Melroy-Greif Whitney E, Simonson Matthew A, Corley Robin P, Lutz Sharon M, Hokanson John E, Ehringer Marissa A
Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, La Jolla, CA.
Massachusetts Institute of Technology, Cambridge, MA.
Nicotine Tob Res. 2017 Apr 1;19(4):417-425. doi: 10.1093/ntr/ntw200.
Cigarette smoking is a physiologically harmful habit. Nicotinic acetylcholine receptors (nAChRs) are bound by nicotine and upregulated in response to chronic exposure to nicotine. It is known that upregulation of these receptors is not due to a change in mRNA of these genes, however, more precise details on the process are still uncertain, with several plausible hypotheses describing how nAChRs are upregulated. We have manually curated a set of genes believed to play a role in nicotine-induced nAChR upregulation. Here, we test the hypothesis that these genes are associated with and contribute risk for nicotine dependence (ND) and the number of cigarettes smoked per day (CPD).
Studies with genotypic data on European and African Americans (EAs and AAs, respectively) were collected and a gene-based test was run to test for an association between each gene and ND and CPD.
Although several novel genes were associated with CPD and ND at P < 0.05 in EAs and AAs, these associations did not survive correction for multiple testing. Previous associations between CHRNA3, CHRNA5, CHRNB4 and CPD in EAs were replicated.
Our hypothesis-driven approach avoided many of the limitations inherent in pathway analyses and provided nominal evidence for association between cholinergic-related genes and nicotine behaviors.
We evaluated the evidence for association between a manually curated set of genes and nicotine behaviors in European and African Americans. Although no genes were associated after multiple testing correction, this study has several strengths: by manually curating a set of genes we circumvented the limitations inherent in many pathway analyses and tested several genes that had not yet been examined in a human genetic study; gene-based tests are a useful way to test for association with a set of genes; and these genes were collected based on literature review and conversations with experts, highlighting the importance of scientific collaboration.
吸烟是一种对生理有害的习惯。烟碱型乙酰胆碱受体（nAChRs）与尼古丁结合，并在长期暴露于尼古丁的情况下上调。已知这些受体的上调并非由于这些基因的mRNA发生变化，然而，关于该过程的更精确细节仍不确定，有几种合理的假设描述了nAChRs是如何上调的。我们手动整理了一组据信在尼古丁诱导的nAChR上调中起作用的基因。在此，我们检验以下假设：这些基因与尼古丁依赖（ND）相关并导致其风险，以及与每日吸烟量（CPD）相关。
收集了有关欧洲裔和非裔美国人（分别为EAs和AAs）基因型数据的研究，并进行了基于基因的测试，以检验每个基因与ND和CPD之间的关联。
尽管在EAs和AAs中，有几个新基因在P < 0.05时与CPD和ND相关，但这些关联在多重检验校正后未通过。之前在EAs中CHRNA3、CHRNA5、CHRNB4与CPD之间的关联得到了重复。
我们基于假设的方法避免了通路分析中固有的许多局限性，并为胆碱能相关基因与尼古丁行为之间的关联提供了名义证据。
我们评估了一组手动整理的基因与欧洲裔和非裔美国人尼古丁行为之间关联的证据。尽管在多重检验校正后没有基因显示出关联，但本研究有几个优点：通过手动整理一组基因，我们规避了许多通路分析中固有的局限性，并测试了一些尚未在人类基因研究中检验过的基因；基于基因的测试是检验与一组基因关联的有用方法；并且这些基因是基于文献综述和与专家的交流收集的，突出了科学合作的重要性。
