Serra-Llovich Alexandre, Cullell Natalia, Maroñas Olalla, José Herrero María, Cruz Raquel, Almoguera Berta, Ayuso Carmen, López-Rodríguez Rosario, Domínguez-Garrido Elena, Ortiz-Lopez Rocio, Barreda-Sánchez María, Corton Marta, Dalmau David, Calbo Esther, Boix-Palop Lucía, Dietl Beatriz, Sangil Anna, Gil-Rodriguez Almudena, Guillén-Navarro Encarna, Mancebo Esther, Lira-Albarrán Saúl, Minguez Pablo, Paz-Artal Estela, Olivera Gladys G, Recarey-Rama Sheila, Sendra Luis, Zucchet Enrique G, López de Heredia Miguel, Flores Carlos, Riancho José A, Rojas-Martinez Augusto, Lapunzina Pablo, Carracedo Ángel, Arranz María J
Fundació Docència i Recerca Mutua Terrassa, 08221 Terrassa, Spain.
Hospital Universitario Mutua Terrassa, 08221 Terrassa, Spain.
Biomedicines. 2025 Feb 21;13(3):553. doi: 10.3390/biomedicines13030553.
: The COVID-19 pandemic resulted in 675 million cases and 6.9 million deaths by 2022. Despite substantial declines in case fatalities following widespread vaccination campaigns, the threat of future coronavirus outbreaks remains a concern. Current treatments for COVID-19 have been repurposed from existing therapies for other infectious and non-infectious diseases. Emerging evidence suggests a role for genetic factors in both susceptibility to SARS-CoV-2 infection and response to treatment. However, comprehensive studies correlating clinical outcomes with genetic variants are lacking. The main aim of our study is the identification of host genetic biomarkers that predict the clinical outcome of COVID-19 pharmacological treatments. : In this study, we present findings from GWAS and candidate gene and pathway enrichment analyses leveraging diverse patient samples from the Spanish Coalition to Unlock Research of Host Genetics on COVID-19 (SCOURGE), representing patients treated with immunomodulators ( = 849), corticoids ( = 2202), and the combined cohort of both treatments ( = 2487) who developed different outcomes. We assessed various phenotypes as indicators of treatment response, including survival at 90 days, admission to the intensive care unit (ICU), radiological affectation, and type of ventilation. : We identified significant polymorphisms in 16 genes from the GWAS and candidate gene studies (TLR1, TLR6, TLR10, CYP2C19, ACE2, UGT1A1, IL-1α, ZMAT3, TLR4, MIR924HG, IFNG-AS1, ABCG1, RBFOX1, ABCB11, TLR5, and ANK3) that may modulate the response to corticoid and immunomodulator therapies in COVID-19 patients. Enrichment analyses revealed overrepresentation of genes involved in the innate immune system, drug ADME, viral infection, and the programmed cell death pathways associated with the response phenotypes. : Our study provides an initial framework for understanding the genetic determinants of treatment response in COVID-19 patients, offering insights that could inform precision medicine approaches for future epidemics.
到2022年，新冠疫情已导致6.75亿例感染和690万人死亡。尽管在广泛开展疫苗接种运动后病死率大幅下降，但未来冠状病毒爆发的威胁仍然令人担忧。目前针对新冠的治疗方法是从现有的其他传染病和非传染病治疗方案中重新调整而来的。新出现的证据表明，遗传因素在感染新冠病毒的易感性和治疗反应中都发挥作用。然而，缺乏将临床结果与基因变异相关联的全面研究。我们研究的主要目的是确定能够预测新冠药物治疗临床结果的宿主遗传生物标志物。
在本研究中，我们展示了全基因组关联研究（GWAS）以及候选基因和通路富集分析的结果，这些分析利用了西班牙新冠宿主遗传学解锁研究联盟（SCOURGE）的多样患者样本，这些样本代表了接受免疫调节剂治疗的患者（n = 849）、接受皮质类固醇治疗的患者（n = 2202）以及两种治疗联合使用的队列（n = 2487），这些患者产生了不同的结果。我们评估了各种表型作为治疗反应的指标，包括90天生存率、入住重症监护病房（ICU）、影像学影响以及通气类型。
我们在GWAS和候选基因研究中确定了16个基因中的显著多态性（TLR1、TLR6、TLR10、CYP2C19、ACE2、UGT1A1、IL - 1α、ZMAT3、TLR4、MIR924HG、IFNG - AS1、ABCG1、RBFOX1、ABCB11、TLR5和ANK3），这些基因可能调节新冠患者对皮质类固醇和免疫调节剂治疗的反应。富集分析显示，与反应表型相关的先天免疫系统、药物ADME、病毒感染和程序性细胞死亡通路中的基因过度表达。
我们的研究为理解新冠患者治疗反应的遗传决定因素提供了一个初步框架，提供了可为未来疫情的精准医学方法提供参考的见解。
