Gaudet D, Vohl M C, Couture P, Moorjani S, Tremblay G, Perron P, Gagné C, Després J P
Chicoutimi Hospital Lipid Clinic, Quebec, Canada.
Atherosclerosis. 1999 Mar;143(1):153-61. doi: 10.1016/s0021-9150(98)00268-8.
Elevated plasma LDL-cholesterol (LDL-C) levels are associated with an increased risk of coronary artery disease (CAD). Familial hypercholesterolemia (FH), a monogenic trait due to mutations in the LDL-receptor (R) gene is characterized by raised plasma LDL-C levels and premature CAD. The aim of the present investigation, derived from the study of a population of 1465 unrelated men aged 25 to 64 years, was to compare the expression of CAD assessed by coronary angiography in young (aged 25-49 years) versus middle-aged (50-64 years) heterozygous FH patients of French Canadian descent. Furthermore, the relationship of binding-defective versus receptor negative mutations in the LDL-R to premature CAD ( < 50 years) was examined and compared with men displaying a normal plasma lipoprotein-lipid profile. From the original study sample, a total of 100 men met the clinical criteria of heterozygous FH. Among them, 30 were carriers of a receptor negative mutation (deletion > 15 kb or point mutations Y468X or R329X) whereas 64 were carriers of a receptor defective mutation (W66G, E207K or C646Y). As expected, in both age groups (25-49 years vs. 50-64 years), carriers of a receptor negative mutation had higher plasma cholesterol and LDL-C levels than carriers of a defective allele or men with a normal plasma lipoprotein-lipid profile. In addition, the mean number of diseased vessels (with > 50% stenosis) was higher in men aged 50-64 years compared to those aged 25 49 years. In the two age groups, FH patients were characterized by a higher number of stenosed coronary vessels than the normal phenotype group. Within each group (either receptor negative, receptor defective or normal phenotype) plasma cholesterol, LDL-C, HDL-C, triglyceride and apolipoprotein B levels were similar irrespective of age (25 49 years vs. 50-64 years). Finally, multiple logistic regression analyses revealed that compared to non-FH men, the relative odds of being affected by CAD before the age of 50 years was 7.3-fold higher for carriers of a receptor negative mutation and 2.7-fold higher for men with a receptor defective mutation at the LDL-R locus. These results suggest that CAD could be an earlier event among heterozygous FH subjects bearing a receptor negative mutation compared to LDL-R defective patients. It also suggest that the selective screening for mutations in the LDL-R gene may allow a better assessment of the individual risk and facilitate the development of family-based preventive strategies or intervention programs in FH.
血浆低密度脂蛋白胆固醇（LDL-C）水平升高与冠状动脉疾病（CAD）风险增加相关。家族性高胆固醇血症（FH）是一种由于低密度脂蛋白受体（R）基因突变导致的单基因性状，其特征为血浆LDL-C水平升高和CAD发病过早。本研究源自对1465名年龄在25至64岁的无亲缘关系男性群体的研究，目的是比较通过冠状动脉造影评估的CAD在年轻（25 - 49岁）与中年（50 - 64岁）法裔加拿大血统杂合子FH患者中的表现。此外，研究了LDL-R中结合缺陷型与受体阴性突变与过早CAD（<50岁）的关系，并与血浆脂蛋白-脂质谱正常的男性进行比较。从原始研究样本中，共有100名男性符合杂合子FH的临床标准。其中，30名是受体阴性突变携带者（缺失>15 kb或点突变Y468X或R329X），而64名是受体缺陷型突变携带者（W66G、E207K或C646Y）。正如预期的那样，在两个年龄组（25 - 49岁与50 - 64岁）中，受体阴性突变携带者的血浆胆固醇和LDL-C水平高于缺陷等位基因携带者或血浆脂蛋白-脂质谱正常的男性。此外，50 - 64岁男性的病变血管平均数量（狭窄>50%）高于25 - 49岁男性。在两个年龄组中，FH患者的冠状动脉狭窄血管数量均高于正常表型组。在每组（受体阴性、受体缺陷或正常表型）中，无论年龄（25 - 49岁与50 - 64岁），血浆胆固醇、LDL-C、HDL-C、甘油三酯和载脂蛋白B水平均相似。最后，多因素逻辑回归分析显示，与非FH男性相比，受体阴性突变携带者在50岁之前患CAD的相对几率高7.3倍，LDL-R位点有受体缺陷型突变的男性高2.7倍。这些结果表明，与LDL-R缺陷患者相比，携带受体阴性突变的杂合子FH受试者中CAD可能是更早发生的事件。这也表明对LDL-R基因中的突变进行选择性筛查可能有助于更好地评估个体风险，并促进FH基于家庭的预防策略或干预计划的制定。
