Frazier-Wood Alexis C, Aslibekyan Stella, Absher Devin M, Hopkins Paul N, Sha Jin, Tsai Michael Y, Tiwari Hemant K, Waite Lindsay L, Zhi Degui, Arnett Donna K
USDA/Agricultural Research Service Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX.
Department of Epidemiology, University of Alabama at Birmingham, School of Public Health, Birmingham, AL.
J Lipid Res. 2014 Jul;55(7):1324-30. doi: 10.1194/jlr.M048504. Epub 2014 Apr 7.
Lipoprotein subfractions help discriminate cardiometabolic disease risk. Genetic loci validated as associating with lipoprotein measures do not account for a large proportion of the individual variation in lipoprotein measures. We hypothesized that DNA methylation levels across the genome contribute to interindividual variation in lipoprotein measures. Using data from participants of the Genetics of Lipid Lowering Drugs and Diet Network (n = 663 for discovery and n = 331 for replication stages, respectively), we conducted the first systematic screen of the genome to determine associations between methylation status at ∼470,000 cytosine-guanine dinucleotide (CpG) sites in CD4(+) T cells and 14 lipoprotein subfraction measures. We modeled associations between methylation at each CpG site and each lipoprotein measure separately using linear mixed models, adjusted for age, sex, study site, cell purity, and family structure. We identified two CpGs, both in the carnitine palmitoyltransferase-1A (CPT1A) gene, which reached significant levels of association with VLDL and LDL subfraction parameters in both discovery and replication phases (P < 1.1 × 10(-7) in the discovery phase, P < .004 in the replication phase, and P < 1.1 × 10(-12) in the full sample). CPT1A is regulated by PPARα, a ligand for drugs used to reduce CVD. Our associations between methylation in CPT1A and lipoprotein measures highlight the epigenetic role of this gene in metabolic dysfunction.
脂蛋白亚组分有助于区分心血管代谢疾病风险。已被证实与脂蛋白测量值相关的基因位点并不能解释脂蛋白测量值个体差异的很大一部分。我们推测，全基因组的DNA甲基化水平有助于脂蛋白测量值的个体间差异。利用降脂药物和饮食网络遗传学研究参与者的数据（发现阶段n = 663，复制阶段n = 331），我们首次对基因组进行了系统筛选，以确定CD4(+) T细胞中约47万个胞嘧啶-鸟嘌呤二核苷酸（CpG）位点的甲基化状态与14种脂蛋白亚组分测量值之间的关联。我们使用线性混合模型分别对每个CpG位点的甲基化与每种脂蛋白测量值之间的关联进行建模，并对年龄、性别、研究地点、细胞纯度和家族结构进行了调整。我们在肉碱棕榈酰转移酶-1A（CPT1A）基因中鉴定出两个CpG，它们在发现阶段和复制阶段均与极低密度脂蛋白（VLDL）和低密度脂蛋白（LDL）亚组分参数达到显著关联水平（发现阶段P < 1.1×10⁻⁷，复制阶段P < 0.004，全样本P < 1.1×10⁻¹²）。CPT1A受PPARα调控，PPARα是用于降低心血管疾病（CVD）药物的配体。我们发现CPT1A甲基化与脂蛋白测量值之间的关联突出了该基因在代谢功能障碍中的表观遗传作用。
