Department of Medical Genetics, Marshfield Clinic, Marshfield, WI; Sections of Cardiovascular Research and Cardiology, Baylor College of Medicine, Houston, TX; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.
Sections of Cardiovascular Research and Cardiology, Baylor College of Medicine, Houston, TX; Center for Cardiovascular Disease Prevention, Methodist DeBakey Heart and Vascular Center, Houston, TX; and; Health Policy and Quality Program, Michael E. DeBakey VA Medical Center Health Services Research and Development Center of Excellence, Houston, TX.
J Lipid Res. 2012 Mar;53(3):556-560. doi: 10.1194/jlr.M020404. Epub 2012 Jan 11.
ApoC-III is a proatherogenic protein associated with elevated triglycerides; its deficiency is associated with reduced atherosclerosis. Mixed dyslipidemia, characterized by elevated triglyceride and apoC-III levels and low HDL cholesterol level, with or without elevated LDL cholesterol, increases cardiovascular disease risk and is commonly treated with combined statin and fibrate therapy. We sought to identify single nucleotide polymorphisms (SNPs) associated with apoC-III level response to combination therapy with statins and fenofibric acid (FA) in individuals with mixed dyslipidemia. Participants (n = 1,250) in a multicenter, randomized, double-blind, active-controlled study examining response to FA alone and in combination with statin were genotyped for candidate SNPs. Multivariate linear regression and two-way ANOVA for percent change in apoC-III level were performed. SNPs in the lipoprotein lipase (LPL) gene region, rs1801177 (P = 4.7 × 10(-8)), rs7016529 (P = 1.2 × 10(-6)), and rs249 (P = 4.1 × 10(-5)), were associated with apoC-III response to combination therapy. A haplotype composed of the minor alleles of these SNPs, with 2% population frequency, was associated with an unexpected apoC-III increase in response to statins and FA. This is the first report to show that genetic variation within the LPL gene region can affect the response of apoC-III levels to combined statin and FA therapy.
载脂蛋白 C-III 是一种促动脉粥样硬化蛋白，与甘油三酯升高有关；其缺乏与动脉粥样硬化减少有关。混合性血脂异常的特征是甘油三酯和载脂蛋白 C-III 水平升高，高密度脂蛋白胆固醇水平降低，伴有或不伴有低密度脂蛋白胆固醇升高，增加了心血管疾病的风险，通常采用联合他汀类药物和贝特类药物治疗。我们试图确定与他汀类药物和非诺贝特联合治疗混合性血脂异常患者的载脂蛋白 C-III 水平反应相关的单核苷酸多态性（SNP）。在一项多中心、随机、双盲、活性对照研究中，对单独使用非诺贝特和联合使用他汀类药物的反应进行了研究，共有 1250 名参与者进行了候选 SNP 基因分型。采用多元线性回归和双向方差分析来评估载脂蛋白 C-III 水平变化的百分比。脂蛋白脂肪酶（LPL）基因区域的 SNP，rs1801177（P=4.7×10(-8)）、rs7016529（P=1.2×10(-6)）和 rs249（P=4.1×10(-5)）与联合治疗的载脂蛋白 C-III 反应相关。由这些 SNP 的次要等位基因组成的单倍型，其在人群中的频率为 2%，与他汀类药物和非诺贝特联合治疗时载脂蛋白 C-III 水平意外升高有关。这是第一项表明 LPL 基因区域内的遗传变异可以影响载脂蛋白 C-III 水平对联合他汀类药物和非诺贝特治疗反应的报告。
