Beaty T H, Kwiterovich P O, Khoury M J, White S, Bachorik P S, Smith H H, Teng B, Sniderman A
Am J Hum Genet. 1986 Apr;38(4):492-504.
We previously reported the finding of phytosterolemia, xanthomatosis, and hyperapobetalipoproteinemia (hyperapoB) in five siblings in a large Amish pedigree ascertained through a 13-year-old boy who died suddenly from advanced coronary atherosclerosis. Here, we present further analyses of the plasma levels of the plant sterol, sitosterol, of low density (beta) lipoprotein (LDL) sterol, and of LDL B protein. Of 254 relatives and spouses of the proband, 90.5% were examined. A series of genetic models were explored using a pedigree analysis where parameters reflecting frequency, transmission, and penetrance of putative genotypes were examined simultaneously using a maximum likelihood approach. Segregation analysis of the sitosterol levels showed that the phenotype of sitosterolemia was controlled by a rare autosomal recessive gene. There was also significant familial correlation in plasma sitosterol levels that was attributed to a polygenic component under a mixed model but could also be due to shared environments such as diets. The recessive model was supported by our finding that the plasma sitosterol levels in the parents and in six children born to three of the five sitosterolemics were less than 1 mg/dl, well within the normal range. The phenotype of hyperapoB is based on an elevated level of LDL B protein in the presence of a normal LDL cholesterol level (low LDL sterol to LDL B ratio). For both LDL sterol and LDL B, a polygenic model showed a slightly greater improvement in ln likelihood than did the Mendelian single locus model when both were compared to a sporadic model. Similar results were obtained for sterol levels of high density (alpha) lipoprotein (HDL) sterol. When segregation analysis was performed using the ratio of LDL sterol to LDL B, the Mendelian single locus model gave a slightly better fit to the data than did the polygenic model. While the analyses presented here provided unequivocal evidence for the recessive phenotype of phytosterolemia, we also identified a possible single gene factor that could account for the major portion of the strong familial aggregation in the ratio of LDL sterol to LDL B, and to a lesser extent LDL B. However, there is clear evidence of familial aggregation for these traits in this pedigree beyond that due to Mendelian components.
我们之前报道过，在一个阿米什大家族中，通过一名因晚期冠状动脉粥样硬化突然死亡的13岁男孩确定了五名兄弟姐妹患有植物甾醇血症、黄瘤病和高载脂蛋白B血症（高apoB）。在此，我们进一步分析了植物甾醇、谷甾醇、低密度（β）脂蛋白（LDL）甾醇以及LDL B蛋白的血浆水平。在先证者的254名亲属和配偶中，90.5%接受了检查。使用系谱分析探索了一系列遗传模型，其中使用最大似然法同时检查反映假定基因型频率、传递和外显率的参数。谷甾醇水平的分离分析表明，植物甾醇血症的表型由一个罕见的常染色体隐性基因控制。血浆谷甾醇水平也存在显著的家族相关性，在混合模型下这归因于一个多基因成分，但也可能是由于饮食等共同环境因素。隐性模型得到了我们这一发现的支持，即五名植物甾醇血症患者中三名患者的父母及六个孩子的血浆谷甾醇水平低于1mg/dl，完全在正常范围内。高apoB的表型是基于在正常LDL胆固醇水平（低LDL甾醇与LDL B比值）下LDL B蛋白水平升高。对于LDL甾醇和LDL B，与散发性模型相比，多基因模型在对数似然度上的改善略大于孟德尔单基因座模型。高密度（α）脂蛋白（HDL）甾醇的甾醇水平也得到了类似结果。当使用LDL甾醇与LDL B的比值进行分离分析时，孟德尔单基因座模型对数据的拟合略优于多基因模型。虽然此处的分析为植物甾醇血症的隐性表型提供了明确证据，但我们也确定了一个可能的单基因因素，该因素可能是LDL甾醇与LDL B比值以及程度较轻的LDL B中强烈家族聚集的主要部分原因。然而，在这个家系中，这些性状存在明显的家族聚集证据，超出了孟德尔成分所导致的范围。
