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胚系凝集素途径基因罕见变异使老年人易无症状感染 SARS-CoV-2。

Germline rare variants of lectin pathway genes predispose to asymptomatic SARS-CoV-2 infection in elderly individuals.

机构信息

European School of Molecular Medicine, Università degli Studi di Milano, Milan, Italy; CEINGE Biotecnologie Avanzate, Naples, Italy.

CEINGE Biotecnologie Avanzate, Naples, Italy.

出版信息

Genet Med. 2022 Aug;24(8):1653-1663. doi: 10.1016/j.gim.2022.04.007. Epub 2022 May 5.

DOI:10.1016/j.gim.2022.04.007
PMID:35511137
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9068606/
Abstract

PURPOSE

Emerging evidence suggest that infection-dependent hyperactivation of complement system (CS) may worsen COVID-19 outcome. We investigated the role of predicted high impact rare variants - referred as qualifying variants (QVs) - of CS genes in predisposing asymptomatic COVID-19 in elderly individuals, known to be more susceptible to severe disease.

METHODS

Exploiting exome sequencing data and 56 CS genes, we performed a gene-based collapsing test between 164 asymptomatic subjects (aged ≥60 years) and 56,885 European individuals from the Genome Aggregation Database. We replicated this test comparing the same asymptomatic individuals with 147 hospitalized patients with COVID-19.

RESULTS

We found an enrichment of QVs in 3 genes (MASP1, COLEC11, and COLEC10), which belong to the lectin pathway, in the asymptomatic cohort. Analyses of complement activity in serum showed decreased activity of lectin pathway in asymptomatic individuals with QVs. Finally, we found allelic variants associated with asymptomatic COVID-19 phenotype and with a decreased expression of MASP1, COLEC11, and COLEC10 in lung tissue.

CONCLUSION

This study suggests that genetic rare variants can protect from severe COVID-19 by mitigating the activity of lectin pathway and prothrombin. The genetic data obtained through ES of 786 asymptomatic and 147 hospitalized individuals are publicly available at http://espocovid.ceinge.unina.it/.

摘要

目的

新出现的证据表明，感染依赖性补体系统（CS）的过度激活可能使 COVID-19 患者的预后恶化。我们研究了 CS 基因中预测的高影响罕见变异（称为合格变异（QV））在使老年无症状 COVID-19 患者易患严重疾病中的作用，这些患者已知更容易患严重疾病。

方法

利用外显子组测序数据和 56 个 CS 基因，我们在 164 名无症状受试者（年龄≥60 岁）和来自基因组聚集数据库的 56885 名欧洲个体之间进行了基于基因的合并测试。我们通过将相同的无症状个体与 147 名 COVID-19 住院患者进行比较，复制了这项测试。

结果

我们发现，在无症状队列中，3 个基因（MASP1、COLEC11 和 COLEC10）中的 QV 丰富，这些基因属于凝集素途径。血清中补体活性分析显示，具有 QV 的无症状个体中凝集素途径的活性降低。最后，我们发现与无症状 COVID-19 表型相关的等位基因变体，以及肺组织中 MASP1、COLEC11 和 COLEC10 表达降低的等位基因变体。

结论

这项研究表明，遗传罕见变异可以通过减轻凝集素途径和凝血酶原的活性来保护免受严重的 COVID-19。通过对 786 名无症状和 147 名住院个体的外显子组测序获得的遗传数据可在 http://espocovid.ceinge.unina.it/ 上公开获取。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aceb/9068606/0f45baa74c20/gr3_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aceb/9068606/c776e481bda9/gr1_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aceb/9068606/56cfa56994dd/gr2_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aceb/9068606/0f45baa74c20/gr3_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aceb/9068606/c776e481bda9/gr1_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aceb/9068606/56cfa56994dd/gr2_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aceb/9068606/0f45baa74c20/gr3_lrg.jpg

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