Chromosome 3 cluster rs11385942 variant links complement activation with severe COVID-19. Issue 117 (February 2021)

• Record Type: Journal Article
• Authors: Valenti, Luca; Griffini, Samantha; Lamorte, Giuseppe; Grovetti, Elena; Uceda Renteria, Sara Colonia; Malvestiti, Francesco; Scudeller, Luigia; Bandera, Alessandra; Peyvandi, Flora; Prati, Daniele; Meroni, Pierluigi; Cugno, Massimo
• Is Part Of: Journal of autoimmunity. Issue 117(2021)
• Publication Date: 2021-02
• Subjects: COVID-19 -- Complement -- SC5b-9 -- C5a -- rs11385942 G>GA variant -- ABO group; Autoimmunity -- Periodicals; Autoimmune diseases -- Periodicals; Autoantibodies -- Periodicals; Autoimmune Diseases -- Periodicals; Auto-immunité -- Périodiques; Maladies auto-immunes -- Périodiques; Electronic journals; 616.978005
• DOI: 10.1016/j.jaut.2021.102595
• Languages: English
• ISSNs: 0896-8411

Abstract

Abstract: Background: Genetic variation at a multigene cluster at chromosome 3p21.31 and the ABO blood group have been associated with the risk of developing severe COVID-19, but the mechanism remains unclear. Complement activation has been associated with COVID-19 severity. Objective: The aim of this study was to examine whether chromosome 3p21.31 and the ABO variants are linked to the activation of the complement cascade in COVID-19 patients. Methods: We considered 72 unrelated European hospitalized patients with genetic data and evaluation of circulating C5a and soluble terminal complement complex C5b-9 (SC5b-9). Twenty-six (36.1%) patients carried the rs11385942 G>GA variant and 44 (66.1%) non-O blood group associated with increased risk of severe COVID-19. Results: C5a and SC5-b9 plasma levels were higher in rs11385949 GA carriers than in non-carriers (P = 0.041 and P = 0.012, respectively), while C5a levels were higher in non-O group than in O group patients (P = 0.019). The association between rs11385949 and SC5b-9 remained significant after adjustment for ABO and disease severity (P = 0.004) and further correction for C5a (P = 0.018). There was a direct relationship between upper airways viral load and SC5b-9 in carriers of the rs11385949 risk allele (P = 0.032), which was not observed in non-carriers. Conclusions: The rs11385949 G>GA variant, tagging the chromosome 3 gene cluster variation and predisposing to severe COVID-19, is associated with enhanced complement activation, both with C5a and terminal complement complex, while non-O blood group with C5a levels. These findings provide a link between genetic susceptibility to more severe COVID-19 and complement activation. Highlights: The rs11385942 G>GA variant and ABO blood group are linked to severe COVID-19. Complement activation parallels severity and disease activity in COVID-19 patients. In COVID-19, we found that rs11385949 G>GA predispose to complement activation. Non-O blood group is also associated with complement activation in COVID-19 patients.