El Houdi Meriem, Skhoun Hanaa, El Fessikh Meriem, Benmansour Reda, El Yousfi Fatima-Zahra, Nebhani Chaimae, Tagajdid Mohamed Rida, Lahlou Amine Idriss, El Annaz Hicham, Ameziane El Hassani Rabii, Ouzzif Zohra, Abouqal Redouane, Ennibi Khalid, Bouhouche Ahmed, El Baghdadi Jamila
Genetics Unit, Military Hospital Mohammed V, Rabat, Morocco; Laboratory of Human Pathologies Biology and Genomic Center of Human Pathologies, Department of Biology, Faculty of Sciences, Mohammed V University in Rabat, Morocco.
Virology Laboratory, Center of Virology, Infectious and Tropical Diseases, Military Hospital Mohammed V, School of Medicine and Pharmacy, University Mohammed V, Rabat, Morocco.
Virus Res. 2025 Jan;351:199509. doi: 10.1016/j.virusres.2024.199509. Epub 2024 Dec 13.
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.
我们研究的目的是采用病例对照方法，探索摩洛哥新冠肺炎患者中JAK/STAT信号通路基因多态性的相关性。采用二代测序技术研究JAK/STAT信号通路中的IFNAR1、IFNAR2、JAK1、TYK2、STAT2和IRF9基因。我们还进行了一项计算机模拟研究，以检查该信号通路中的罕见变异。使用MedCalc软件进行统计分析。通过I-TASSER服务器确定蛋白质的3D结构，并使用PyMOL生成变异结构。YASARA View软件允许对致病性罕见变异的天然结构和变异结构进行局部3D分析比较。该研究纳入了206例新冠肺炎患者，平均年龄为45.70±12.73岁，以及一个对照组（N=118）。在所检测的基因中，共鉴定出15个常见多态性和7个罕见变异体。在对年龄和性别进行校正后，发现TYK2基因p.Gly363Ser位点（p=0.036）与新冠肺炎感染之间存在显著关联，其中GA变异体具有保护作用（0.6361 [0.3405-1.1884]，p=0.035）。此外，STAT2基因p.Met594Ile位点与新冠肺炎风险相关（p=0.042），杂合子GC型与感染相关（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基因p.Val168Leu位点突变产生的C等位基因与新冠肺炎严重程度易感性降低显著相关（p=0.028, OR=0.5936 [0.3725 - 0.9461]）。罕见变异体IFNAR1基因p.Trp318Cys、p.Ser476Phe以及IFNAR2基因p.Cys271Tyr被预测具有有害性，可通过改变氢键和疏水相互作用影响蛋白质结构。对罕见变异体的负担分析显示，在显性模型下TYK2基因对新冠肺炎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新冠肺炎易感性中的作用，并提倡进一步探索JAK/STAT信号通路罕见变异体的功能影响。
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