Background: Pathological remodelling of native vascular smooth muscle cells (VSMC) within the arterial wall is a key contributor to vascular disease. A driver of this remodelling is platelet-derived growth factor BB (PDGF-BB) and its signalling via activation of the calcium ion channel, ORAI1. Here, we investigated if there are associations of ORAI1 polymorphisms with human cardiovascular disease. Methods and results: We conducted candidate gene association analysis and revealed that a missense ORAI1 variant (rs3741596, S218G) associates with an increased risk of hospital-diagnosed peripheral vascular disease, generalised atherosclerosis, acute ischaemic heart disease, and atrioventricular and left bundle-branch block in White British UK Biobank participants. Rs3741596 is also associated with higher circulating platelet counts and reduced total triglyceride levels. Functional analysis of the effects of rs3741596 S218G variant on ORAI1 channel function, via introduction of the S218G ORAI1 variant in HEK293 cells using CRISPR/Cas9 and investigation of its effects on SOCE, showed significantly enhanced SOCE compared to wild type cells, suggesting that the S218G variant enhances ORAI1 function. Conclusions: Our results reveal an association between an ORAI1 missense variant and occlusive vascular diseases. These findings provide a novel insight into the role of ORAI1 in vascular remodelling and highlight its potential as a treatment target for vascular pathologies.

中文翻译：

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一种罕见的 ORAI1 错义变异与英国白人成年人患血管疾病的风险相关

背景：动脉壁内天然血管平滑肌细胞（VSMC）的病理重塑是血管疾病的关键因素。这种重塑的驱动因素是血小板衍生生长因子 BB (PDGF-BB) 及其通过激活钙离子通道 ORAI1 发出的信号。在这里，我们研究了 ORAI1 多态性是否与人类心血管疾病存在关联。方法和结果：我们进行了候选基因关联分析，发现错义 ORAI1 变异（rs3741596，S218G）与医院诊断的外周血管疾病、全身动脉粥样硬化、急性缺血性心脏病以及房室和左束支的风险增加相关阻止英国白人生物银行参与者。 Rs3741596 还与较高的循环血小板计数和降低的总甘油三酯水平相关。通过使用 CRISPR/Cas9 在 HEK293 细胞中引入 S218G ORAI1 变体并研究其对 SOCE 的影响，对 rs3741596 S218G 变体对 ORAI1 通道功能的影响进行功能分析，结果显示与野生型细胞相比，SOCE 显着增强，这表明 S218G变体增强了 ORAI1 功能。结论：我们的结果揭示了 ORAI1 错义变异与闭塞性血管疾病之间的关联。这些发现为 ORAI1 在血管重塑中的作用提供了新的见解，并强调了其作为血管病理治疗靶点的潜力。