吸烟行为及尼古丁成瘾的遗传学和表观遗传学机制探索

发布时间：2018-01-03 07:22

本文关键词：吸烟行为及尼古丁成瘾的遗传学和表观遗传学机制探索　出处：《浙江大学》2017年博士论文　论文类型：学位论文

【摘要】：吸烟行为严重危害着人们的身体健康,它能导致多种疾病产生,如癌症。全球每年约有600万人死于吸烟导致的相关疾病。人类正面临着吸烟带来的巨大的健康挑战,急需要大量吸烟相关研究的开展。因为吸烟行为受到环境因素和遗传因素的共同影响,我们从流行病学、遗传学和表观遗传学等不同的角度对吸烟行为及其危害进行研究。1)流行病学研究:尽管一些研究报道了中国人群的吸烟率很高及其流行情况,但仍没有开展关于中国尼古丁成瘾流行情况的研究。为了进一步探究这些问题,我们在山西和浙江两省进行了大规模的流行病学调查。从2012年到2014年,总共收集了 17,057个成年人样本(男性为13,476个;女性为3,581个)。我们发现中国男性的吸烟率高达66.1%,而女性的吸烟率仅为3.2%。在男性吸烟者中,有18.2%是高度成瘾者和39.8%为中度成瘾者,这些成瘾的吸烟者很难在无外界帮助下自行戒烟。我们还发现尼古丁成瘾的程度与年龄、教育程度和家庭收入呈显著相关,并且社会环境对吸烟的起始影响明显,尤其是受到身旁朋友吸烟的影响。另外,吸烟者患呼吸道和消化道疾病的风险显著增加。2)遗传学研究:为了探索遗传因素对戒烟的作用,我们整合了 22项关于DRD2/ANKK1 Taq1A突变位点与戒烟关联的研究(N=11,075)进行Meta分析。在横断面研究和纵向研究中,我们分别发现Taq1AA1/*基因型和戒烟之间存在显著关联。通过合并两种研究分析,我们发现Taq1AA1/*基因型与戒烟之间关联变得更加显著(p=3.9×10-5)且无任何研究间异质性或者发表偏倚存在。3)表观遗传学研究:DNA甲基化修饰在致癌过程中发挥着重要调节作用。此前全基因组甲基化关联研究已经发现了大量与吸烟相关的甲基化位点,因此,我们检验的假设是这些已发现的甲基化位点很可能富集在癌症和其它疾病相关的基因和信号通路上。我们从28项基于血液和口腔组织样本(N=18,677)的研究中收集了两组吸烟相关的差异甲基化基因。首先对血液样本的320个基因进行通路富集分析,我们发现了 57条通路与癌症相关(FDR0.05)。然后,我们用相同的方法对口腔组织样本的661个基因进行分析,有11条通路在口腔样本中被验证(p0.05)。最后我们对共有通路中48个基因进行癌症致病蛋白网络构建。在这些48个基因中,许多基因如DUSP4和AKT3在吸烟相关的肺癌发生中发挥重要作用。总结起来,我们第一次大规模研究中国人群中吸烟及尼古丁成瘾流行情况。通过Meta分析,我们发现Taq1A突变位点在戒烟过程中发挥着重要作用,带有A2/A2基因型的吸烟者提高22%的戒烟率。最后我们提供了系统而有力的证据支持吸烟可以通过DNA甲基化修饰导致癌症发生。
[Abstract]:Smoking seriously harms people's health, it can lead to a variety of diseases. For example, cancer. Every year about 6 million people worldwide die from smoking-related diseases. Human beings are facing the enormous health challenges posed by smoking. There is an urgent need for a large number of smoking-related studies. Because smoking behavior is influenced by both environmental and genetic factors, we start from epidemiology. (1) Epidemiological studies on smoking behavior and its hazards from different perspectives such as genetics and epigenetics: although some studies have reported high smoking rates and their prevalence in Chinese population. However, no study has been carried out on the prevalence of nicotine addiction in China. We conducted large-scale epidemiological surveys in Shanxi and Zhejiang provinces. From 2012 to 2014, we collected a total of 17,057 adult samples (13,476 males; We found that the smoking rate of Chinese men was as high as 66.1%, while the female smoking rate was only 3.2% among male smokers. 18.2% were highly addicted and 39.8% were moderately addicted, and it was difficult for addicted smokers to quit without outside help. We also found the extent and age of nicotine addiction. Education level was significantly related to family income, and the social environment had a significant impact on the onset of smoking, especially by friends around the influence of smoking. Genetic studies: to explore the role of genetic factors in smoking cessation, a significant increase in the risk of respiratory and digestive tract diseases in smokers. We integrated 22 studies on the association of DRD2/ANKK1 Taq1A mutation sites with smoking cessation. In cross-sectional and longitudinal studies, we found a significant correlation between Taq1AA1 * genotype and smoking cessation. We found that the association between Taq1AA1 / * genotype and smoking cessation became more significant (p3.9 脳 10-5) and there was no inter-study heterogeneity or publication bias. 3). Epigenetics study: DNA methylation modification plays an important regulatory role in carcinogenesis. Previous genome-wide methylation association studies have identified a large number of smoking related methylation sites. Therefore, we examined the hypothesis that these identified methylation sites are likely to be enriched in genes and signaling pathways associated with cancer and other diseases. Two groups of differentially methylated genes related to smoking were collected in the study. Firstly 320 genes in blood samples were analyzed for pathway enrichment. We found 57 pathways associated with cancer. Then we analyzed 661 genes in oral tissue samples using the same method. Eleven pathways were confirmed in oral samples. Finally, we constructed a network of cancer causing proteins for 48 genes in a common pathway. Of these 48 genes. Many genes such as DUSP4 and AKT3 play an important role in smoking-related lung cancer. For the first time, we studied the prevalence of smoking and nicotine addiction in Chinese population. By Meta analysis, we found that Taq1A mutation site plays an important role in smoking cessation. Smokers with the A2 / A2 genotype increased the smoking cessation rate by 22%. Finally, we provide systematic and strong evidence that smoking can lead to cancer through DNA methylation.
【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R749.64

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