Università degli Studi di Milano, Department of Pathophysiology and Transplantation, Milan, Italy; Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Department of Transfusion Medicine and Hematology, Milan, Italy.
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Internal Medicine and Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy.
J Autoimmun. 2021 Feb;117:102595. doi: 10.1016/j.jaut.2021.102595. Epub 2021 Jan 9.
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.
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.
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.
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.
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.
染色体 3p21.31 上的多基因簇和 ABO 血型与发生严重 COVID-19 的风险相关，但机制尚不清楚。补体激活与 COVID-19 的严重程度有关。
本研究旨在探讨染色体 3p21.31 和 ABO 变体是否与 COVID-19 患者补体级联的激活有关。
我们考虑了 72 名具有遗传数据和循环 C5a 和可溶性末端补体复合物 C5b-9（SC5b-9）评估的无关欧洲住院患者。26 名（36.1%）患者携带 rs11385942 G>GA 变体，44 名（66.1%）非 O 血型与严重 COVID-19 风险增加相关。
rs11385949 GA 携带者的 C5a 和 SC5-b9 血浆水平高于非携带者（P=0.041 和 P=0.012），而非 O 组患者的 C5a 水平高于 O 组患者（P=0.019）。在调整 ABO 和疾病严重程度后，rs11385949 与 SC5b-9 的关联仍然显著（P=0.004），并进一步校正 C5a（P=0.018）。在 rs11385949 风险等位基因携带者中，上呼吸道病毒载量与 SC5b-9 呈直接关系（P=0.032），而非携带者则没有。
rs11385949 G>GA 变体，标记染色体 3 基因簇变异并易患严重 COVID-19，与补体激活有关，无论是 C5a 还是末端补体复合物，而非 O 血型与 C5a 水平有关。这些发现为更严重的 COVID-19 的遗传易感性与补体激活之间提供了联系。
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