Cigarette smoking reduces DNA methylation levels at multiple genomic loci but the effect is partially reversible upon cessation
Cigarette smoking reduces DNA methylation levels at multiple genomic loci but the effect is partially reversible upon cessation
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DOI：
10.4161/15592294.2014.969637
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发表时间：
2014-10-01
期刊：
影响因子：
3.7
通讯作者：
Deloukas, Panos
中科院分区：
文献类型：
--
作者：
Tsaprouni, Loukia G.;Yang, Tsun-Po;Deloukas, Panos
吸烟是许多疾病的主要危险因素。全基因组关联研究已将尼古丁依赖和吸烟行为的基因与心血管、肺部和恶性疾病的风险增加联系起来。我们使用人类甲基化 450K 芯片对 464 名个体（22 名当前吸烟者和 263 名戒烟者）的外周血 DNA 进行了表观基因组广泛关联研究。在 356 名双胞胎（41 名当前吸烟者和 104 名戒烟者）的独立样本中进行复制后，我们在 15 个不同基因座中鉴定了 30 个探针，所有这些探针在组合分析中均达到全基因组显着性 P < 5 x 10(-8)。在调整血细胞计数后，除一个探针 (cg17024919) 之外的所有探针仍然显着。我们复制了所有 9 个已知基因座，并在 GPR15 附近的 CPOX 处发现了一个独立信号。此外，我们在 PRSS23、AVPR1B、PSEN2、LINC00299、RPS6KA2 和 KIAA0087 上发现了 6 个新基因座。大多数先导探针（15 个中的 13 个）与吸烟相关，开放染色质的重叠区域（FAIRE 和 DNaseI 超敏感位点）或/和 H3K27Ac 峰（ENCODE 数据集），这些峰标记了调控元件。吸烟对 DNA 甲基化的影响在戒烟超过 3 个月后可部分逆转。我们报告了 SNP (rs2697768) 和吸烟对 DNA 甲基化 (cg03329539) 之间第一个具有统计学意义的相互作用。我们提供的证据表明，cg03329539 的 metSNP 调节位于甲基化位点下游约 95Kb 处的 CHRND 基因的表达。我们的研究结果表明，吸烟引起的动态、可逆的位点特异性甲基化变化的存在，这可能会导致与吸烟相关的健康风险的扩大。
Smoking is a major risk factor in many diseases. Genome wide association studies have linked genes for nicotine dependence and smoking behavior to increased risk of cardiovascular, pulmonary, and malignant diseases. We conducted an epigenome wide association study in peripheral-blood DNA in 464 individuals (22 current smokers and 263 ex-smokers), using the Human Methylation 450K array. Upon replication in an independent sample of 356 twins (41 current and 104 ex-smokers), we identified 30 probes in 15 distinct loci, all of which reached genome-wide significance in the combined analysis P < 5 x 10(-8). All but one probe (cg17024919) remained significant after adjusting for blood cell counts. We replicated all 9 known loci and found an independent signal at CPOX near GPR15. In addition, we found 6 new loci at PRSS23, AVPR1B, PSEN2, LINC00299, RPS6KA2, and KIAA0087. Most of the lead probes (13 out of 15) associated with cigarette smoking, overlapped regions of open chromatin (FAIRE and DNaseI hypersensitive sites) or / and H3K27Ac peaks (ENCODE data set), which mark regulatory elements. The effect of smoking on DNA methylation was partially reversible upon smoking cessation for longer than 3 months. We report the first statistically significant interaction between a SNP (rs2697768) and cigarette smoking on DNA methylation (cg03329539). We provide evidence that the metSNP for cg03329539 regulates expression of the CHRND gene located circa 95Kb downstream of the methylation site. Our findings suggest the existence of dynamic, reversible site-specific methylation changes in response to cigarette smoking , which may contribute to the extended health risks associated with cigarette smoking.