Genetic determinants of mannose-binding lectin activity predispose to thromboembolic complications in critical COVID-19

Complement lectin pathway activation is associated with COVID-19 disease severity, independent of MBL2 genotype subgroups

“…Also Stravalaci and colleagues found an increased risk of disease development in individuals bearing two of the exonic disruptive variants by comparing severe COVID-19 cases and controls (26). Correspondingly, Hultström et al performed extensive genetic studies in a multicentre cohort of severely infected COVID-19 cases, further including publicly available genetic data from the COVID-19 Human Genetics Initiative (39). In their study, genetic MBL2 variants were not associated with the need for hospitalization or ICU admission during SARS-CoV-2 infection, but haplotype combinations with intermediate MBL expression (LXA/LXA, HYA/0, LYA/0) were found to be protective when it comes to thromboembolic complications in critically ill COVID-19 patients (39).…”

“…Correspondingly, Hultström et al performed extensive genetic studies in a multicentre cohort of severely infected COVID-19 cases, further including publicly available genetic data from the COVID-19 Human Genetics Initiative (39). In their study, genetic MBL2 variants were not associated with the need for hospitalization or ICU admission during SARS-CoV-2 infection, but haplotype combinations with intermediate MBL expression (LXA/LXA, HYA/0, LYA/0) were found to be protective when it comes to thromboembolic complications in critically ill COVID-19 patients (39). In this analysis, providing information from two independent cohorts, we could not find any association genetic variations in MBL2 and the risk of SARS-CoV-2 infection, when investigating distributions of either short or long MBL2 haplotype combinations or exonic wildtype (A) and variant alleles between COVID-19 cases and controls.…”

Targeting thromboinflammation in COVID-19 – A narrative review of the potential of C1 inhibitor to prevent disease progression

“…These haplotypes are often grouped according to their associated MBL protein concentrations into high, medium and low activity haplotypes. Conflicting results regarding the association of MBL activity and SARS-CoV-2 outcome have been reported ( Charitos et al, 2021 , Hultstrom et al, 2022 ; Stravalaci et al, 2022). Recently, Hultström M et al described a U-shaped association between MBL haplotypes and thrombotic complications/pulmonary embolism.…”

“…Recently, Hultström M et al described a U-shaped association between MBL haplotypes and thrombotic complications/pulmonary embolism. They speculate, that high MBL activity may predispose to excessive complement activation and subsequent thrombosis ( Eriksson et al, 2019 , Hultstrom et al, 2022 , Pavlov et al, 2015 ), whereas an increased thrombosis risk in individuals with low MBL activity is driven by the failure to remove SARS-CoV-2 and prevent subsequent endothelial cell activation and thrombosis. Along the same lines, an interaction of highly pathogenic CoVs (MERS-CoV, SARS-CoV-1 and SARS-CoV-2) with mannose-binding lectin associated serine protease-2 (MASP-2), the key activator of the lectin pathway of complement ( Heja et al, 2012 ), was demonstrated leading to uncontrolled activation of the complement cascade ( Gao et al, 2020 ).…”

A Complement Atlas identifies interleukin 6 dependent alternative pathway dysregulation as a key druggable feature of COVID-19

“…The key importance of complement and its regulation is best illustrated by genetic complement deficiencies 9,10 , which lead to immunodeficiency, auto-immunity, endothelial damage and/or kidney injury. In addition to these inborn disorders, dysregulation of the complement system has been reported across a spectrum of infectious diseases, including those caused by emerging coronaviruses [11][12][13][14][15][16] .…”