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

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

Luca Valenti  1 , Samantha Griffini  2 , Giuseppe Lamorte  3 , Elena Grovetti  2 , Sara Colonia Uceda Renteria  4 , Francesco Malvestiti  1 , Luigia Scudeller  5 , Alessandra Bandera  6 , Flora Peyvandi  7 , Daniele Prati  3 , Pierluigi Meroni  8 , Massimo Cugno  9
Affiliations

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

Luca Valenti et al. J Autoimmun. 2021 Feb.

Erratum in

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.

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

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Conflict of interest statement

The authors declare that they have no relevant conflicts of interest.

Figures

Fig. 1
Fig. 1
Impact of genetic predisposition to COVID-19 on complement activation. Impact of rs11385942 G>GA and ABO on circulating C5a (panel A and B, respectively) and SC5b-9 (panel C and D, respectively). At generalized linear models unadjusted (P values), and multivariate models considering rs11385942, ABO blood groups, and disease severity (adj P).
Fig. 2
Fig. 2
Combined impact of rs11385942 G>GA and non-O blood group on complement activation. P values are reported for ANOVA test; #P < 0.05 vs. group O, rs11385942 G allele; $ P < 0.05 vs. group O, rs11385942 GA allele.
Fig. 3
Fig. 3
Correlation between upper airways viral load, ferritin and soluble complement terminal complex (SC5b-9) in COVID-19 patients stratified by carriage of the rs11385942 GA risk variant. Relationship between upper respiratory viral load (Ct threshold) and SC5b-9 (A), and ferritin (B). Regression lines and 95% c.i. are shown; associations were tested at linear regression models.
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