Rajput-Williams J, Knott T J, Wallis S C, Sweetnam P, Yarnell J, Cox N, Bell G I, Miller N E, Scott J
Division of Molecular Medicine, Medical Research Council Clinical Research Centre, Harrow, Middlesex.
Lancet. 1988;2(8626-8627):1442-6. doi: 10.1016/s0140-6736(88)90930-0.
A random sample of 290 white men was examined for association between restriction fragment length polymorphism (RFLP) haplotypes (closely linked RFLPs on a single chromosome) of the apolipoprotein-B gene and serum levels of cholesterol, triglyceride, and high-density lipoprotein, obesity, smoking, alcohol consumption, and coronary heart disease. Haplotype or single RFLP frequencies differed significantly for obesity (p less than 0.005), serum cholesterol (p less than 0.005), and coronary heart disease (p less than 0.05), but for no other variable. Obesity was associated with haplotypes involving minimum PvuII and XbaI RFLPs are likely to be in linkage disequilibrium with nearby functional variation predisposing to obesity. Significant variation in serum cholesterol levels was associated with three functional alleles defined by MspI and EcoRI RFLP pairs (p less than 0.03). These RFLPs correspond to charged aminoacid variants at positions 3611 (arginine to glutamine) and 4154 (glutamic acid to lysine), which lie near the low-density-lipoprotein (LDL) receptor binding region of apolipoprotein-B. The three alleles showed stratification of serum cholesterol between low, normal, and high levels. Coronary heart disease was associated with minimum haplotypes involving XbaI and MspI RFLPs. Together these results suggest that inherited variations of the apolipoprotein-B gene, probably in the form of charged aminoacid substitutions, influence circulating cholesterol concentration, and that these and other functional variants of the apolipoprotein-B gene affect susceptibility to coronary heart disease and obesity.
对290名白人男性的随机样本进行了检查，以研究载脂蛋白B基因的限制性片段长度多态性（RFLP）单倍型（单条染色体上紧密连锁的RFLP）与胆固醇、甘油三酯和高密度脂蛋白的血清水平、肥胖、吸烟、饮酒以及冠心病之间的关联。肥胖（p<0.005）、血清胆固醇（p<0.005）和冠心病（p<0.05）的单倍型或单个RFLP频率存在显著差异，但其他变量不存在这种差异。肥胖与涉及最小PvuII和XbaI RFLP的单倍型相关，这些RFLP可能与附近易导致肥胖的功能变异处于连锁不平衡状态。血清胆固醇水平的显著差异与由MspI和EcoRI RFLP对定义的三个功能等位基因相关（p<0.03）。这些RFLP对应于载脂蛋白B的低密度脂蛋白（LDL）受体结合区域附近位置3611（精氨酸变为谷氨酰胺）和4154（谷氨酸变为赖氨酸）处的带电荷氨基酸变体。这三个等位基因在低、正常和高水平的血清胆固醇之间表现出分层。冠心病与涉及XbaI和MspI RFLP的最小单倍型相关。这些结果共同表明，载脂蛋白B基因的遗传变异，可能以带电荷氨基酸替代的形式，影响循环胆固醇浓度，并且载脂蛋白B基因的这些及其他功能变异会影响冠心病和肥胖的易感性。
