Interaction of methylation-related genetic variants with circulating fatty acids on plasma lipids: a meta-analysis of 7 studies and methylation analysis of 3 studies in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium
Interaction of methylation-related genetic variants with circulating fatty acids on plasma lipids: a meta-analysis of 7 studies and methylation analysis of 3 studies in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium
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DOI：
10.3945/ajcn.115.112987
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发表时间：
2016-02-01
影响因子：
7.1
通讯作者：
Lemaitre, Rozenn N.
中科院分区：
文献类型：
--
作者：
Ma, Yiyi;Follis, Jack L.;Lemaitre, Rozenn N.
背景资料：DNA甲基化受饮食和单核苷酸多态性（single nucleotide polymorphisms，SNPs）的影响，而甲基化调节基因的表达。目的：我们旨在探讨基因与饮食的相互作用是否通过DNA甲基化对血脂起作用。设计：我们根据脂肪酸、甲基化和血脂的预测关系选择了7个SNPs。我们使用CHARGE的数据进行了荟萃分析以及甲基化和中介分析。（基因组流行病学中心脏和衰老研究队列）联盟和ENCODE（DNA元素百科全书）财团。基于CHARGE联盟中7个队列的荟萃分析，血浆高密度脂蛋白胆固醇升高与ATP结合盒亚家族A成员1（ABCA 1）rs 2246293的C等位基因减少相关（β =-0.6 mg/dL，P = 0.015）和较高的循环二十碳五烯酸（EPA）（β = 3.87 mg/dL，P = 5.62 × 1021）。与较高循环EPA相关的HDL胆固醇的差异取决于rs 2246293的基因型，并且对于每个额外的C等位基因（β = 1.69 mg/dL，P = 0.006）更大。在GOLDN（Genetics of Lipid Lowering Drugs and Diet Network）研究发现，ABCA 1启动子cg 14019050甲基化水平越高，rs 2246293处的C等位基因越多（β = 8.84%，P = 3.51 x 10（18））和较低的循环EPA（p =-1.46%，P = 0.009），并且与较高EPA相关的cg 14019050甲基化的平均差异随着rs 2246293的每个额外C等位基因而较小=-2.83%，P = 0.007）。在ENCODE研究中，较高的ABCA 1 cg 14019050甲基化与较低的ABCA 1表达相关（r =-0.61，P = 0.009），在GOLDN研究中，较高的ABCA 1 cg 14019050甲基化与较低的血浆HDL胆固醇相关（r =-0.12，P = 0.0002）。在GOLDN研究、心血管健康研究和多种族动脉粥样硬化研究中进行了额外的中介分析。与未调整cg 14019050甲基化的模型相比，调整后的模型提供了与rs 2246293 C等位基因和EPA相关的平均血浆HDL胆固醇浓度的较小估计值，以及EPA相关HDL胆固醇中rs 2246293基因型的较小差异。结论：基因与脂肪酸的相互作用对血脂的影响是通过DNA甲基化来实现的，但没有证据表明基因与脂肪酸的相互作用是通过DNA甲基化来实现的。
Background: DNA methylation is influenced by diet and single nucleotide polymorphisms (SNPs), and methylation modulates gene expression.Objective: We aimed to explore whether the gene-by-diet interactions on blood lipids act through DNA methylation.Design: We selected 7 SNPs on the basis of predicted relations in fatty acids, methylation, and lipids. We conducted a meta-analysis and a methylation and mediation analysis with the use of data from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium and the ENCODE (Encyclopedia of DNA Elements) consortium.Results: On the basis of the meta-analysis of 7 cohorts in the CHARGE consortium, higher plasma HDL cholesterol was associated with fewer C alleles at ATP-binding cassette subfamily A member 1 (ABCA1) rs2246293 (beta =-0.6 mg/dL, P = 0.015) and higher circulating eicosapentaenoic acid (EPA) (beta = 3.87 mg/dL, P = 5.62 X 1021). The difference in HDL cholesterol associated with higher circulating EPA was dependent on genotypes at rs2246293, and it was greater for each additional C allele (beta = 1.69 mg/dL, P = 0.006). In the GOLDN (Genetics of Lipid Lowering Drugs and Diet Network) study, higher ABCA1 promoter cg14019050 methylation was associated with more C alleles at rs2246293 (beta = 8.84%, P = 3.51 x 10(18)) and lower circulating EPA (p =-1.46%, P = 0.009), and the mean difference in methylation of cg14019050 that was associated with higher EPA was smaller with each additional C allele of rs2246293 =-2.83%, P = 0.007). Higher ABCA1 cg14019050 methylation was correlated with lower ABCA1 expression (r =-0.61, P = 0.009) in the ENCODE consortium and lower plasma HDL cholesterol in the GOLDN study (r =-0.12, P = 0.0002). An additional mediation analysis was meta-analyzed across the GOLDN study, Cardiovascular Health Study, and the Multi-Ethnic Study of Atherosclerosis. Compared with the model without the adjustment of cg14019050 methylation, the model with such adjustment provided smaller estimates of the mean plasma HDL cholesterol concentration in association with both the rs2246293 C allele and EPA and a smaller difference by rs2246293 genotypes in the EPA-associated HDL cholesterol. However, the differences between 2 nested models were NS (P > 0.05).Conclusion: We obtained little evidence that the gene-by-fatty acid interactions on blood lipids act through DNA methylation.