Department of Epidemiology, University of Alabama, Birmingham.
The Robert N. Butler Columbia Aging Center, Columbia University Mailman School of Public Health, New York, New York.
JAMA Cardiol. 2018 Jun 1;3(6):463-472. doi: 10.1001/jamacardio.2018.0510.
Tumor necrosis factor α (TNF-α) is a proinflammatory cytokine with manifold consequences for mammalian pathophysiology, including cardiovascular disease. A deeper understanding of TNF-α biology may enhance treatment precision.
To conduct an epigenome-wide analysis of blood-derived DNA methylation and TNF-α levels and to assess the clinical relevance of findings.
DESIGN, SETTING, AND PARTICIPANTS: This meta-analysis assessed epigenome-wide associations in circulating TNF-α concentrations from 5 cohort studies and 1 interventional trial, with replication in 3 additional cohort studies. Follow-up analyses investigated associations of identified methylation loci with gene expression and incident coronary heart disease; this meta-analysis included 11 461 participants who experienced 1895 coronary events.
Circulating TNF-α concentration.
DNA methylation at approximately 450 000 loci, neighboring DNA sequence variation, gene expression, and incident coronary heart disease.
The discovery cohort included 4794 participants, and the replication study included 816 participants (overall mean [SD] age, 60.7 [8.5] years). In the discovery stage, circulating TNF-α levels were associated with methylation of 7 cytosine-phosphate-guanine (CpG) sites, 3 of which were located in or near DTX3L-PARP9 at cg00959259 (β [SE] = -0.01 [0.003]; P = 7.36 × 10-8), cg08122652 (β [SE] = -0.008 [0.002]; P = 2.24 × 10-7), and cg22930808(β [SE] = -0.01 [0.002]; P = 6.92 × 10-8); NLRC5 at cg16411857 (β [SE] = -0.01 [0.002]; P = 2.14 × 10-13) and cg07839457 (β [SE] = -0.02 [0.003]; P = 6.31 × 10-10); or ABO, at cg13683939 (β [SE] = 0.04 [0.008]; P = 1.42 × 10-7) and cg24267699 (β [SE] = -0.009 [0.002]; P = 1.67 × 10-7), after accounting for multiple testing. Of these, negative associations between TNF-α concentration and methylation of 2 loci in NLRC5 and 1 in DTX3L-14 PARP9 were replicated. Replicated TNF-α-linked CpG sites were associated with 9% to 19% decreased risk of incident coronary heart disease per 10% higher methylation per CpG site (cg16411857: hazard ratio [HR], 0.86; 95% CI, 0.78-1.95; P = .003; cg07839457: HR, 0.89; 95% CI, 0.80-0.94; P = 3.1 × 10-5; cg00959259: HR, 0.91; 95% CI, 0.84-0.97; P = .002; cg08122652: HR, 0.81; 95% CI, 0.74-0.89; P = 2.0 × 10-5).
We identified and replicated novel epigenetic correlates of circulating TNF-α concentration in blood samples and linked these loci to coronary heart disease risk, opening opportunities for validation and therapeutic applications.
重要性：肿瘤坏死因子-α（TNF-α）是一种促炎细胞因子，对哺乳动物的病理生理学有多种影响，包括心血管疾病。更深入地了解 TNF-α 的生物学特性可能会提高治疗的精确性。
目的：对血液来源的 DNA 甲基化和 TNF-α 水平进行全基因组关联分析，并评估发现的临床相关性。
设计、地点和参与者：这项荟萃分析评估了来自 5 项队列研究和 1 项干预试验的循环 TNF-α 浓度的全基因组关联，在另外 3 项队列研究中进行了复制。随访分析调查了鉴定的甲基化部位与基因表达和冠心病事件的关联；本荟萃分析纳入了经历 1895 例冠心病事件的 11461 名参与者。
暴露：循环 TNF-α 浓度。
主要结果和措施：大约 450000 个位置的 DNA 甲基化、邻近的 DNA 序列变异、基因表达和冠心病事件。
结果：发现队列包括 4794 名参与者，复制研究包括 816 名参与者（平均[标准差]年龄 60.7[8.5]岁）。在发现阶段，循环 TNF-α 水平与 7 个胞嘧啶-磷酸-鸟嘌呤（CpG）位点的甲基化有关，其中 3 个位于 DTX3L-PARP9 内或附近的 cg00959259（β[标准误] = -0.01[0.003]；P = 7.36×10-8）、cg08122652（β[标准误] = -0.008[0.002]；P = 2.24×10-7）和 cg22930808（β[标准误] = -0.01[0.002]；P = 6.92×10-8）；NLRC5 在 cg16411857（β[标准误] = -0.01[0.002]；P = 2.14×10-13）和 cg07839457（β[标准误] = -0.02[0.003]；P = 6.31×10-10）；或 ABO，在 cg13683939（β[标准误] = 0.04[0.008]；P = 1.42×10-7）和 cg24267699（β[标准误] = -0.009[0.002]；P = 1.67×10-7），在考虑到多次检验后。在这些基因中，NLRC5 中的 2 个基因和 DTX3L-14 PARP9 中的 1 个基因与 TNF-α 浓度呈负相关，这在复制中得到了验证。复制的 TNF-α 相关 CpG 位点与冠心病事件风险降低相关，每个 CpG 位点的甲基化增加 10%，冠心病事件风险降低 9%至 19%（cg16411857：风险比[HR]，0.86；95%CI，0.78-1.95；P = 0.003；cg07839457：HR，0.89；95%CI，0.80-0.94；P = 3.1×10-5；cg00959259：HR，0.91；95%CI，0.84-0.97；P = 0.002；cg08122652：HR，0.81；95%CI，0.74-0.89；P = 2.0×10-5）。
结论和相关性：我们在血液样本中发现并复制了与循环 TNF-α 浓度相关的新型表观遗传标志物，并将这些标志物与冠心病风险联系起来，为验证和治疗应用提供了机会。
