血清脂蛋白的遗传和环境变异与冠心病的关系

Robertson F W, Cumming A M

J Med Genet. 1979 Apr;16(2):85-100. doi: 10.1136/jmg.16.2.85.

Variation in the serum concentration of VLDL, IDL, LDL, and HDL was studied in (a) 192 survivors of myocardial infarction under the age of 50 living in the north-east of Scotland; (b) 250 relatives, mostly first degree; and (c) 259 unrelated individuals, comprising mostly spouses and their relatives. The biochemical characterisation of the lipids, which were separated by preparative ultracentrifugation, included (a) determination of total serum cholesterol and triglyceride; and (b) determination of the content of cholesterol in the four fractions, and also of triglyceride in the VLDL fraction. In male survivors of infarction there is a significant negative regression of VLDL and a significant positive regression of HDL on peak aspartate aminotransferase activity in blood samples taken within 24 hours of the incident. In later samples correlations were not evident. Serum lipoprotein concentrations have been compared in samples taken at different times after the incident. The average value of samples taken within 24 hours is similar to the mean scores for LDL and VLDL of repeat samples taken, on average, 9 months later. The incidence of hyperlipidaemia in samples taken within 24 hours of the infarction is about the same for total cholesterol and triglyceride and LDL or VLDL. Respectively, 18·3%, 16·1%, and 7·5% of the survivors exceed the 90th centile value for either LDL, VLDL, or both fractions, while, for the 95th centile limit, the corresponding figures are 8·6%, 9·7%, and 2·2%. In samples taken within 24 hours of the incident, the LDL concentration is, on average, 20 to 30% higher, and the VLDL concentration 50 to 60% higher, than the controls. The corresponding HDL difference in males, though negative, is trivial and statistically insignificant, but in females the difference is greater and significantly so. VLDL levels are substantially increased in regular cigarette smokers in both sexes, especially in males. HDL levels tend to be lower, though not significantly so. The frequency of persons who are or have been regular cigarette smokers is higher in index cases than in controls. Correlation analysis of individual variation of controls and index case relatives indicates a substantial level of independence between the major lipoprotein fractions. There is no correlation between LDL and HDL. There are positive correlations between VLDL, IDL, and LDL, though when IDL is held constant by multiple regression, the correlation between VLDL and LDL is removed. There is a low but consistent negative correlation between VLDL and HDL cholesterol. About a quarter of the variance of VLDL in males is accounted for by multiple regression on measures of body fatness, that is, relative weight and subscapular skinfold thickness. In females only about 10% of the variance is thus accounted for, and only in males do LDL levels show correlated changes with fatness. There are no significant differences for either relative body weight or subscapular skinfold thickness between the means of first degree relatives of survivors of infarction and controls. The concentrations of VLDL and LDL in first degree relatives of survivors of infarction are significantly higher than the control means. HDL shows no significant difference. The evidence for genetic variation in serum lipoprotein is based on the polygenic model and the analysis of the correlation between parents and offspring and the correlation between sibs. From the pooled regression on single parents, heritabilities for HDL, LDL, and VLDL work out at 0·67 ± 0·21, 0·36 ± 0·18, and 0·23 ± 0.20, respectively. The lower heritability of VLDL is consistent with the variance of repeat measurements on the same control individuals, which is much higher for VLDL than for LDL or HDL. The high correlation between VLDL and measures of fatness, for which heritability estimates are statistically insignificant, as well as the association between raised VLDL concentration and smoking, also provide confirmatory evidence of the major importance of non-genetic causes in the variation of VLDL. The results are discussed in relation to the origin of the effects of smoking, variation in proneness to coronary disease, and the biological significance of differences in HDL concentration.

对以下人群的极低密度脂蛋白（VLDL）、中间密度脂蛋白（IDL）、低密度脂蛋白（LDL）和高密度脂蛋白（HDL）的血清浓度变化进行了研究：（a）192名年龄在50岁以下、居住在苏格兰东北部的心肌梗死幸存者；（b）250名亲属，大多为一级亲属；（c）259名无亲属关系的个体，主要包括配偶及其亲属。通过制备性超速离心分离出的脂质进行生化特性分析，包括：（a）测定血清总胆固醇和甘油三酯；（b）测定四个组分中的胆固醇含量，以及VLDL组分中的甘油三酯含量。在梗死男性幸存者中，在事件发生后24小时内采集的血样中，VLDL呈显著负回归，HDL呈显著正回归，与峰值天冬氨酸转氨酶活性相关。在后续样本中，相关性不明显。对事件发生后不同时间采集的样本中的血清脂蛋白浓度进行了比较。在24小时内采集的样本的平均值与平均9个月后采集的重复样本中LDL和VLDL的平均分数相似。梗死发生后24小时内采集的样本中，总胆固醇、甘油三酯以及LDL或VLDL的高脂血症发生率大致相同。分别有18.3%、16.1%和7.5%的幸存者的LDL、VLDL或两者的分数超过第90百分位数，而对于第95百分位数界限，相应数字分别为8.6%、9.7%和2.2%。在事件发生后24小时内采集的样本中，LDL浓度平均比对照组高20%至30%，VLDL浓度高50%至60%。男性中相应的HDL差异虽为负值，但微不足道且无统计学意义，而女性中的差异更大且具有统计学意义。男女中经常吸烟的人，VLDL水平均显著升高，尤其是男性。HDL水平往往较低，但无显著差异。指数病例中经常吸烟或曾经吸烟的人的频率高于对照组。对对照组和指数病例亲属个体差异的相关分析表明，主要脂蛋白组分之间存在相当程度的独立性。LDL与HDL之间无相关性。VLDL、IDL和LDL之间存在正相关，不过当通过多元回归使IDL保持恒定时，VLDL与LDL之间的相关性消失。VLDL与HDL胆固醇之间存在低但一致的负相关。男性中约四分之一的VLDL变异可通过对身体肥胖指标（即相对体重和肩胛下皮褶厚度）的多元回归来解释。女性中只有约10%的变异可由此解释，且只有男性的LDL水平显示出与肥胖相关的变化。梗死幸存者的一级亲属与对照组的相对体重或肩胛下皮褶厚度的平均值之间无显著差异。梗死幸存者的一级亲属中VLDL和LDL的浓度显著高于对照组平均值。HDL无显著差异。血清脂蛋白遗传变异的证据基于多基因模型以及对父母与后代之间的相关性和同胞之间的相关性的分析。根据对单亲的合并回归，HDL、LDL和VLDL的遗传力分别为0.67±0.21、0.36±0.18和0.23±0.20。VLDL较低的遗传力与对同一对照个体的重复测量的变异一致，VLDL的变异远高于LDL或HDL。VLDL与肥胖指标之间的高相关性（其遗传力估计无统计学意义）以及VLDL浓度升高与吸烟之间的关联，也提供了非遗传因素在VLDL变异中起主要作用的确证。结合吸烟的影响来源、冠心病易感性的差异以及HDL浓度差异的生物学意义对结果进行了讨论。