Takeuchi Fumihiko, Takano Kozue, Yamamoto Masaya, Isono Masato, Miyake Wataru, Mori Kotaro, Hara Hisao, Hiroi Yukio, Kato Norihiro
Department of Gene Diagnostics and Therapeutics, Research Institute, National Center for Global Health and Medicine.
Medical Genomics Center, Research Institute, National Center for Global Health and Medicine.
Circ J. 2022 May 25;86(6):986-992. doi: 10.1253/circj.CJ-21-0958. Epub 2022 Feb 1.
Tobacco smoking is a leading preventable cause of morbidity and mortality worldwide; still, the success rate of smoking cessation is low in general. From the viewpoint of public health and clinical care, an objective biomarker of long-term smoking behavior is sought.
This study assessed DNA methylation as a biomarker of smoking in a hospital setting through a combination of molecular approaches including genetic, DNA methylation and mRNA expression analyses. First, in an epigenome-wide association study involving Japanese individuals with chronic cardiovascular disease (n=94), genome-wide significant smoking association was identified at 2 CpG sites on chromosome 5, with the strongest signal at cg05575921 located in intron 3 of the aryl-hydrocarbon receptor repressor (AHRR) gene. Highly significant (P<1×10) smoking-cg05575921 association was validated in 2 additional panels (n=339 and n=300). For the relationship of cg05575921 methylation extent with time after smoking cessation and cumulative cigarette consumption among former smokers, smoking-related hypomethylation was found to remain for ≥20 years after smoking cessation and to be affected by multiple factors, such as cis-interaction of genetic variation. There was a significant inverse correlation (P=0.0005) between cg05575921 methylation extent and AHRR mRNA expression.
The present study results support that reversion of AHRR hypomethylation can be a quantifiable biomarker for progress in and observance of smoking cessation, although some methodological points need to be considered.
吸烟是全球可预防的主要发病和死亡原因；然而，总体戒烟成功率较低。从公共卫生和临床护理的角度来看，人们一直在寻找长期吸烟行为的客观生物标志物。
本研究通过结合包括基因、DNA甲基化和mRNA表达分析在内的分子方法，在医院环境中评估DNA甲基化作为吸烟的生物标志物。首先，在一项涉及日本慢性心血管疾病患者（n = 94）的全表观基因组关联研究中，在5号染色体上的2个CpG位点发现了全基因组显著的吸烟关联，最强信号位于芳烃受体阻遏物（AHRR）基因内含子3中的cg05575921。在另外两个队列（n = 339和n = 300）中验证了高度显著（P < 1×10）的吸烟与cg05575921的关联。对于前吸烟者中cg05575921甲基化程度与戒烟后时间和累积吸烟量的关系，发现吸烟相关的低甲基化在戒烟后≥20年仍存在，并受多种因素影响，如基因变异的顺式相互作用。cg05575921甲基化程度与AHRR mRNA表达之间存在显著负相关（P = 0.0005）。
本研究结果支持AHRR低甲基化的逆转可以作为戒烟进展和依从性的可量化生物标志物，尽管需要考虑一些方法学要点。
