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

J Autoimmun. 2021 Feb;117:102595. doi: 10.1016/j.jaut.2021.102595. Epub 2021 Jan 9.


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.

Keywords: ABO group; C5a; COVID-19; Complement; SC5b-9; rs11385942 G>GA variant.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ABO Blood-Group System / genetics*
  • Aged
  • COVID-19 / genetics*
  • Chromosomes, Human, Pair 3 / genetics*
  • Complement Activation / genetics*
  • Complement C5a / genetics
  • Disease Progression
  • European Continental Ancestry Group*
  • Female
  • Gene Frequency
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Genotype*
  • Hospitalization
  • Humans
  • Male
  • Middle Aged
  • Multigene Family / genetics*
  • Polymorphism, Single Nucleotide
  • Risk
  • SARS-CoV-2 / physiology
  • Viral Load


  • ABO Blood-Group System
  • Complement C5a