随着自闭症谱系障碍 (ASD) 患病率的上升，需要更多的医疗关注。心血管疾病（CVD）和高脂血症都与成人自闭症谱系障碍（ASD）密切相关。 Shank3 在 ASD 中发挥着关键的遗传作用。我们假设 Shank3 有助于患有 ASD 的年轻人的 CVD 发展。在这项研究中，我们研究了 Shank3 是否促进动脉粥样硬化的发展。使用基因集富集分析软件（版本号：GSEA-4.0.3），我们分析了从 Shank3 敲除小鼠（基因表达综合数据库）获得的数据，这是一个基于人群的研究队列（来自台湾国家健康保险研究数据库） ，以及 Shank3 敲除细胞模型。 Shank3敲除上调了胆固醇稳态和脂肪酸代谢基因的表达，但下调了与炎症反应相关的基因的表达。与年龄相比，自闭症患者发生高脂血症（调整后风险比 (aHR)：1.39；p < 0.001）、主要不良心脏事件（aHR：2.67；p < 0.001）和中风（aHR：3.55；p < 0.001）的风险更高- 性别匹配的没有自闭症的人也这么做了。 Shank3下调抑制肿瘤坏死因子-α诱导的脂肪酸合酶表达；血管细胞粘附分子1的表达;以及涉及 p38、Jun N 末端激酶和核因子-κB 的下游信号通路。因此，Shank3 可能影响 ASD 中早发性动脉粥样硬化和 CVD 的发展。此外，调节Shank3表达可以通过抑制肿瘤坏死因子-α介导的炎症级联反应来减少炎症相关疾病，例如动脉粥样硬化。

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. Shank3 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 Shank3 knockout mice (Gene Expression Omnibus database), a human population-based study cohort (from Taiwan's National Health Insurance Research Database), and a Shank3 knockdown cellular model. Shank3 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; p < 0.001), major adverse cardiac events (aHR: 2.67; p < 0.001), and stroke (aHR: 3.55; p < 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.