Low-density lipoprotein receptor genotype and response to pravastatin in children with familial hypercholesterolemia - Substudy of an intima-media thickness trial
Low-density lipoprotein receptor genotype and response to pravastatin in children with familial hypercholesterolemia - Substudy of an intima-media thickness trial
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DOI：
10.1161/circulationaha.105.565507
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发表时间：
2005-11-15
期刊：
影响因子：
37.8
通讯作者：
Sijbrands, EJG
中科院分区：
文献类型：
--
作者：
Koeijvoets, KCMC;Rodenburg, J;Sijbrands, EJG
背景：他汀类药物治疗的降脂作用在家族性高胆固醇血症（FH）患者中表现出相当大的个体差异。 LDL 受体突变类型是否可以预测他汀类药物治疗的反应尚未确定。我们使用颈动脉内膜中层厚度 (IMT) 来衡量疗效，分析了 LDL 受体基因型与 FH 儿童对普伐他汀治疗反应之间的关系。方法和结果：在一项随机、安慰剂对照、双盲、为期 2 年的普伐他汀试验中，193 名儿童经基因证实患有 FH，并被纳入本次研究。在基线时，与受体缺陷突变的儿童相比，具有无效等位基因的儿童具有较高的 LDL 胆固醇水平（差异，0.94 +/- 0.19 mmol/ L [SEM]；P < 0.001）和较高的颈动脉 IMT（差异，0.019 +/- 0.01 mm；P = 0.02）。试验期间颈动脉 IMT 的降低在具有无效等位基因和受体缺陷突变的儿童中没有显着差异（0.018 +/- 0.012 和 0.012 +/- 0.010 mm；2 路 ANCOVA，P = 0.7）。治疗 2 年后，具有无效等位基因的儿童的颈动脉 IMT 继续高于具有受体缺陷突变的儿童（差异，0.016 +/- 0.01 mm；P = 0.02）。与受体缺陷突变携带者相比，无效等位基因携带者的 LDL 胆固醇降低幅度往往较小（1.30 +/- 0.25 和 1.85 +/- 0.20 mmol/L；2 路 ANCOVA，P = 0.08）。结论：在 FH 儿童中，我们发现无效等位基因基因型与较大的颈动脉 IMT、较高的 LDL 胆固醇水平相关，且趋势不显着。与受体缺陷突变相比，LDL 胆固醇降低减弱。无效等位基因识别出心血管疾病风险最高的 FH 患者，他们可能受益于从儿童时期开始的更积极的治疗。
Background: The lipid-lowering effects of statin therapy show considerable interindividual variation in patients with familial hypercholesterolemia (FH). Whether the type of LDL receptor mutation predicts the response to statin treatment is not yet established. We analyzed the relationship between LDL receptor genotype and response to pravastatin treatment in children with FH using carotid intima-media thickness (IMT) to measure efficacy.Methods and Results: In a randomized, placebo-controlled, double-blind, 2-year trial with pravastatin, 193 children had genetically confirmed FH and were included in the present substudy. At baseline, children with null alleles had higher LDL cholesterol levels (difference, 0.94 +/- 0.19 mmol/ L [SEM]; P < 0.001) and a greater carotid IMT ( difference, 0.019 +/- 0.01 mm; P = 0.02) compared with children with receptor-defective mutations. The decrease in carotid IMT during the trial was not significantly different in children with null alleles and receptor- defective mutations (0.018 +/- 0.012 and 0.012 +/- 0.010 mm; 2-way ANCOVA, P = 0.7). After 2 years of treatment, the children with null alleles continued to have greater carotid IMT than children with receptor- defective mutations ( difference, 0.016 +/- 0.01 mm; P = 0.02). LDL cholesterol lowering tended to be less in carriers of null alleles compared with carriers of receptor-defective mutations (1.30 +/- 0.25 and 1.85 +/- 0.20 mmol/L; 2-way ANCOVA, P = 0.08).Conclusions: In FH children, we found that the null allele genotype was associated with a greater carotid IMT, higher LDL cholesterol levels, and a nonsignificant tendency to attenuated LDL cholesterol lowering compared with receptor- defective mutations. Null alleles identify FH patients at the highest cardiovascular disease risk who may benefit from more aggressive treatment started in childhood.