We previously identified a highly consanguineous familial hypercholesterolemia (FH) family demonstrating segregation of the JD Bari mutation in the LDL receptor as well as a putative cholesterol-lowering trait. We aimed to identify genes related to the latter effect. LDL cholesterol (LDLc) values were normalized for FH affectation status, age, and gender. Using genome-wide SNP data, we examined whether known SNPs gleaned from a genome-wide association study could explain the variation observed in LDLc. Four individuals with markedly reduced LDL levels underwent whole exome sequencing. After prioritizing all potential mutations, we identified the most promising candidate genes and tested them for segregation with the lowering trait. We transfected a plasmid carrying the top candidate mutation, microsomal triglyceride transfer protein (MTTP) R634C, into COS-7 cells to test enzymatic activity. The SNP score explained 3% of the observed variability. MTTP R634C showed reduced activity (49.1 nmol/ml) compared with the WT allele (185.8 nmol/ml) (P = 0.0012) and was marginally associated with reduced LDLc in FH patients (P = 0.05). Phenotypic variability in a FH pedigree can only partially be explained by a combination of common SNPs and a rare mutation and a rare variant in the MTTP gene. LDLc variability in FH patients may have nongenetic causes.

中文翻译：

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为了寻找FH家族LDLc变异的遗传学解释：常见的SNP和MTTP中的罕见突变仅解释了FH家族LDL变异的一部分。

我们先前确定了一个高度血缘的家族性高胆固醇血症（FH）家族，该家族表现出LDL受体中JD Bari突变的分离以及推定的降低胆固醇的特征。我们旨在鉴定与后一种效应有关的基因。将LDL胆固醇（LDLc）值针对FH感染状态，年龄和性别进行了标准化。使用全基因组SNP数据，我们检查了从全基因组关联研究中收集到的已知SNP是否可以解释LDLc中观察到的变异。LDL水平明显降低的四个人接受了完整的外显子组测序。在对所有潜在突变进行优先排序后，我们确定了最有前途的候选基因，并测试了它们的分离性和降低的性状。我们转染了带有最高候选突变的质粒，即微粒体甘油三酸酯转移蛋白（将MTTP）R634C注入COS-7细胞以测试酶活性。SNP得分解释了观察到的变异性的3％。与WT等位基因（185.8 nmol / ml）相比，MTTP R634C的活性降低（49.1 nmol / ml）（P = 0.0012），与FH患者的LDLc降低相关（P = 0.05）。FH系谱中的表型变异性只能通过共同的SNP和MTTP基因中的罕见突变和罕见变体的组合来部分解释。FH患者的LDLc变异可能是非遗传原因。