Sijbrands E J, Lombardi M P, Westendorp R G, Leuven J A, Meinders A E, Van der Laarse A, Frants R R, Havekes L M, Smelt A H
Department of General Internal Medicine, Medical Faculty, Leiden, The Netherlands.
Atherosclerosis. 1998 Feb;136(2):247-54. doi: 10.1016/s0021-9150(97)00216-5.
In patients heterozygous for familial hypercholesterolemia, the low-density lipoprotein (LDL) cholesterol lowering effect of beta-hydroxy-beta-methylglutaryl coenzyme A reductase inhibitors may depend on the nature of the mutation in the LDL receptor gene. To test this hypothesis, we compared the response to simvastatin, 20 mg daily for 9 weeks, between heterozygous carriers of functionally different classes of mutations, i.e. mRNA negative or mRNA positive mutations. Out of 116 consecutive, unrelated patients with familial hypercholesterolemia, 27 patients were selected for molecular analyses: 14 patients with mRNA negative and 13 with mRNA positive mutations. Before simvastatin treatment, patients with mRNA negative mutations had higher levels of LDL cholesterol, lower levels of high-density lipoprotein (HDL) cholesterol and significantly more often tendon xanthomas, compared to patients with mRNA positive mutations. Simvastatin reduced the mean fasting LDL cholesterol levels to a similar percentage in the mRNA negative and mRNA positive patients (37, 36%, respectively, 95% CI of difference--8 to 5%, P = 0.2). This effect was similar to the 37% decrease observed in our total series of patients with familial hypercholesterolemia (n = 116). The increase in mean concentration of HDL cholesterol was greater in the mRNA negative group than in the mRNA positive group (16, 0%, respectively, 95%, CI of difference 8-25%, P = 0.002) independent of the response of total triglycerides to simvastatin. The percentage LDL cholesterol lowering response varied among multiple carriers of the same mutation, even in the case of mRNA negative mutations. We conclude that the percentage LDL lowering response to simvastatin treatment was similar in patients with mRNA negative and mRNA positive mutations. Moreover, variation of this response within multiple carriers of the same mutation suggests an influence of additional factors.
在家族性高胆固醇血症杂合子患者中，β-羟基-β-甲基戊二酰辅酶A还原酶抑制剂降低低密度脂蛋白（LDL）胆固醇的效果可能取决于LDL受体基因突变的性质。为了验证这一假设，我们比较了功能不同类型突变（即mRNA阴性或mRNA阳性突变）的杂合子携带者对辛伐他汀（每日20mg，共9周）的反应。在116例连续的、无亲缘关系的家族性高胆固醇血症患者中，选择27例患者进行分子分析：14例mRNA阴性突变患者和13例mRNA阳性突变患者。与mRNA阳性突变患者相比，mRNA阴性突变患者在辛伐他汀治疗前LDL胆固醇水平更高，高密度脂蛋白（HDL）胆固醇水平更低，且肌腱黄色瘤更为常见。辛伐他汀使mRNA阴性和mRNA阳性患者的平均空腹LDL胆固醇水平降低至相似的百分比（分别为37%、36%，差异的95%CI为-8%至5%，P = 0.2）。这一效果与我们家族性高胆固醇血症患者总系列（n = 116）中观察到的37%的降低相似。HDL胆固醇平均浓度的增加在mRNA阴性组大于mRNA阳性组（分别为16%、0%，差异的95%CI为8% - 25%，P = 0.002），与总甘油三酯对辛伐他汀的反应无关。即使在mRNA阴性突变的情况下，同一突变的多个携带者之间LDL胆固醇降低反应的百分比也有所不同。我们得出结论，mRNA阴性和mRNA阳性突变患者对辛伐他汀治疗的LDL降低反应百分比相似。此外，同一突变的多个携带者中这种反应的变化表明存在其他因素的影响。
