Genetic justification of severe COVID-19 using a rigorous algorithm

Abstract

Recent studies suggest excessive complement activation in severe coronavirus disease-19 (COVID-19). The latter shares common characteristics with complement-mediated thrombotic microangiopathy (TMA). We hypothesized that genetic susceptibility would be evident in patients with severe COVID-19 (similar to TMA) and associated with disease severity. We analyzed genetic and clinical data from 97 patients hospitalized for COVID-19. Through targeted next-generation-sequencing we found an ADAMTS13 variant in 49 patients, along with two risk factor variants ( C3 , 21 patients; CFH ,34 patients). 31 (32%) patients had a combination of these, which was independently associated with ICU hospitalization ( p = 0.022). Analysis of almost infinite variant combinations showed that patients with rs1042580 in thrombomodulin and without rs800292 in complement factor H did not require ICU hospitalization. We also observed gender differences in ADAMTS13 and complement-related variants. In light of encouraging results by complement inhibitors, our study highlights a patient population that might benefit from early initiation of specific treatment.

Pathogenic Basis of Thromboinflammation and Endothelial Injury in COVID-19: Current Findings and Therapeutic Implications

“…In addition, it was reported that the median activity of the VWF cleaving protease ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) in COVID-19 patients was lower than the expected median of the normal reference range, and the VWF to ADAMTS-13 ratio was associated with COVID-19 disease severity [ 95 ]. Interestingly, genetic analysis demonstrated that a missense variant of ADAMTS-13 was associated with ICU hospitalization in COVID-19 [ 96 ]. These findings suggested that SARS-CoV-2 infection is associated with consumption and hyperactivation of platelets.…”

“…Furthermore, C5a induces NET formation through activation of its receptor on neutrophils, which triggers thromboinflammation and endothelial injury in COVID-19 [ 136 ]. Interestingly, genetic variants of complement pathway genes, including C3, factor H, and complement decay-accelerating factor, were reported to be significantly associated with clinical outcomes in COVID-19 [ 96 , 137 ]. Collectively, SARS-CoV-2 infection might result in unrestrained complement activation for endothelial cell dysfunction and thrombosis.…”

Complement activation and increased expression of Syk, mucin-1 and CaMK4 in kidneys of patients with COVID-19

“…Our finding revealed, like in the lung tissues infected with SARS-CoV-2 [ 52 ], decreased deposition of the regulatory complement component FH in the kidney tissues of COVID-19 patients, which may have enabled uncontrolled complement activation and deposition. Recently, variants of the FH gene were reported to be associated with severe clinical outcome in COVID-19 patients [ 53 ]. This implies that certain individuals have limited ability to control complement activation and accordingly they are more susceptible to severe disease.…”

Does ABO Blood Groups Affect Outcomes in Hospitalized COVID-19 Patients?

“…They reported multiple other associations such as chromosome 12q24.13 (encodes antiviral restriction enzyme activators), chromosome 19p13.2 (encodes tyrosine kinase 2), chromosome 19p13.3 (encodes dipeptidyl peptidase 9) and chromosome 21q22.1 (encodes interferon receptor IFNAR2). Gavriilaki et al reported ADAMTS13 variants which were associated with ICU hospitalizations [ 27 ]. These findings may also explain variability of association between blood group types in different studies from different regions in the world.…”