Goldstein J L, Schrott H G, Hazzard W R, Bierman E L, Motulsky A G
J Clin Invest. 1973 Jul;52(7):1544-68. doi: 10.1172/JCI107332.
To assess the genetics of hyperlipidemia in coronary heart disease, family studies were carried out in 2520 relatives and spouses of 176 survivors of myocardial infarction, including 149 hyperlipidemic and 27 normolipidemic individuals. The distribution of fasting plasma cholesterol and triglyceride values in relatives, together with segregation analyses, suggested the presence of five distinct lipid disorders. Three of these-familial hypercholesterolemia, familial hypertriglyceridemia, and familial combined hyperlipidemia-appeared to represent dominant expression of three different autosomal genes, occurring in about 20% of survivors below 60 yr of age and 7% of all older survivors. Two other disorders-polygenic hypercholesterolemia and sporadic hypertriglyceridemia-each affected about 6% of survivors in both age groups. The most common genetic form of hyperlipidemia identified in this study has hitherto been poorly defined and has been designated as familial combined hyperlipidemia. Affected family members characteristically had elevated levels of both cholesterol and triglyceride. However, increased cholesterol or increased triglyceride levels alone were also frequently observed. The combined disorder was shown to be genetically distinct from familial hypercholesterolemia and familial hypertriglyceridemia for the following reasons: (a) the distribution pattern of cholesterol and triglyceride levels in relatives of probands was unique; (b) children of individuals with combined hyperlipidemia did not express hypercholesterolemia in contrast to the finding of hypercholesterolemic children from families with familial hypercholesterolemia; and (c) analysis of informative matings suggested that the different lipid phenotypes owed their origin to variable expression of a single autosomal dominant gene and not to segregation of two separate genes, such as one elevating the level of cholesterol and the other elevating the level of triglyceride. Heterozygosity for one of the three lipid-elevating genes identified in this study may have a frequency in the general population of about 1%, constituting a major problem in early diagnosis and preventive therapy.
为评估冠心病中高脂血症的遗传学特征，对176例心肌梗死幸存者的2520名亲属及配偶进行了家系研究，其中包括149例高脂血症患者和27例血脂正常者。亲属中空腹血浆胆固醇和甘油三酯值的分布情况以及分离分析表明存在五种不同的脂质紊乱。其中三种——家族性高胆固醇血症、家族性高甘油三酯血症和家族性混合型高脂血症——似乎代表了三种不同常染色体基因的显性表达，在60岁以下的幸存者中约占20%，在所有老年幸存者中约占7%。另外两种紊乱——多基因高胆固醇血症和散发性高甘油三酯血症——在两个年龄组中各影响约6%的幸存者。本研究中确定的最常见的高脂血症遗传形式迄今定义尚不明确，被命名为家族性混合型高脂血症。受影响的家庭成员通常胆固醇和甘油三酯水平均升高。然而，也经常单独观察到胆固醇升高或甘油三酯水平升高的情况。这种混合型紊乱在遗传上与家族性高胆固醇血症和家族性高甘油三酯血症不同，原因如下：(a) 先证者亲属中胆固醇和甘油三酯水平的分布模式独特；(b) 与家族性高胆固醇血症家族中高胆固醇血症儿童的情况相反，混合型高脂血症患者的子女并未表现出高胆固醇血症；(c) 对有信息价值的交配分析表明，不同的脂质表型源于单个常染色体显性基因的可变表达，而非两个独立基因的分离，例如一个升高胆固醇水平，另一个升高甘油三酯水平。本研究中确定的三种脂质升高基因之一的杂合子在一般人群中的频率可能约为1%，这在早期诊断和预防性治疗中构成了一个主要问题。
