Channing Laboratory and the Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, 181 Longwood Avenue, Boston, MA 02115, USA.
Hum Mol Genet. 2012 Jul 1;21(13):3073-82. doi: 10.1093/hmg/dds135. Epub 2012 Apr 6.
The impact of cigarette smoking can persist for extended periods following smoking cessation and may involve epigenetic reprogramming. Changes in DNA methylation associated with smoking may help to identify molecular pathways that contribute to the latency between exposure and disease onset. Cross-sectional cohort data from subjects in the International COPD Genetics Network (n = 1085) and the Boston Early-Onset COPD study (n = 369) were analyzed as the discovery and replication cohorts, respectively. Genome-wide methylation data on 27 578 CpG sites in 14 475 genes were obtained on DNA from peripheral blood leukocytes using the Illumina HumanMethylation27K Beadchip in both cohorts. We identified 15 sites significantly associated with current smoking, 2 sites associated with cumulative smoke exposure, and, within the subset of former smokers, 3 sites associated with time since quitting cigarettes. Two loci, factor II receptor-like 3 (F2RL3) and G-protein-coupled receptor 15 (GPR15), were significantly associated in all three analyses and were validated by pyrosequencing. These findings (i) identify a novel locus (GPR15) associated with cigarette smoking and (ii) suggest the existence of dynamic, site-specific methylation changes in response to smoking which may contribute to the extended risks associated with cigarette smoking that persist after cessation.
吸烟对健康的影响可能在戒烟后持续很长时间，并可能涉及表观遗传重编程。与吸烟相关的 DNA 甲基化变化有助于确定导致暴露和疾病发作之间潜伏期的分子途径。国际 COPD 遗传学网络（n=1085）和波士顿早发性 COPD 研究（n=369）中的受试者的横断面队列数据分别被分析为发现和复制队列。在两个队列中，使用 Illumina HumanMethylation27K Beadchip 从外周血白细胞 DNA 中获得了 27578 个 CpG 位点的全基因组甲基化数据，这些数据涉及 14475 个基因。我们鉴定出 15 个与当前吸烟显著相关的位点，2 个与累计吸烟暴露相关的位点，以及在以前吸烟者的亚组中，3 个与戒烟时间相关的位点。两个基因座，凝血因子 II 受体样 3（F2RL3）和 G 蛋白偶联受体 15（GPR15），在所有三种分析中均显著相关，并通过焦磷酸测序进行了验证。这些发现：(i) 鉴定了一个与吸烟相关的新基因座（GPR15）；(ii) 表明存在针对吸烟的动态、特定部位的甲基化变化，这可能导致戒烟后持续存在的与吸烟相关的长期风险。
