Chromosome 3 cluster rs11385942 variant links complement activation with severe COVID-19

Luca Valenti, Samantha Griffini, Giuseppe Lamorte, Elena Grovetti, Sara Colonia Uceda Renteria, Francesco Malvestiti, Luigia Scudeller, Alessandra Bandera, Flora Peyvandi, Daniele Prati, Pierluigi Meroni, Massimo Cugno

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Article number102595
JournalJournal of Autoimmunity
Publication statusPublished - Feb 2021


  • ABO group
  • C5a
  • Complement
  • COVID-19
  • rs11385942 G>GA variant
  • SC5b-9

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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