A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25

Hung, Rayjean J.; McKay, James; Gaborieau, Valérie; Boffetta, Paolo; Hashibe, Mia; Заридзе, Давид; Mukeria, Anush; Szeszenia-Dabrowska, Neonilia; Lissowska, Jolanta; Rudnai, Péter; Fabiánovà, Eleonóra; Mateș, Dana; Bencko, Vladimír; Foretová, Lenka; Janout, Vladimí­r; Chen, Chu; Goodman, Gary E.; Field, John K.; Liloglou, Triantafillos; Xinarianos, George; Cassidy, Adrian; McLaughlin, John; Liu, Geoffrey; Narod, Steven A.; Krokan, Hans E.; Skorpen, Frank; Elvestad, Maiken B.; Hveem, Kristian; Vatten, Lars J.; Linseisen, Jakob; Clavel‐Chapelon, Françoise; Víneis, Paolo; Bueno-De-Mesquita, H. Bas; Lund, Eiliv; Martı́nez, Carmen; Bingham, Sheila; Rasmuson, Torgny; Hainaut, Pierre; Riboli, Elio; Ahrens, Wolfgang; Benhamou, Simone; Λάγιου, Παγώνα; Trichopoulos, Dimitrios; Holcátová, Ivana; Merletti, Franco; Kjærheim, Kristina; Agudo, Antonio; Macfarlane, Gary J.; Talamini, Renato; Simonato, Lorenzo; Lowry, Ray; Conway, David I.; Znaor, Ariana; Healy, Claire M.; Zélénika, Diana; Boland, Anne; Délépine, Marc; Foglio, Mario; Lechner, Doris; Matsuda, Fumihiko; Blanché, Hélène; Gut, Ivo; Heath, Simon; Lathrop, Mark; Brennan, Paul

doi:10.1038/nature06885

Cited by 1,148 publications

(1,045 citation statements)

References 22 publications

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“…We also confirmed the associations between this variance and incident COPD 4, 13, 14, tobacco‐related cancers 7, 15, 16, lung cancer 4, 7, 15, 17, 18, 19, 20, 21 and smoking quantity 2, 3, 7, indicating an exciting overlap of genetic influence on ND and smoking‐related diseases. As mentioned above, this region of the nAChRs is characterized by high correlation and the results should be interpreted as an association with the cluster instead of the rs1051730.…”

Section: Discussionsupporting

confidence: 74%

Gene variance in the nicotinic receptor cluster (CHRNA5‐CHRNA3‐CHRNB4) predicts death from cardiopulmonary disease and cancer in smokers

et al. 2015

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BackgroundGenetic variation in the cluster on chromosome 15, encoding the nicotinic acetylcholine receptor subunits (CHRNA5‐CHRNA3‐CHRNB4), has shown strong associations with tobacco consumption and an additional risk increase in smoking‐related diseases such as chronic obstructive pulmonary disease (COPD), peripheral artery disease and lung cancer.ObjectivesTo test whether rs1051730 (C/T), a tag for multiple variants in the CHRNA5‐CHRNA3‐CHRNB3 cluster, is associated with a change in risk of smoking‐related mortality and morbidity in the Malmö Diet and Cancer study, a population‐based prospective cohort study.MethodsAt baseline participants were classified as current (n = 6951), previous (n = 8426) or never (n = 9417) smokers. Cox‐proportional hazards models were used to determine the correlation between rs1051730 and incidence of first COPD, tobacco‐related cancer, other cancer and cardiovascular disease (CVD), and total mortality due to these causes, during approximately 14 years of follow‐up.ResultsAmongst current smokers there were 480 first incident COPD events, 852 tobacco‐related cancers, 810 other cancers and 1022 CVD events. A total of 1508 deaths occurred, including 500 due to CVD, 102 due to respiratory diseases and 677 due to cancer. In adjusted additive models, an increasing number of T alleles were associated with a gradual increase in total mortality, incident COPD and tobacco‐related cancer, even after adjustment for smoking quantity. No significant associations were observed amongst never smokers.ConclusionOur data suggest that gene variance in the CHRNA5‐CHRNA3‐CHRNB4 cluster is associated with an increased risk of death, incidence of COPD and tobacco‐related cancer in smokers. These findings indicate an individual susceptibility to tobacco use and its complications; this may be important when targeting and designing smoking cessation therapies.

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Section: Discussionsupporting

confidence: 74%

Gene variance in the nicotinic receptor cluster (CHRNA5‐CHRNA3‐CHRNB4) predicts death from cardiopulmonary disease and cancer in smokers

et al. 2015

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“…A SNP in CHRNA3 (rs1051730) that is in linkage disequilibrium with other SNPs in the CHRNA5-CHRNA3-CHRNB4 gene cluster [142] was associated with smoking quantity, nicotine dependence, risk for peripheral arterial disease [171], and risk for lung cancer [1,74,171]. Furthermore, Hung and colleagues [74] identified a non-synonymous SNP in CHRNA5 (rs16969968) that was associated with risk for lung cancer, and this finding was replicated in five independent studies. Although these data suggest that the CHRNA5-CHRNA3-CHRNB4 gene cluster is directly associated with risk for lung cancer, it is possible that this gene cluster alters risk for nicotine dependence, and subsequent tobacco smoking increases risk for lung cancer.…”

Section: The Chrnb3-chrna6 and Chrna5-chrna3-chrnb4 Gene Clustersmentioning

confidence: 83%

“…These SNPs, along with those identified by Saccone and colleagues [142], belong to a common CHRNA5-CHRNA3 haplotype that is associated with risk for smoking quantity. Three independent genome-wide association studies have also linked the CHRNA5-CHRNA3-CHRNB4 gene cluster to risk for lung cancer, smoking quantity, and nicotine dependence [1,74,171]. A SNP in CHRNA3 (rs1051730) that is in linkage disequilibrium with other SNPs in the CHRNA5-CHRNA3-CHRNB4 gene cluster [142] was associated with smoking quantity, nicotine dependence, risk for peripheral arterial disease [171], and risk for lung cancer [1,74,171].…”

Section: The Chrnb3-chrna6 and Chrna5-chrna3-chrnb4 Gene Clustersmentioning

confidence: 99%

“…Three independent genome-wide association studies have also linked the CHRNA5-CHRNA3-CHRNB4 gene cluster to risk for lung cancer, smoking quantity, and nicotine dependence [1,74,171]. A SNP in CHRNA3 (rs1051730) that is in linkage disequilibrium with other SNPs in the CHRNA5-CHRNA3-CHRNB4 gene cluster [142] was associated with smoking quantity, nicotine dependence, risk for peripheral arterial disease [171], and risk for lung cancer [1,74,171]. Furthermore, Hung and colleagues [74] identified a non-synonymous SNP in CHRNA5 (rs16969968) that was associated with risk for lung cancer, and this finding was replicated in five independent studies.…”

Section: The Chrnb3-chrna6 and Chrna5-chrna3-chrnb4 Gene Clustersmentioning

confidence: 99%

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Genetic variability in nicotinic acetylcholine receptors and nicotine addiction: Converging evidence from human and animal research

Portugal

Gould

2008

Behavioural Brain Research

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Tobacco smoking is a leading preventable cause of death in the United States and produces a major health and economic burden. Although the majority of smokers want to quit, few are successful. These data highlight the need for additional research into the neurobiology of tobacco dependence. Addiction to nicotine, the main psychoactive component of tobacco, is influenced by multiple factors that include individual differences in genetic makeup. Twin studies have demonstrated that genetic factors can influence vulnerability to nicotine addiction, and subsequent research has identified genes that may alter sensitivity to nicotine. In humans, genome-wide and candidate gene association studies have demonstrated that genes encoding nicotinic acetylcholine receptor (nAChR) proteins are associated with multiple smoking phenotypes. Similarly, research in mice has provided evidence that naturally occurring variability in nAChR genes is associated with changes in nicotine sensitivity. Furthermore, the use of genetic knockout mice has allowed researchers to determine the nAChR genes that mediate the effects of nicotine, whereas research with knockin mice has demonstrated that changes to nAChR genes can dramatically alter nicotine sensitivity. This review will examine the genetic factors that alter susceptibility to nicotine addiction, with an emphasis on the genes that encode nAChR proteins.

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“…[85][86][87] For lung cancer, the first convincing genetic locus also emerged, 15q25, which contained several genes encoding for nicotinic acetylcholine receptors. [88][89][90] The combination of three GWAS further identified additional susceptibility loci for this common cancer, 75 where one of the loci (5p15.33) was also identified by another GWAS. 91 The 5p15.33 locus contains two genes, TERT and CLPTM1L, and interestingly the sequence variants at this locus were found to be associated with several cancers.…”

Section: The Recent 2 Years: 2008 and 2009mentioning

confidence: 96%

The pursuit of genome-wide association studies: where are we now?

et al. 2010

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It is now 5 years since the first genome-wide association studies (GWAS), published in 2005, identified a common risk allele with large effect size for age-related macular degeneration in a small sample set. Following this exciting finding, researchers have become optimistic about the prospect of the genome-wide association approach. However, most of the risk alleles identified in the subsequent GWAS for various complex diseases are common with small effect sizes (odds ratio o1.5). So far, more than 450 GWAS have been published and the associations of greater than 2000 single nucleotide polymorphisms (SNPs) or genetic loci were reported. The aim of this review paper is to give an overview of the evolving field of GWAS, discuss the progress that has been made by GWAS and some of the interesting findings, and summarize what we have learned over the past 5 years about the genetic basis of human complex diseases. This review will focus on GWAS of SNPs association for complex diseases but not studies of copy number variations.

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A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25

Cited by 1,148 publications

References 22 publications

Gene variance in the nicotinic receptor cluster (CHRNA5‐CHRNA3‐CHRNB4) predicts death from cardiopulmonary disease and cancer in smokers

Gene variance in the nicotinic receptor cluster (CHRNA5‐CHRNA3‐CHRNB4) predicts death from cardiopulmonary disease and cancer in smokers

Genetic variability in nicotinic acetylcholine receptors and nicotine addiction: Converging evidence from human and animal research

The pursuit of genome-wide association studies: where are we now?

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