system genomic variations on the course of COVID-19

ABSTRACT

Background: The pandemic of SARS-CoV- 2 is a severe worldwide problem increasing morbidity and mortality.1, 2 Severe COVID-19 presents as multiple organ failure caused by systemic inflammation, thrombin generation, and hypofibrinolysis. Diffuse microvascular thrombi and inter-alveolar deposits of complement fragments are observed. The enhanced immunothrombosis is mediated by direct overactivation of complement by virus surface components or damaged cells.3-5 Aims: The study aimed to find whether genetic changes responsible for complement dysregulation known in atypical hemolytic-uremic syndrome (aHUS) can be found in severe COVID-19 patients. Method(s) The study included adult COVID-19 subjects undergoing extracorporeal membrane oxygenation support for severe acute respiratory distress syndrome. Two independent physicians signed informed consent, and the study was approved by a local ethics committee (No. 109/2021) and supported by the University Hospital fund. Next-Generation Sequencing Panel of C3 component, membrane cofactor protein (CD46), complement factor B (CFB), complement factor H (CFH), complement factor H related genes 1-5 (CFHR 1-5), diacylglycerol Kinase Epsilon, thrombomodulin (THBD) and mannose-binding lectin (MBL) genes were performed, with confirmations of positive results by Sanger sequencing. Result(s) Twenty-two patients (13 were male) aged 33 to 65 years were included. No pathogenic gene variants in the C3, CD46, CFB, CFH genes, CFHR 5, CFI, THBD were detected. However, we have shown the presence of modifiers (CFH-H3 haplotype, MCP-GGAAC haplotype, and CFH/CFHR1), which may, together with triggers (infection), increase the severity of the disease (aHUS).6-8 Moreover, we have identified single nucleotide polymorphisms in exon 1 at codon 52 (c.154C>T) and 54 (c.161G>A) of the MBL2 gene promoter associated with low serum levels or dysfunctional MBL and higher incidence of infections. Conclusion(s) We did not detect any complement-related pathogenic gene variants known in aHUS. Thus, It is unlikely that complement dysregulation is the main factor influencing immunothrombosis in a cohort of the most severe COVID-19 patients.