Common and rare variants in complement genes as biomarkers of COVID-19 infection and severity. A lesson to learn for emerging pathogens.

INTRODUCTION: The first wave of Coronavirus disease 2019 (COVID-19), driven by the global emergence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), severely affected Spain with high infection and mortality rates across the country. Although numerous common and rare genetic variants affecting immune-related pathways have been associated with susceptibility to infection and severe disease, the contribution of complement system remains comparatively understudied.

METHODS: In this work, we analyzed the frequencies and severity associations of complotype-related common polymorphisms and rare complement variants in whole-exome sequencing data from a Spanish cohort accounting for 154 adults hospitalized due to severe COVID-19.

RESULTS: Our results indicate that the CFHR4 rs7417769 (p.N209S) and CFH rs1061170 (p. Y402H) common polymorphisms are significantly associated with protection against acute respiratory distress syndrome (ARDS), while the C3 rs2230199 (p.R102G) and MASP2 rs7255087 (p.D120G) polymorphisms respectively correlated with low and high C3 levels. The marked over-representation of the C1R rs117402032 and C8A rs143523574 polymorphisms and increased frequency of heterozygous carriers of alleles previously associated with low FCN2 and FCN3 levels, suggest a link beween defective complement activation and increased rates of SARS-CoV-2 infection and support a pivotal role for the lectin pathway in the pathogenesis of COVID-19.

DISCUSSION: Together, these results demonstrate that common variants in complement genes modulate susceptibility to severe COVID-19 and its clinical complications. They also identify promising, testable genetic biomarkers with potential utility not only for SARS-CoV-2, but also for preparedness against future emerging infectious threats.