Epigenome-wide association study of fasting blood lipids in the Genetics of Lipid-lowering Drugs and Diet Network study.
Epigenome-wide association study of fasting blood lipids in the Genetics of Lipid-lowering Drugs and Diet Network study.
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DOI：
10.1161/circulationaha.114.009158
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发表时间：
2014-08-12
期刊：
影响因子：
37.8
通讯作者：
Arnett DK
中科院分区：
文献类型：
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作者：
Irvin MR;Zhi D;Joehanes R;Mendelson M;Aslibekyan S;Claas SA;Thibeault KS;Patel N;Day K;Jones LW;Liang L;Chen BH;Yao C;Tiwari HK;Ordovas JM;Levy D;Absher D;Arnett DK
关于血脂的遗传研究主要集中在DNA序列变异上，很少有研究探讨表观遗传效应。DNA甲基化的全基因组调查可能揭示影响脂质代谢的表观遗传因素。为了确定胞嘧啶-鸟嘌呤二核苷酸（CpG）的差异甲基化是否与脂质表型相关，我们从CD 4 + T细胞中分离DNA，并使用Illumina Infinium HumanMethylation 450 Beadchip在991名参与者中定量超过450，000个CpG的样本甲基化比例。我们使用混合线性回归对个体CpG的甲基化百分比作为空腹极低密度脂蛋白胆固醇（VLDL-C）和甘油三酯（TG）的函数进行建模，该混合线性回归针对年龄、性别、研究部位、细胞纯度和家族结构进行了调整。肉毒碱棕榈酰转移酶1A（CPT 1A）内含子1中的4个CpG（cg 00574958、cg 17058475、cg 01082498、cg 09737197）与VLDL-C（P=1.8*10-21 ~ 1.6*10-8）和TG（P=1.6*10-26 ~ 1.5*10-9）强相关。通过亚硫酸氢盐测序验证阵列结果。我们进行了qPCR实验，证明顶部CpG（cg 00574958）的甲基化与CPT 1A表达相关。cg 00574958与TG和CPT 1A表达的相关性在心脏功能研究中得到重复（分别为P=4.1*10-14和3.1*10-13）。CPT 1A cg 00574958的DNA甲基化分别解释了发现和复制队列中TG变异的11.6%和5.5%。这项全基因组表观基因组研究发现，CPT 1A甲基化与空腹VLDL-C和TG密切相关。确定新的表观遗传对脂质性状的贡献可能会为未来确定新的治疗靶点和/或疾病风险生物标志物的工作提供信息。
Genetic research regarding blood lipids has largely focused on DNA sequence variation; few studies have explored epigenetic effects. Genome-wide surveys of DNA methylation may uncover epigenetic factors influencing lipid metabolism. To identify whether differential methylation of cytosine-guanine dinucleotides (CpGs) correlated with lipid phenotypes, we isolated DNA from CD4+ T-cells and quantified proportion of sample methylation at over 450,000 CpGs using the Illumina Infinium HumanMethylation450 Beadchip in 991 participants of the Genetics of Lipid Lowering Drugs and Diet Network. We modeled percent methylation at individual CpGs as a function of fasting very low density lipoprotein cholesterol (VLDL-C) and triglycerides (TG) using mixed linear regression adjusted for age, gender, study site, cell purity, and family structure. Four CpGs (cg00574958, cg17058475, cg01082498, cg09737197) in intron 1 of carnitine palmitoyltransferase 1A (CPT1A) were strongly associated with VLDL-C (P=1.8*10-21 to 1.6*10-8) and TG (P=1.6*10-26 to 1.5*10-9). Array findings were validated by bisulfite sequencing. We performed qPCR experiments demonstrating that methylation of the top CpG (cg00574958) was correlated with CPT1A expression. The association of cg00574958 with TG and CPT1A expression were replicated in the Framingham Heart Study (P=4.1*10-14 and 3.1*10-13, respectively). DNA methylation at CPT1A cg00574958 explained 11.6% and 5.5% of the variation in TG in the discovery and replication cohorts, respectively. This genome-wide epigenomic study identified CPT1A methylation as strongly and robustly associated with fasting VLDL-C and TG. Identifying novel epigenetic contributions to lipid traits may inform future efforts to identify new treatment targets and/or biomarkers of disease risk.