Kakko S, Tamminen M, Kesäniemi Y A, Savolainen M J
Department of Internal Medicine and Biocenter Oulu, University of Oulu, Finland.
Atherosclerosis. 1998 Feb;136(2):233-40. doi: 10.1016/s0021-9150(97)00201-3.
Cholesteryl ester transfer protein (CETP), as a candidate gene for dyslipoproteinemia and coronary heart disease, was studied in 105 men with low plasma concentrations of high density lipoprotein cholesterol (HDL-C) and established coronary heart disease as well as in 515 randomly selected men and women. A one-nucleotide substitution (G to A) in exon 15, which changes arginine (451) to glutamine in CETP protein, was detected by PCR-SSCP and direct sequencing and screened in the population sample by a simple PCR-based restriction assay. In the random population sample the allele frequency of the R451Q mutation was 1.9%. Men heterozygous for the R451Q mutation (n = 7) had 27% higher CETP activity than age-, body mass index-, smoking- and alcohol consumption-matched controls with normal genotype (n = 21; P = 0.003). Women heterozygous for the R451Q mutation (n = 7) had 16% lower total cholesterol compared to matched controls (n = 21; P = 0.07), but no such difference was detected in men. In the random population sample the correlation between plasma total cholesterol level and CETP activity was 0.19 (P = 0.044), both in men and women. When women with total cholesterol over 5.2 mmol/l were excluded from analysis, heterozygotes (n = 4) had plasma CETP activity of 113 nmol/h/ml plasma, whereas those of normal genotype (n = 12) had 103 nmol/h/ml plasma, but this difference was not statistically significant. Women heterozygous for the R451Q mutation and consuming less than 10 g alcohol a week had 23% lower HDL-C compared to women with the normal genotype (P = 0.032). In conclusion, we describe a mutation in the CETP gene associated with high plasma CETP activity in men and with low total cholesterol in women. Further studies are needed to evaluate the effect of mutation on the risk of coronary heart disease.
胆固醇酯转运蛋白（CETP）作为血脂异常和冠心病的候选基因，在105名血浆高密度脂蛋白胆固醇（HDL-C）浓度低且已确诊冠心病的男性以及515名随机选取的男性和女性中进行了研究。通过PCR-SSCP和直接测序检测到外显子15中的一个单核苷酸替换（G到A），该替换使CETP蛋白中的精氨酸（451）变为谷氨酰胺，并通过基于PCR的简单限制性分析在人群样本中进行筛选。在随机人群样本中，R451Q突变的等位基因频率为1.9%。R451Q突变杂合子男性（n = 7）的CETP活性比年龄、体重指数、吸烟和饮酒量相匹配的正常基因型对照者（n = 21；P = 0.003）高27%。R451Q突变杂合子女性（n = 7）的总胆固醇比匹配的对照者低16%（n = 21；P = 0.07），但在男性中未检测到这种差异。在随机人群样本中，男性和女性的血浆总胆固醇水平与CETP活性之间的相关性均为0.19（P = 0.044）。当将总胆固醇超过5.2 mmol/l的女性排除在分析之外时，杂合子（n = 4）的血浆CETP活性为113 nmol/h/ml血浆，而正常基因型者（n = 12）为103 nmol/h/ml血浆，但这种差异无统计学意义。每周饮酒少于10 g的R451Q突变杂合子女性的HDL-C比正常基因型女性低23%（P = 0.032）。总之，我们描述了一种CETP基因突变，该突变与男性血浆CETP活性高和女性总胆固醇低有关。需要进一步研究来评估该突变对冠心病风险的影响。
