A phenome-wide association study of genetically determined nicotine metabolism reveals novel links with health-related outcomes.

IF 5.9 1区 医学 Q1 PUBLIC, ENVIRONMENTAL & OCCUPATIONAL HEALTH
Jadwiga Buchwald, Terho Lehtimäki, Olli Raitakari, Veikko Salomaa, Jaakko Kaprio, Matti Pirinen
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引用次数: 0

Abstract

Faster nicotine metabolism, defined as the nicotine metabolite ratio (NMR), is known to associate with heavier smoking and challenges in smoking cessation. However, the broader health implications of genetically determined nicotine metabolism are not well characterized. We performed a hypothesis-free phenome-wide association study (PheWAS) of over 21,000 outcome variables from UK Biobank (UKB) to explore how the NMR (measured as the 3-hydroxycotinine-to-cotinine ratio) associates with the phenome. As the exposure variable, we used a genetic score for faster nicotine metabolism based on 10 putative causal genetic variants, explaining 33.8 % of the variance in the NMR. We analysed ever and never smokers separately to assess whether a causal pathway through nicotine metabolism is plausible. A total of 57 outcome variables reached phenome-wide significance at a false discovery rate of 5 %. We observed expected associations with several phenotypes related to smoking and nicotine, but could not replicate prior findings on cessation. Importantly, we found novel associations between genetically determined faster nicotine metabolism and adverse health outcomes, including unfavourable liver enzyme and lipid values, as well as increased caffeine consumption. These associations did not appear to differ between ever and never smokers, suggesting the corresponding pathways may not involve nicotine metabolism. No favourable health outcomes were linked to genetically determined faster nicotine metabolism. Our findings support a possibility that a future smoking cessation therapy converting fast metabolizers of nicotine to slower ones could work without adverse side effects and potentially even provide other health-related benefits.

基因决定尼古丁代谢的全现象关联研究揭示了与健康相关结果的新联系。
更快的尼古丁代谢,定义为尼古丁代谢物比率(NMR),已知与更严重的吸烟和戒烟的挑战有关。然而,基因决定尼古丁代谢的更广泛的健康影响尚未得到很好的表征。我们对来自UK Biobank (UKB)的超过21,000个结果变量进行了无假设的全表型关联研究(PheWAS),以探索NMR(以3-羟基可替宁与可替宁的比率测量)如何与表型相关。作为暴露变量,我们基于10个假定的因果遗传变异使用了尼古丁代谢更快的遗传评分,解释了核磁共振中33.8%的方差。我们分别分析了曾经吸烟者和从未吸烟者,以评估通过尼古丁代谢的因果途径是否合理。共有57个结果变量在5%的错误发现率下达到全现象显著性。我们观察到与吸烟和尼古丁相关的几种表型的预期关联,但无法复制先前在戒烟方面的发现。重要的是,我们发现了基因决定的更快的尼古丁代谢与不良健康结果之间的新关联,包括不利的肝酶和脂质值,以及咖啡因摄入量的增加。这些关联在从不吸烟者和从不吸烟者之间似乎没有区别,这表明相应的途径可能与尼古丁代谢无关。没有有利的健康结果与基因决定的更快的尼古丁代谢有关。我们的研究结果支持一种可能性,即未来的戒烟疗法将尼古丁的快速代谢物转化为较慢的代谢物,可能没有不良副作用,甚至可能提供其他与健康相关的益处。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
European Journal of Epidemiology
European Journal of Epidemiology 医学-公共卫生、环境卫生与职业卫生
CiteScore
21.40
自引率
1.50%
发文量
109
审稿时长
6-12 weeks
期刊介绍: The European Journal of Epidemiology, established in 1985, is a peer-reviewed publication that provides a platform for discussions on epidemiology in its broadest sense. It covers various aspects of epidemiologic research and statistical methods. The journal facilitates communication between researchers, educators, and practitioners in epidemiology, including those in clinical and community medicine. Contributions from diverse fields such as public health, preventive medicine, clinical medicine, health economics, and computational biology and data science, in relation to health and disease, are encouraged. While accepting submissions from all over the world, the journal particularly emphasizes European topics relevant to epidemiology. The published articles consist of empirical research findings, developments in methodology, and opinion pieces.
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