Lee Chi-Ying, Lai Zih-Yin, Chuang Yung-Jen
School of Medicine, National Tsing Hua University, Hsinchu 300044, Taiwan, ROC; Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu 300044, Taiwan, ROC.
School of Medicine, National Tsing Hua University, Hsinchu 300044, Taiwan, ROC; Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu 300044, Taiwan, ROC.
Exp Mol Pathol. 2024 Dec;140:104946. doi: 10.1016/j.yexmp.2024.104946. Epub 2024 Nov 29.
During the COVID-19 pandemic, the viral illness caused by SARS-CoV-2 spread through respiratory droplets, resulting in a global pandemic with a range of symptoms from mild to severe. Pathological inflammation posed a critical issue, yet the genetic mechanisms behind the excessive activation of inflammatory responses remained unclear. To uncover the genetic and regulatory basis of the pathogenesis, we first explored possible genetic mechanisms from phenome-wide association studies (PWAS) with different severity levels of COVID-19. PWAS is a genetic research approach that identifies pleiotropic risk variants that contribute to elucidating potential physiological mechanisms from different traits.
We used the PWAS approach to link the multiple clinical symptoms to the variants. We discovered a common variant, rs2109069, in dipeptidyl peptidase 9 (DPP9), which relates to the elevated odds ratio of developing severe illness from COVID-19. Interestingly, the proxy of rs2109069 has been identified as the susceptible locus of interstitial lung disease (ILD) and idiopathic pulmonary fibrosis (IPF). We thus examined the DPP9 expression patterns in selected organs, including the lungs, blood vessels, and skin.
In silico analysis revealed conserved driver activation between COVID-19-induced inflammation and the association with ILD and IPF. Multi-omics analysis further verified the association of DPP9 with abnormal inflammatory responses in COVID-19. Lastly, gene homology analysis inferred a potential regulatory role of DPP9 in inhibiting inflammasome activation, which suggests that DPP9 deficiency may exacerbate inflammation observed in some COVID-19 patients.
Our in silico findings reveal that severe COVID-19 inflammatory responses and inflammatory lung diseases share the same genetic risk loci, helping to elucidate the underlying physiological mechanisms of severe COVID-19 inflammation. Additionally, the individual differences in immune sensitivity may contribute to the varying multi-organ inflammatory effects among patients. The rs2109069 of DPP9 could be a genetic marker to predict the risk of specific COVID-19 symptoms and severity.
在新冠疫情期间，由严重急性呼吸综合征冠状病毒2（SARS-CoV-2）引起的病毒性疾病通过呼吸道飞沫传播，导致了一场全球大流行，出现了一系列从轻度到重度的症状。病理性炎症是一个关键问题，然而炎症反应过度激活背后的遗传机制仍不清楚。为了揭示发病机制的遗传和调控基础，我们首先从针对不同严重程度的新冠病毒病（COVID-19）的全表型组关联研究（PWAS）中探索可能的遗传机制。PWAS是一种遗传研究方法，可识别多效性风险变异，有助于从不同性状阐明潜在的生理机制。
我们使用PWAS方法将多种临床症状与变异联系起来。我们在二肽基肽酶9（DPP9）中发现了一个常见变异rs2109069，它与COVID-19发展为重症的比值比升高有关。有趣的是，rs2109069的替代标记已被确定为间质性肺疾病（ILD）和特发性肺纤维化（IPF）的易感位点。因此，我们检查了DPP9在包括肺、血管和皮肤在内的选定器官中的表达模式。
生物信息学分析揭示了COVID-19诱导的炎症与ILD和IPF关联之间保守的驱动因子激活。多组学分析进一步验证了DPP9与COVID-19中异常炎症反应的关联。最后，基因同源性分析推断DPP9在抑制炎性小体激活方面具有潜在调控作用，这表明DPP9缺乏可能会加剧一些COVID-19患者中观察到的炎症。
我们的生物信息学研究结果表明，重症COVID-19炎症反应和炎性肺病共享相同的遗传风险位点，有助于阐明重症COVID-19炎症的潜在生理机制。此外，免疫敏感性的个体差异可能导致患者之间多器官炎症效应的差异。DPP9的rs2109069可能是预测特定COVID-19症状和严重程度风险的遗传标记。
