de Graaf J, Swinkels D W, de Haan A F, Demacker P N, Stalenhoef A F
Department of Medicine, University Hospital, Nijmegen, The Netherlands.
Am J Hum Genet. 1992 Dec;51(6):1295-310.
A lipoprotein profile characterized by a predominance of small, dense, low-density lipoprotein (LDL) particles has been associated with an increased risk of atherosclerosis. To investigate whether genetic factors are involved in determining this heavy LDL subfraction pattern, this study was undertaken with the aim of resolving the effects that major genes, multifactorial heritability, and environmental exposures have on the LDL subfraction pattern. In a random sample of 19 healthy Dutch families including 162 individuals, the distribution of the LDL subfraction pattern was determined by density gradient ultracentrifugation. For each subject a specific LDL subfraction profile was observed, characterized by the relative contribution of the three major LDL subfractions--LDL1 (d = 1.030-1.033 g/ml), LDL2 (d = 1.033-1.040 g/ml), and LDL3 (d = 1.040-1.045 g/ml)--to total LDL. A continuous variable, parameter K, was defined to characterize each individual LDL subfraction pattern. Complex segregation analysis of this quantitative trait, under a model which includes a major locus, polygenes, and both common and random environment, was applied to analyze the distribution of the LDL subfraction pattern in these families. The results indicate that the LDL subfraction pattern, described by parameter K, is controlled by a major autosomal, highly penetrant, recessive allele with a population frequency of .19 and an additional multifactorial inheritance component. The penetrance of the more dense LDL subfraction patterns, characterized by values of K < 0, was dependent on age, gender, and, in women, on oral contraceptive use and postmenopausal status. Furthermore, multiple regression analysis revealed that approximately 60% of the variation in the LDL subfraction pattern could be accounted for by alterations in age, gender, relative body weight, smoking habits, hormonal status in women, and lipid and lipoprotein levels. In conclusion, our results indicate that genetic influences as well as environmental exposure, sex, age and hormonal status in women are important in determining the distribution of the LDL subfraction patterns in this population and that these influences may contribute to the explanation of familial clustering of coronary heart disease.
以小而密的低密度脂蛋白（LDL）颗粒占优势为特征的脂蛋白谱与动脉粥样硬化风险增加相关。为了研究遗传因素是否参与决定这种重度LDL亚组分模式，开展了本研究，目的是解析主要基因、多因子遗传力和环境暴露对LDL亚组分模式的影响。在一个包含162名个体的19个健康荷兰家庭的随机样本中，通过密度梯度超速离心法确定LDL亚组分模式的分布。对每个受试者观察到一种特定的LDL亚组分谱，其特征在于三种主要LDL亚组分——LDL1（d = 1.030 - 1.033 g/ml）、LDL2（d = 1.033 - 1.040 g/ml）和LDL3（d = 1.040 - 1.045 g/ml）——对总LDL的相对贡献。定义了一个连续变量参数K来表征每个个体的LDL亚组分模式。在一个包括一个主基因座、多基因以及共同和随机环境的模型下，对该数量性状进行复杂分离分析，以分析这些家庭中LDL亚组分模式的分布。结果表明，由参数K描述的LDL亚组分模式由一个常染色体上的、高度显性的隐性等位基因控制，群体频率为0.19，并且还有一个额外的多因子遗传成分。以K < 0值为特征的更致密LDL亚组分模式的显性取决于年龄、性别，在女性中还取决于口服避孕药的使用情况和绝经后状态。此外，多元回归分析显示，LDL亚组分模式中约60%的变异可由年龄、性别、相对体重、吸烟习惯、女性激素状态以及脂质和脂蛋白水平的改变来解释。总之，我们的结果表明，遗传影响以及环境暴露、性别、年龄和女性激素状态在决定该人群中LDL亚组分模式的分布方面很重要，并且这些影响可能有助于解释冠心病的家族聚集现象。
