Department of Radiology, Second Xiangya Hospital, Central South University, Changsha, China.
Fujian University of Traditional Chinese Medicine, Fuzhou, China.
Front Immunol. 2024 Mar 18;15:1277720. doi: 10.3389/fimmu.2024.1277720. eCollection 2024.
The existence of chronic pain increases susceptibility to virus and is now widely acknowledged as a prominent feature recognized as a major manifestation of long-term coronavirus disease 2019 (COVID-19) infection. Given the ongoing COVID-19 pandemic, it is imperative to explore the genetic associations between chronic pain and predisposition to COVID-19.
We conducted genetic analysis at the single nucleotide polymorphism (SNP), gene, and molecular levels using summary statistics of genome-wide association study (GWAS) and analyzed the drug targets by summary data-based Mendelian randomization analysis (SMR) to alleviate the multi-site chronic pain in COVID-19. Additionally, we performed a latent causal variable (LCV) method to investigate the causal relationship between chronic pain and susceptibility to COVID-19.
The cross-trait meta-analysis identified 19 significant SNPs shared between COVID-19 and chronic pain. Coloc analysis indicated that the posterior probability of association (PPH4) for three loci was above 70% in both critical COVID-19 and COVID-19, with the corresponding top three SNPs being rs13135092, rs7588831, and rs13135092. A total of 482 significant overlapped genes were detected from MAGMA and CPASSOC results. Additionally, the gene ANAPC4 was identified as a potential drug target for treating chronic pain (P=7.66E-05) in COVID-19 (P=8.23E-03). Tissue enrichment analysis highlighted that the amygdala (P=7.81E-04) and prefrontal cortex (P=8.19E-05) as pivotal in regulating chronic pain of critical COVID-19. KEGG pathway enrichment further revealed the enrichment of pleiotropic genes in both COVID-19 (P=3.20E-03,Padjust=4.77E-02,hsa05171) and neurotrophic pathways (P=9.03E-04,Padjust =2.55E-02,hsa04621). Finally, the latent causal variable (LCV) model was applied to find the genetic component of critical COVID-19 was causal for multi-site chronic pain (P=0.015), with a genetic causality proportion (GCP) of was 0.60.
In this study, we identified several functional genes and underscored the pivotal role of the inflammatory system in the correlation between the paired traits. Notably, heat shock proteins emerged as potential objective biomarkers for chronic pain symptoms in individuals with COVID-19. Additionally, the ubiquitin system might play a role in mediating the impact of COVID-19 on chronic pain. These findings contribute to a more comprehensive understanding of the pleiotropy between COVID-19 and chronic pain, offering insights for therapeutic trials.
慢性疼痛的存在增加了对病毒的易感性，现在被广泛认为是长期 2019 冠状病毒病（COVID-19）感染的主要表现之一。考虑到持续的 COVID-19 大流行，探索慢性疼痛与 COVID-19 易感性之间的遗传关联至关重要。
我们使用全基因组关联研究（GWAS）的汇总统计数据在单核苷酸多态性（SNP）、基因和分子水平上进行遗传分析，并通过基于汇总数据的孟德尔随机化分析（SMR）分析药物靶点，以减轻 COVID-19 中的多部位慢性疼痛。此外，我们进行了潜在因果变量（LCV）方法来研究慢性疼痛和 COVID-19 易感性之间的因果关系。
跨特征荟萃分析确定了 COVID-19 和慢性疼痛之间共享的 19 个显著 SNP。共定位分析表明，三个位点的关联后概率（PPH4）在关键 COVID-19 和 COVID-19 中均超过 70%，相应的前三个 SNP 为 rs13135092、rs7588831 和 rs13135092。MAGMA 和 CPASSOC 结果共检测到 482 个显著重叠基因。此外，ANAPC4 基因被确定为 COVID-19 中治疗慢性疼痛的潜在药物靶点（P=7.66E-05）（P=8.23E-03）。组织富集分析强调了杏仁核（P=7.81E-04）和前额叶皮层（P=8.19E-05）在调节关键 COVID-19 慢性疼痛方面的重要作用。KEGG 途径富集进一步揭示了 COVID-19（P=3.20E-03，Padjust=4.77E-02，hsa05171）和神经营养途径（P=9.03E-04，Padjust=2.55E-02，hsa04621）中多效性基因的富集。最后，应用潜在因果变量（LCV）模型发现，关键 COVID-19 的遗传成分对多部位慢性疼痛具有因果关系（P=0.015），遗传因果比例（GCP）为 0.60。
在这项研究中，我们确定了一些功能基因，并强调了炎症系统在配对特征之间相关性中的关键作用。值得注意的是，热休克蛋白作为 COVID-19 患者慢性疼痛症状的潜在客观生物标志物出现。此外，泛素系统可能在介导 COVID-19 对慢性疼痛的影响方面发挥作用。这些发现有助于更全面地了解 COVID-19 和慢性疼痛之间的多效性，为治疗试验提供了见解。
