新型NUDCD1基因变异通过调节抗病毒的DHX15和MAVS介导的信号通路，使亚洲人易患重症COVID-19疾病。

Novel NUDCD1 gene variant predisposes to severe COVID-19 disease in Asians through modulation of antiviral DHX15- and MAVS-mediated signalling.

作者信息

Anusha Amali Aseervatham, Tay Douglas Jie Wen, Seow Yiqi, Loh Marie, Ravikumar Sharada, Yu Jocelyn Jin, Loong Shaun Seh Ern, Fong Siew Wai, Lee Chang Jie Mick, Lim Jonathan Jordon Cailu, Gan Louis Hanqiang, Koh Winston Lian Chye, Ding Ying, Sam Qi Hui, Tan Zhaohong, Tan Rachel Ying Min, Lua Chong Boon, Chu Justin Jang Hann, Singhal Amit, Prabhakar Shyam, Chng Wee Joo, Renia Laurent, Lye David Chien Boon, Ng Lisa F P, Tan Kai Sen, Foo Roger, Lee Chang Chuan Melvin, Young Barnaby, Chai Louis Yi Ann

机构信息

Division of Infectious Diseases, Department of Medicine, National University Health System, Singapore, Singapore.

Infectious Diseases Translational Research Programme and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.

出版信息

Front Immunol. 2025 Jun 4;16:1581293. doi: 10.3389/fimmu.2025.1581293. eCollection 2025.

DOI:10.3389/fimmu.2025.1581293

PMID:40534864

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12174371/

Abstract

BACKGROUND

Genome-wide associative studies can potentially uncover novel pathways which modulate anti-viral immune responses against SARS-CoV-2 or identify drivers of severe disease. To date, these studies have yielded loci mostly in non-functional domains of unknown biological significance and invariably require large sample sizes, potentially missing lower frequency variants, especially in under-represented or minority populations.

METHODS

To identify unique genetic traits predisposing to severe COVID-19 in Asians, we employed an alternative strategy using whole exome sequencing of representative cohort of severe versus mild COVID-19 patients. Candidate gene variants were identified by performing logistic regression against top genetic principal components, prioritised for missense variants with likely causal impact. Then, functional sequelae of variants were replicated and re-validated in patients ex vivo to demonstrate causality between genotype and clinical phenotype.

RESULTS

Of 136 COVID-19 patients in Singapore (of whom 25% had severe disease), a single nucleotide polymorphism rs2980619 (p.L252F substitution) belonging to NudC-Domain-Containing-1 (NUDCD1) was highly-placed. Homozygous bearers of variant p.L252F had higher (3.97x) odds of severe disease. Age >50 years and male sex were significant covariates which increased the odds of severe disease by 3.38x and 3.16x, respectively. We showed that variant p.L252F reduced NUDCD1 activity, leading to reduced antiviral signalling through RNA helicase DHX15 and antiviral signalling adaptor MAVS, reduced activation of NFκB components RelB and p65, and resultant 1-log higher SARS-CoV-2 viral load compared to wild type (L252) cells. Patients bearing p.L252F had lower NUDCD1, MAVS, and RelB expressions, affirming the above findings.

CONCLUSION

A gene variant of NUDCD1 influences COVID-19 severity in Asians through interacting with DHX15 and MAVS, affecting effective response against SARS-CoV-2.

摘要

背景

全基因组关联研究有可能揭示调节针对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的抗病毒免疫反应的新途径，或识别重症疾病的驱动因素。迄今为止，这些研究发现的基因座大多位于生物学意义不明的非功能区域，而且总是需要大样本量，可能会遗漏低频变异，尤其是在代表性不足或少数族裔人群中。

方法

为了识别亚洲人中易患重症2019冠状病毒病（COVID-19）的独特遗传特征，我们采用了另一种策略，即对重症与轻症COVID-19患者的代表性队列进行全外显子组测序。通过对顶级遗传主成分进行逻辑回归来识别候选基因变异，优先考虑可能具有因果影响的错义变异。然后，在患者体外复制并重新验证变异的功能后遗症，以证明基因型与临床表型之间的因果关系。

结果

在新加坡的136例COVID-19患者中（其中25%患有重症疾病），属于含NudC结构域蛋白1（NUDCD1）的单核苷酸多态性rs2980619（p.L252F替换）位居前列。p.L252F变异的纯合携带者患重症疾病的几率更高（3.97倍）。年龄>50岁和男性是显著的协变量，分别使患重症疾病的几率增加3.38倍和3.16倍。我们发现，p.L252F变异降低了NUDCD1的活性，导致通过RNA解旋酶DHX15和抗病毒信号衔接蛋白MAVS的抗病毒信号传导减少，NFκB成分RelB和p65的激活减少，与野生型（L252）细胞相比，SARS-CoV-2病毒载量高出1个对数级。携带p.L252F的患者NUDCD1、MAVS和RelB的表达较低，证实了上述发现。