In Silico analysis unveils rs2109069 of DPP9 as a potential catalyst for COVID-19 severity and risk of inflammatory symptoms
Background: 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 activat...
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Elsevier
2024-12-01
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| Series: | Experimental and Molecular Pathology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0014480024000662 |
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| author | Chi-Ying Lee Zih-Yin Lai Yung-Jen Chuang |
| author_facet | Chi-Ying Lee Zih-Yin Lai Yung-Jen Chuang |
| author_sort | Chi-Ying Lee |
| collection | DOAJ |
| description | Background: 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. Methods: 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. Results: 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. Conclusions: 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. |
| format | Article |
| id | doaj-art-008c6f16a16a4e02b77289f24ead0747 |
| institution | OA Journals |
| issn | 1096-0945 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Experimental and Molecular Pathology |
| spelling | doaj-art-008c6f16a16a4e02b77289f24ead07472025-08-20T02:37:05ZengElsevierExperimental and Molecular Pathology1096-09452024-12-0114010494610.1016/j.yexmp.2024.104946In Silico analysis unveils rs2109069 of DPP9 as a potential catalyst for COVID-19 severity and risk of inflammatory symptomsChi-Ying Lee0Zih-Yin Lai1Yung-Jen Chuang2School of Medicine, National Tsing Hua University, Hsinchu 300044, Taiwan, ROC; Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu 300044, Taiwan, ROCSchool of Medicine, National Tsing Hua University, Hsinchu 300044, Taiwan, ROC; Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu 300044, Taiwan, ROCSchool of Medicine, National Tsing Hua University, Hsinchu 300044, Taiwan, ROC; Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu 300044, Taiwan, ROC; Corresponding author at: School of Medicine, National Tsing Hua University, 101 Section 2, Kuang-Fu Road, Hsinchu 300044, Taiwan, ROC.Background: 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. Methods: 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. Results: 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. Conclusions: 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.http://www.sciencedirect.com/science/article/pii/S0014480024000662Covid-19Immune responsesOmics global analysesGenetic risk lociDPP9 variant |
| spellingShingle | Chi-Ying Lee Zih-Yin Lai Yung-Jen Chuang In Silico analysis unveils rs2109069 of DPP9 as a potential catalyst for COVID-19 severity and risk of inflammatory symptoms Experimental and Molecular Pathology Covid-19 Immune responses Omics global analyses Genetic risk loci DPP9 variant |
| title | In Silico analysis unveils rs2109069 of DPP9 as a potential catalyst for COVID-19 severity and risk of inflammatory symptoms |
| title_full | In Silico analysis unveils rs2109069 of DPP9 as a potential catalyst for COVID-19 severity and risk of inflammatory symptoms |
| title_fullStr | In Silico analysis unveils rs2109069 of DPP9 as a potential catalyst for COVID-19 severity and risk of inflammatory symptoms |
| title_full_unstemmed | In Silico analysis unveils rs2109069 of DPP9 as a potential catalyst for COVID-19 severity and risk of inflammatory symptoms |
| title_short | In Silico analysis unveils rs2109069 of DPP9 as a potential catalyst for COVID-19 severity and risk of inflammatory symptoms |
| title_sort | in silico analysis unveils rs2109069 of dpp9 as a potential catalyst for covid 19 severity and risk of inflammatory symptoms |
| topic | Covid-19 Immune responses Omics global analyses Genetic risk loci DPP9 variant |
| url | http://www.sciencedirect.com/science/article/pii/S0014480024000662 |
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