Meriem El Houdi , Hanaa Skhoun , Meriem El Fessikh , Reda Benmansour , Fatima-Zahra El Yousfi , Chaimae Nebhani , Mohamed Rida Tagajdid , Idriss Lahlou Amine , Hicham El Annaz , Rabii Ameziane El Hassani , Zohra Ouzzif , Redouane Abouqal , Khalid Ennibi , Ahmed Bouhouche , Jamila El Baghdadi
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Protein 3D structures were determined via the I-TASSER server, with variant structures generated using PyMOL. YASARA View allowed local 3D analysis comparing native and variant structures for pathogenic rare variants.</div><div>The study encompassed 206 COVID-19 patients, averaging 45.70 ± 12.73 years and a control group (N=118). Among the examined genes, 15 common polymorphisms and 7 rare variants were identified. Adjustment for age and gender revealed a significant association between <em>TYK2</em> p.Gly363Ser (p=0.036) and COVID-19 infection, where the GA variant exhibited protective effects (0.6361 [0.3405–1.1884], p=0.035). Additionally, <em>STAT2</em> p.Met594Ile showed an association to COVID-19 risk (p=0.042), with heterozygous GC being linked to infection (p=0.037, OR=2.7135 [0.5684 -12.9532]). 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引用次数: 0
摘要
本研究的目的是采用病例对照方法，探讨摩洛哥COVID-19患者中JAK/STAT通路多态性的相关性。采用新一代测序技术研究JAK/STAT通路中的IFNAR1、IFNAR2、JAK1、TYK2、STAT2和IRF9基因。我们还进行了一项计算机研究，以检查这一途径中的罕见变异。采用MedCalc软件进行统计分析。通过I-TASSER服务器确定蛋白质的三维结构，并使用PyMOL生成变体结构。YASARA视图允许局部3D分析，比较病原罕见变异的原生和变异结构。研究纳入206例COVID-19患者，平均年龄45.70±12.73岁，对照组118例。在检测的基因中，鉴定出15个常见多态性和7个罕见变异。调整年龄和性别后发现TYK2 p. gly363ser与COVID-19感染之间存在显著相关性（p=0.036），其中GA变异具有保护作用（0.6361 [0.3405-1.1884],p=0.035）。此外，STAT2 p. met594ile与COVID-19风险相关（p=0.042），杂合子GC与感染相关（p=0.037， OR=2.7135[0.5684 -12.9532]）。值得注意的是，在加性模型下（p=0.045， OR=0.626 [0.3958 - 0.9899]）， IFNAR1 p. val168leu突变C等位基因与COVID-19严重程度易感性降低显著相关（p=0.028， OR=0.5936[0.3725 - 0.9461]）。罕见变异IFNAR1 p.Trp318Cys, p.Ser476Phe和IFNAR2 p.Cys271Tyr被预测为有害的，通过氢键和疏水相互作用改变影响蛋白质结构。对罕见变异的负荷分析显示，在优势模型下，TYK2对COVID-19严重程度具有保护性累积效应（p=0.0013， OR=0.1438[0.04237 - 0.4803]）。本研究强调了遗传因素在COVID-19易感性中的作用，并倡导进一步探索JAK/STAT通路罕见变异对功能的影响。
Association study of the JAK/STAT signaling pathway with susceptibility to COVID-19 in moroccan patient and in-silico analysis of rare variants
The goal of our study was to explore the association of the polymorphisms in the JAK/STAT pathway among Moroccan COVID-19 patients, using a case-control approach. Next-generation sequencing was employed to investigate the IFNAR1, IFNAR2, JAK1, TYK2, STAT2, and IRF9 genes within the JAK/STAT pathway. We also performed an in silico study to examine the rare variants in this pathway. Statistical analyses were conducted using MedCalc software. Protein 3D structures were determined via the I-TASSER server, with variant structures generated using PyMOL. YASARA View allowed local 3D analysis comparing native and variant structures for pathogenic rare variants.
The study encompassed 206 COVID-19 patients, averaging 45.70 ± 12.73 years and a control group (N=118). Among the examined genes, 15 common polymorphisms and 7 rare variants were identified. Adjustment for age and gender revealed a significant association between TYK2 p.Gly363Ser (p=0.036) and COVID-19 infection, where the GA variant exhibited protective effects (0.6361 [0.3405–1.1884], p=0.035). Additionally, STAT2 p.Met594Ile showed an association to COVID-19 risk (p=0.042), with heterozygous GC being linked to infection (p=0.037, OR=2.7135 [0.5684 -12.9532]). Notably, IFNAR1 p.Val168Leu mutated C allele was significantly associated with reduced susceptibility to COVID-19 severity (p=0.028, OR=0.5936 [0.3725 – 0.9461]), under the additive model (p=0.045, OR=0.626 [0.3958 – 0.9899]).
Rare variants IFNAR1 p.Trp318Cys, p.Ser476Phe, and IFNAR2 p.Cys271Tyr were predicted deleterious, impacting protein structure via hydrogen bond and hydrophobic interaction alterations. Burden analysis of rare variants revealed a protective cumulative effect against COVID-19 severity for TYK2 (p=0.0013, OR=0.1438 [0.04237 – 0.4803]) under the dominant model.
This study underscores the role of genetic factors in COVID-19 susceptibility and advocates further explorations regarding functional impacts of JAK/STAT pathway rare variants.
期刊介绍：
Virus Research provides a means of fast publication for original papers on fundamental research in virology. Contributions on new developments concerning virus structure, replication, pathogenesis and evolution are encouraged. These include reports describing virus morphology, the function and antigenic analysis of virus structural components, virus genome structure and expression, analysis on virus replication processes, virus evolution in connection with antiviral interventions, effects of viruses on their host cells, particularly on the immune system, and the pathogenesis of virus infections, including oncogene activation and transduction.
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