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Dissecting the genetic overlap of smoking behaviors, lung cancer, and chronic obstructive pulmonary disease: A focus on nicotinic receptors and nicotine metabolizing enzyme.
Genetic Epidemiology ( IF 2.1 ) Pub Date : 2020-08-16 , DOI: 10.1002/gepi.22331
Michael J Bray 1 , Li-Shiun Chen 1, 2 , Louis Fox 1 , Dana B Hancock 3 , Robert C Culverhouse 4, 5 , Sarah M Hartz 1 , Eric O Johnson 3, 6 , Mengzhen Liu 7 , James D McKay 8 , Nancy L Saccone 5, 9 , John E Hokanson 10 , Scott I Vrieze 7 , Rachel F Tyndale 11, 12 , Timothy B Baker 13 , Laura J Bierut 1, 2
Affiliation  

Smoking is a major contributor to lung cancer and chronic obstructive pulmonary disease (COPD). Two of the strongest genetic associations of smoking‐related phenotypes are the chromosomal regions 15q25.1, encompassing the nicotinic acetylcholine receptor subunit genes CHRNA5‐CHRNA3‐CHRNB4, and 19q13.2, encompassing the nicotine metabolizing gene CYP2A6. In this study, we examined genetic relations between cigarettes smoked per day, smoking cessation, lung cancer, and COPD. Data consisted of genome‐wide association study summary results. Genetic correlations were estimated using linkage disequilibrium score regression software. For each pair of outcomes, z‐score‐z‐score (ZZ) plots were generated. Overall, heavier smoking and decreased smoking cessation showed positive genetic associations with increased lung cancer and COPD risk. The chromosomal region 19q13.2, however, showed a different correlational pattern. For example, the effect allele‐C of the sentinel SNP (rs56113850) within CYP2A6 was associated with an increased risk of heavier smoking (z‐score = 19.2; p = 1.10 × 10−81), lung cancer (z‐score = 8.91; p = 5.02 × 10−19), and COPD (z‐score = 4.04; p = 5.40 × 10−5). Surprisingly, this allele‐C (rs56113850) was associated with increased smoking cessation (z‐score = −8.17; p = 2.52 × 10−26). This inverse relationship highlights the need for additional investigation to determine how CYP2A6 variation could increase smoking cessation while also increasing the risk of lung cancer and COPD likely through increased cigarettes smoked per day.

中文翻译:

剖析吸烟行为、肺癌和慢性阻塞性肺疾病的基因重叠:重点关注烟碱受体和尼古丁代谢酶。

吸烟是导致肺癌和慢性阻塞性肺病(COPD)的主要原因。吸烟相关表型的两个最强的遗传关联是染色体区域 15q25.1(包含烟碱乙酰胆碱受体亚基基因CHRNA5-CHRNA3-CHRNB4)和 19q13.2(包含尼古丁代谢基因CYP2A6)。在这项研究中,我们研究了每天吸烟的数量、戒烟、肺癌和慢性阻塞性肺病之间的遗传关系。数据包括全基因组关联研究总结结果。使用连锁不平衡评分回归软件估计遗传相关性。对于每对结果,生成 z-score-z-score (ZZ) 图。总体而言,吸烟量增加和戒烟率下降与肺癌和慢性阻塞性肺病风险增加呈正相关。然而,染色体区域 19q13.2 显示出不同的相关模式。例如, CYP2A6内前哨 SNP (rs56113850) 的效应等位基因-C与大量吸烟 ( z分数 = 19.2; p  = 1.10 × 10 −81 )、肺癌 ( z分数 = 8.91)的风险增加相关。;p  = 5.02 × 10 −19)和 COPD(z评分 = 4.04;p  = 5.40 × 10 −5)。令人惊讶的是,该等位基因-C (rs56113850) 与戒烟率增加相关( z分数= -8.17;p  = 2.52 × 10 -26 )。这种反比关系凸显了需要进行额外的研究,以确定CYP2A6变异如何促进戒烟,同时还可能通过增加每天吸烟量来增加患肺癌和慢性阻塞性肺病的风险。
更新日期:2020-09-11
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