Rosa-Baez Carlos, Borrego-Yaniz Gonzalo, Rodriguez-Martin Inmaculada, Kerick Martin, Acosta-Herrera Marialbert, Martín Javier, Ortiz-Fernández Lourdes
Department of Cell Biology and Immunology, Institute of Parasitology and Biomedicine López-Neyra, CSIC, Granada, Spain.
Systemic Autoimmune Disease Unit, Hospital Clínico San Cecilio, Instituto de Investigación Biosanitaria Ibs. GRANADA, Granada, Spain.
Rheumatology (Oxford). 2025 Jun 1;64(6):4022-4031. doi: 10.1093/rheumatology/keaf028.
Coronavirus disease 2019 (COVID-19) and SSc share multiple similarities in their clinical manifestations, alterations in immune response and therapeutic options. These resemblances have also been identified in other immune-mediated inflammatory diseases where a common genetic component has been found. Thus, we decided to evaluate for the first time this shared genetic architecture with SSc.
For this study, we retrieved genomic data from two European-ancestry cohorts: 2 597 856 individuals from The COVID-19 Host Genetics Initiative consortium, and 26 679 individuals from the largest genomic scan in SSc. We performed a cross-trait meta-analyses including >9.3 million single nucleotide polymorphisms. Finally, we conducted functional annotation to prioritize potential causal genes and performed drug repurposing analysis.
Our results revealed a total of 19 non-HLA pleiotropic loci, including 2 novel associations for both conditions (BMP1 and PPARG) and 12 emerging as new shared loci. Functional annotation of these regions underscored their potential regulatory role and identified potential causal genes, many of which are implicated in fibrotic and inflammatory pathways. Remarkably, we observed an antagonistic pleiotropy model of the IFN signalling between COVID-19 and SSc, including the well-known TYK2 P1104A missense variant, showing a protective effect for SSc while being a risk factor for COVID-19, along with two additional novel pleiotropic associations (IRF8 and SENP7). Finally, our findings provide new therapeutic options that could potentially benefit both conditions.
Our study confirms the genetic resemblance between susceptibility to and severity of COVID-19 and SSc, revealing a novel common genetic contribution affecting fibrotic and immune pathways.
2019年冠状病毒病（COVID-19）与系统性硬化症（SSc）在临床表现、免疫反应改变和治疗选择方面有诸多相似之处。在其他已发现共同遗传成分的免疫介导性炎症疾病中也发现了这些相似之处。因此，我们首次决定评估与SSc共享的这种遗传结构。
在本研究中，我们从两个欧洲血统队列中检索了基因组数据：来自COVID-19宿主遗传学倡议联盟的2597856名个体，以及来自SSc最大基因组扫描的26679名个体。我们进行了跨性状荟萃分析，包括超过930万个单核苷酸多态性。最后，我们进行了功能注释以对潜在的因果基因进行优先级排序，并进行了药物重新利用分析。
我们的结果共揭示了19个非HLA多效性位点，包括两种疾病的2个新关联（BMP1和PPARG）以及12个新出现的共享位点。这些区域的功能注释强调了它们的潜在调控作用，并确定了潜在的因果基因，其中许多基因与纤维化和炎症途径有关。值得注意的是，我们观察到COVID-19和SSc之间IFN信号传导的拮抗性多效性模型，包括著名的TYK2 P1104A错义变体，该变体对SSc具有保护作用，而对COVID-19是一个危险因素，以及另外两个新的多效性关联（IRF8和SENP7）。最后，我们的研究结果提供了可能对两种疾病都有益的新治疗选择。
我们的研究证实了COVID-19易感性和严重程度与SSc之间的遗传相似性，揭示了一种影响纤维化和免疫途径的新的共同遗传作用。
