Laffranchi Mattia, Paraboschi Elvezia Maria, Bianchetto-Aguilera Francisco, Tamassia Nicola, Gasperini Sara, Gardiman Elisa, Piserà Arianna, Del Prete Annalisa, Invernizzi Pietro, Gismondi Angela, Mantovani Alberto, Cassatella Marco A, Asselta Rosanna, Sozzani Silvano
Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
Istituto Pasteur-Fondazione Cenci Bolognetti, Rome, Italy.
Heliyon. 2024 Dec 17;11(1):e41267. doi: 10.1016/j.heliyon.2024.e41267. eCollection 2025 Jan 15.
The 3p21.31 locus is the most robust genomic region associated with COVID-19 severity. This locus contains a main chemokine receptor (CKR) cluster. We tested expression quantitative trait loci (eQTL) targeting the 3p21.31 CKR cluster linked to COVID-19 hospitalization in Europeans from the COVID-19 HGI meta-analysis. Among these, , a key regulator of neutrophil trafficking, was targeted by neutrophil-restricted eQTLs. We confirmed these eQTLs in an Italian COVID-19 cohort. Haplotype analysis revealed a link between an increased expression and COVID-19 severity and hospitalization. By the exposure of neutrophils to a TLR8 ligand, reflecting a viral infection, we revealed specific chromatin domains within the 3p21.31 locus exclusive to neutrophils. In addition, the identified variants mapped within these regions altered the binding motif of neutrophils-expressed transcription factors. These results support that eQTL variants contribute to the risk of severe COVID-19 by selectively affecting neutrophil functions.
3p21.31基因座是与新冠病毒疾病严重程度相关的最稳定的基因组区域。该基因座包含一个主要的趋化因子受体（CKR）簇。我们在新冠病毒宿主遗传学计划（COVID-19 HGI）荟萃分析中，对欧洲人针对与新冠病毒住院相关的3p21.31 CKR簇的表达定量性状基因座（eQTL）进行了测试。其中，作为中性粒细胞迁移的关键调节因子，被中性粒细胞限制性eQTL靶向。我们在一个意大利新冠病毒队列中证实了这些eQTL。单倍型分析揭示了表达增加与新冠病毒疾病严重程度和住院之间的联系。通过使中性粒细胞暴露于反映病毒感染的Toll样受体8（TLR8）配体，我们揭示了3p21.31基因座内中性粒细胞特有的特定染色质结构域。此外，在这些区域内定位的已鉴定变体改变了中性粒细胞表达的转录因子的结合基序。这些结果支持eQTL变体通过选择性影响中性粒细胞功能而导致严重新冠病毒疾病的风险。
