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Genetic Determinants of Mannose-binding Lectin Activity Predispose to Thromboembolic Complications in Critical COVID-19

ABSTRACT: A recent study demonstrated that the complement recognition protein Mannose-binding lectin (MBL) can bind to glycosylated SARS-CoV-2 spike protein. Binding activated complement in a spike-dependent manner and inhibited SARS-CoV-2 in in vitro models. Furthermore, genetic variants near or in the MBL2 gene that encodes MBL in humans were suggested to be associated with COVID-19 requiring hospitalization. Here, we carried out genetic and biochemical analyses of MBL activity in plasma in a multi-center cohort of critically ill COVID-19 patients, and interrogated the publicly available summary statistics from the COVID-19 Human Genetics Initiative (COVID-19 HGI). We find no evidence that genetic variants that determine activity of the MBL pathway are associated with hospitalization or intensive care admission due to SARS-CoV-2 infection. Instead, we demonstrate that MBL2 haplotypes determine risk for thrombotic complications in critically ill COVID-19 patients. Specifically, genetically determined MBL activity confers risk for pulmonary embolism in a U-shaped manner, where haplotypes associated with intermediate MBL activity are protective. Our results demonstrate a complement-dependent mechanism for COVID-19 associated thrombosis and provide an example of how genetic variation in the innate immune system modulates thrombosis risk.

PROVIDER: EGAS00001006266 | EGA |

REPOSITORIES: EGA

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