Role of the Autism Risk Gene <i>Shank3</i> in the Development of Atherosclerosis: Insights from Big Data and Mechanistic Analyses
Increased medical attention is needed as the prevalence of autism spectrum disorder (ASD) rises. Both cardiovascular disorder (CVD) and hyperlipidemia are closely associated with adult ASD. <i>Shank3</i> plays a key genetic role in ASD. We hypothesized that Shank3 contributes to CVD deve...
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| Format: | Article |
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MDPI AG
2023-10-01
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| Online Access: | https://www.mdpi.com/2073-4409/12/21/2546 |
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| author | Hsiu-Wen Chang Ming-Jen Hsu Li-Nien Chien Nai-Fang Chi Meng-Chieh Yu Hsiu-Chen Chen Yuan-Feng Lin Chaur-Jong Hu |
| author_facet | Hsiu-Wen Chang Ming-Jen Hsu Li-Nien Chien Nai-Fang Chi Meng-Chieh Yu Hsiu-Chen Chen Yuan-Feng Lin Chaur-Jong Hu |
| author_sort | Hsiu-Wen Chang |
| collection | DOAJ |
| description | Increased medical attention is needed as the prevalence of autism spectrum disorder (ASD) rises. Both cardiovascular disorder (CVD) and hyperlipidemia are closely associated with adult ASD. <i>Shank3</i> plays a key genetic role in ASD. We hypothesized that Shank3 contributes to CVD development in young adults with ASD. In this study, we investigated whether Shank3 facilitates the development of atherosclerosis. Using Gene Set Enrichment Analysis software (Version No.: GSEA-4.0.3), we analyzed the data obtained from <i>Shank3</i> knockout mice (Gene Expression Omnibus database), a human population-based study cohort (from Taiwan’s National Health Insurance Research Database), and a <i>Shank3</i> knockdown cellular model. <i>Shank3</i> knockout upregulated the expression of genes of cholesterol homeostasis and fatty acid metabolism but downregulated the expression of genes associated with inflammatory responses. Individuals with autism had higher risks of hyperlipidemia (adjusted hazard ratio (aHR): 1.39; <i>p</i> < 0.001), major adverse cardiac events (aHR: 2.67; <i>p</i> < 0.001), and stroke (aHR: 3.55; <i>p</i> < 0.001) than age- and sex-matched individuals without autism did. Shank3 downregulation suppressed tumor necrosis factor-α-induced fatty acid synthase expression; vascular cell adhesion molecule 1 expression; and downstream signaling pathways involving p38, Jun N-terminal kinase, and nuclear factor-κB. Thus, Shank3 may influence the development of early-onset atherosclerosis and CVD in ASD. Furthermore, regulating Shank3 expression may reduce inflammation-related disorders, such as atherosclerosis, by inhibiting tumor necrosis factor-alpha-mediated inflammatory cascades. |
| first_indexed | 2024-03-11T11:33:03Z |
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| language | English |
| last_indexed | 2024-03-11T11:33:03Z |
| publishDate | 2023-10-01 |
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| series | Cells |
| spelling | doaj.art-d574d3b48c1e4affbb26ad9726fecb552023-11-10T15:00:43ZengMDPI AGCells2073-44092023-10-011221254610.3390/cells12212546Role of the Autism Risk Gene <i>Shank3</i> in the Development of Atherosclerosis: Insights from Big Data and Mechanistic AnalysesHsiu-Wen Chang0Ming-Jen Hsu1Li-Nien Chien2Nai-Fang Chi3Meng-Chieh Yu4Hsiu-Chen Chen5Yuan-Feng Lin6Chaur-Jong Hu7Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, TaiwanGraduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, TaiwanInstitute of Health and Welfare Policy, National Yang Ming Chiao Tung University, Taipei 11221, TaiwanDepartment of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei 11267, TaiwanDepartment of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, TaiwanDepartment of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, TaiwanGraduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, TaiwanDepartment of Neurology, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, TaiwanIncreased medical attention is needed as the prevalence of autism spectrum disorder (ASD) rises. Both cardiovascular disorder (CVD) and hyperlipidemia are closely associated with adult ASD. <i>Shank3</i> plays a key genetic role in ASD. We hypothesized that Shank3 contributes to CVD development in young adults with ASD. In this study, we investigated whether Shank3 facilitates the development of atherosclerosis. Using Gene Set Enrichment Analysis software (Version No.: GSEA-4.0.3), we analyzed the data obtained from <i>Shank3</i> knockout mice (Gene Expression Omnibus database), a human population-based study cohort (from Taiwan’s National Health Insurance Research Database), and a <i>Shank3</i> knockdown cellular model. <i>Shank3</i> knockout upregulated the expression of genes of cholesterol homeostasis and fatty acid metabolism but downregulated the expression of genes associated with inflammatory responses. Individuals with autism had higher risks of hyperlipidemia (adjusted hazard ratio (aHR): 1.39; <i>p</i> < 0.001), major adverse cardiac events (aHR: 2.67; <i>p</i> < 0.001), and stroke (aHR: 3.55; <i>p</i> < 0.001) than age- and sex-matched individuals without autism did. Shank3 downregulation suppressed tumor necrosis factor-α-induced fatty acid synthase expression; vascular cell adhesion molecule 1 expression; and downstream signaling pathways involving p38, Jun N-terminal kinase, and nuclear factor-κB. Thus, Shank3 may influence the development of early-onset atherosclerosis and CVD in ASD. Furthermore, regulating Shank3 expression may reduce inflammation-related disorders, such as atherosclerosis, by inhibiting tumor necrosis factor-alpha-mediated inflammatory cascades.https://www.mdpi.com/2073-4409/12/21/2546<i>Shank3</i>autism spectrum disorderatherosclerosislipid metabolisminflammationcardiovascular disorder |
| spellingShingle | Hsiu-Wen Chang Ming-Jen Hsu Li-Nien Chien Nai-Fang Chi Meng-Chieh Yu Hsiu-Chen Chen Yuan-Feng Lin Chaur-Jong Hu Role of the Autism Risk Gene <i>Shank3</i> in the Development of Atherosclerosis: Insights from Big Data and Mechanistic Analyses Cells <i>Shank3</i> autism spectrum disorder atherosclerosis lipid metabolism inflammation cardiovascular disorder |
| title | Role of the Autism Risk Gene <i>Shank3</i> in the Development of Atherosclerosis: Insights from Big Data and Mechanistic Analyses |
| title_full | Role of the Autism Risk Gene <i>Shank3</i> in the Development of Atherosclerosis: Insights from Big Data and Mechanistic Analyses |
| title_fullStr | Role of the Autism Risk Gene <i>Shank3</i> in the Development of Atherosclerosis: Insights from Big Data and Mechanistic Analyses |
| title_full_unstemmed | Role of the Autism Risk Gene <i>Shank3</i> in the Development of Atherosclerosis: Insights from Big Data and Mechanistic Analyses |
| title_short | Role of the Autism Risk Gene <i>Shank3</i> in the Development of Atherosclerosis: Insights from Big Data and Mechanistic Analyses |
| title_sort | role of the autism risk gene i shank3 i in the development of atherosclerosis insights from big data and mechanistic analyses |
| topic | <i>Shank3</i> autism spectrum disorder atherosclerosis lipid metabolism inflammation cardiovascular disorder |
| url | https://www.mdpi.com/2073-4409/12/21/2546 |
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