OBJECTIVE STAP1, encoding for STAP1 (signal transducing adaptor family member 1), has been reported as a candidate gene associated with familial hypercholesterolemia. Unlike established familial hypercholesterolemia genes, expression of STAP1 is absent in liver but mainly observed in immune cells. In this study, we set out to validate STAP1 as a familial hypercholesterolemia gene. Approach and Results: A whole-body Stap1 knockout mouse model (Stap1-/-) was generated and characterized, without showing changes in plasma lipid levels compared with controls. In follow-up studies, bone marrow from Stap1-/- mice was transplanted to Ldlr-/- mice, which did not show significant changes in plasma lipid levels or atherosclerotic lesions. To functionally assess whether STAP1 expression in B cells can affect hepatic function, HepG2 cells were cocultured with peripheral blood mononuclear cells isolated from heterozygotes carriers of STAP1 variants and controls. The peripheral blood mononuclear cells from STAP1 variant carriers and controls showed similar LDLR mRNA and protein levels. Also, LDL (low-density lipoprotein) uptake by HepG2 cells did not differ upon coculturing with peripheral blood mononuclear cells isolated from either STAP1 variant carriers or controls. In addition, plasma lipid profiles of 39 carriers and 71 family controls showed no differences in plasma LDL cholesterol, HDL (high-density lipoprotein) cholesterol, triglycerides, and lipoprotein(a) levels. Similarly, B-cell populations did not differ in a group of 10 STAP1 variant carriers and 10 age- and sex-matched controls. Furthermore, recent data from UK Biobank do not show association between STAP1 rare gene variants and LDL cholesterol. CONCLUSIONS Our combined studies in mouse models and carriers of STAP1 variants indicate that STAP1 is not a familial hypercholesterolemia gene.

中文翻译：

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在家族性高胆固醇血症中退一步：STAP1不会改变小鼠和人类血浆LDL（低密度脂蛋白）胆固醇。

目的STAP1，编码STAP1（信号转导衔接子家族成员1）的编码，是与家族性高胆固醇血症相关的候选基因。与已建立的家族性高胆固醇血症基因不同，STAP1的表达在肝脏中不存在，但主要在免疫细胞中观察到。在这项研究中，我们着手验证STAP1是家族性高胆固醇血症基因。方法和结果：生成并表征了全身Stap1基因敲除小鼠模型（Stap1-/-），与对照组相比，血浆脂质水平没有变化。在后续研究中，将来自Stap1-/-小鼠的骨髓移植至Ldlr-/-小鼠，其血浆脂质水平或动脉粥样硬化病变未见明显变化。为了从功能上评估B细胞中STAP1的表达是否会影响肝功能，HepG2细胞与从STAP1变体和对照的杂合子载体分离的外周血单个核细胞共培养。来自STAP1变异载体和对照的外周血单核细胞显示相似的LDLR mRNA和蛋白质水平。此外，HepG2细胞对LDL（低密度脂蛋白）的摄取与从STAP1变异载体或对照中分离的外周血单个核细胞共培养时也没有差异。此外，39个携带者和71个家庭对照的血浆脂质谱显示血浆LDL胆固醇，HDL（高密度脂蛋白）胆固醇，甘油三酸酯和脂蛋白（a）水平无差异。同样，在10个STAP1变异携带者和10个年龄和性别匹配的对照组中，B细胞群体也没有差异。此外，UK Biobank的最新数据未显示STAP1稀有基因变异与LDL胆固醇之间的关联。结论我们在小鼠模型和STAP1变异携带者中的联合研究表明STAP1不是家族性高胆固醇血症基因。