Sequence variants at CHRNB3–CHRNA6 and CYP2A6 affect smoking behavior

Thorgeirsson, Thorgeir E.; Guðbjartsson, Daníel F.; Surakka, Ida; Vink, Jacqueline M.; Amin, Najaf; Geller, Frank; Sulem, Patrick; Rafnar, Thorunn; Esko, Tõnu; Walter, Stefan; Gieger, Christian; Rawal, Rajesh; Mangino, Massimo; Prokopenko, Inga; Mägi, Reedik; Keskitalo, Kaisu; Gudjonsdottir, Iris H; Grétarsdóttir, Sólveig; Stefánsson, Hreinn; Thompson, John R.; Aulchenko, Yurii S.; Nelis, Mari; Aben, Katja K.H.; Heijer, Martin den; Dirksen, Asger; Ashraf, Haseem; Soranzo, Nicole; Valdes, Ana M.; Steves, Claire J.; Uitterlinden, André G.; Hofman, Albert; Tönjes, Anke; Kovacs, Peter; Hottenga, Jouke Jan; Willemsen, Gonneke; Vogelzangs, Nicole; Döring, Angela; Dahmen, Norbert; Nitz, Barbara; Pergadia, Michele L.; Sáez, Berta; Diego, Veronica De; Lezcano, Victoria; García-Prats, María Dolores; Ripatti, Samuli; Perola, Markus; Kettunen, Johannes; Hartikainen, Anna-Liisa; Pouta, Anneli; Laitinen, Jaana; Isohanni, Matti; Shen, Huei-Yi; Allen, Maxine; Krestyaninova, Maria; Hall, Alistair S.; Jones, Gregory T.; Rij, André M. van; Mueller, Thomas; Dieplinger, Benjamin; Haltmayer, Meinhard; Jónsson, Steinn; Matthíasson, Stefán E.; Óskarsson, Högni; Tyrfingsson, Þorarinn; Kiemeney, Lambertus A.; Mayordomo, J. I.; Lindholt, Jes Sanddal; Pedersen, Jesper Holst; Franklin, Wilbur A.; Wolf, Holly J.; Montgomery, Grant W.; Heath, Andrew C.; Martin, Nicholas G.; Madden, Pamela A. F.; Giegling, Ina; Rujescu, Dan; Järvelin, Marjo‐Riitta; Salomaa, Veikko; Stümvoll, Michael; Spector, Tim D.; Wichmann, H‐Erich; Metspalu, Andres; Samani, Nilesh J.; Penninx, Brenda W. J. H.; Oostra, Ben A.; Boomsma, Dorret I.; Tiemeier, Henning; Duijn, Cornelia M. van; Kaprio, Jaakko; Gulcher, Jeffrey R.; McCarthy, Mark I.; Peltonen, Leena; Þorsteinsdóttir, Unnur; Stefánsson, Kāri

doi:10.1038/ng.573

Cited by 644 publications

(760 citation statements)

References 35 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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“…The variant rs28399442 is strongly associated with CO (b = 25.45; 95% The results for these two loci are summarized in Table 2, and association In contrast to the CHRNA5-CHRNA3-CHRNB4 and CYP2A6 results, the region spanning CHRNB3-CHRNA6 on chromosome 8 does not have any genotyped variants that show association with CO, cigarettes per day, or nicotine dependence. For example, rs4950, a variant strongly associated with nicotine dependence at a genomewide significance level in previous studies (28,37), is not associated with CO (b = 20.25; 95% CI, 21.33 to 0.83; P = 0.647).…”

Section: Resultsmentioning

confidence: 99%

“…Analyses were performed using PLINK v1.07 (27). Additional association analyses with CO focused on targeted regions that represent three key genetic loci known to be associated with smoking behavior at genomewide significance in Europeanancestry populations (28,29): the chromosome 15q25.1 locus, which includes the a5-a3-b4 nicotinic receptor subunit genes (CHRNA5-CHRNA3-CHRNB4); the chromosome 19q13.2 locus, which includes the primary gene responsible for nicotinic metabolism (CYP2A6); and the chromosome 8p11.21 locus, which includes the b3-a6 nicotinic receptor subunit genes (CHRNB3-CHRNA6). Analyses were performed using SAS (Cary, NC).…”

Section: Methodsmentioning

confidence: 99%

Beyond Cigarettes Per Day. A Genome-Wide Association Study of the Biomarker Carbon Monoxide

Bloom¹,

Hartz²,

Baker

et al. 2014

Annals ATS

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Rationale: The CHRNA5-CHRNA3-CHRNB4 locus is associated with self-reported smoking behavior and also harbors the strongest genetic associations with chronic obstructive pulmonary disease (COPD) and lung cancer. Because the associations with lung disease remain after adjustment for self-reported smoking behaviors, it has been asserted that CHRNA5-CHRNA3-CHRNB4 variants increase COPD and lung cancer susceptibility independently of their effects on smoking.Objectives: To compare the genetic associations of exhaled carbon monoxide (CO), a biomarker of current cigarette exposure, with self-reported smoking behaviors.Methods: A total of 1,521 European American and 247 African American current smokers recruited into smoking cessation studies were assessed for CO at intake before smoking cessation. DNA samples were genotyped using the Illumina Omni2.5 microarray. Genetic associations with CO and smoking behaviors (cigarettes smoked per day, Fagerstrom test for nicotine dependence) were studied. Measurements and Main Results:Variants in the CHRNA5-CHRNA3-CHRNB4 locus, including rs16969968, a nonsynonymous variant in CHRNA5, are genomewide association study-significantly associated with CO (b = 2.66; 95% confidence interval [CI], 1.74-3.58; P = 1.65 3 10 28 ), and this association remains strong after adjusting for smoking behavior (b = 2.18; 95% CI, 1.32-3.04; P = 7.47 3 10 27 ). The correlation between CO and cigarettes per day is statistically significantly lower (z = 3.43; P = 6.07 3 10 24 ) in African Americans (r = 0.14; 95% CI, 0.02-0.26; P = 0.003) than in European-Americans (r = 0.36; 95% CI, 0.31-0.40; P = 0.0001).Conclusions: Exhaled CO, a biomarker that is simple to measure, captures aspects of cigarette smoke exposure in current smokers beyond the number of cigarettes smoked per day. Behavioral measures of smoking are therefore insufficient indices of cigarette smoke exposure, suggesting that genetic associations with COPD or lung cancer that persist after adjusting for self-reported smoking behavior may still reflect genetic effects on smoking exposure.

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“…Several single-nucleotide polymorphisms (SNPs) in the gene cluster CHRNA3/CHRNB4/CHRNA5 were reported to be associated with the risk of both diseases. [11][12][13] These variants are also associated with prognosis of lung cancer. 11,14,15 However, these SNPs can only explain a small proportion of disease heritability as shown by the relatively small increments in risk they have, reflecting 'Missing heritability' exists.…”

Section: Introductionmentioning

confidence: 99%

Duplicated copy of CHRNA7 increases risk and worsens prognosis of COPD and lung cancer

Yang

Qiu

et al. 2014

Eur J Hum Genet

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Recent genome-wide association studies implicated that the nicotinic acetylcholine receptors (nAChRs) are common susceptible genes of two contextual diseases: chronic obstructive pulmonary disease (COPD) and lung cancer. We aimed to test whether the copy number variations (CNVs) in nAChRs have hereditary contributions to development of the two diseases. In two, two-stage, case-control studies of southern and eastern Chinese, a common CNV-3956 that duplicates the cholinergic receptor, nicotinic, α7 (CHRNA7) gene was genotyped in a total of 7880 subjects and its biological phenotype was assessed. The ≥ 4-copy of CNV-3956 increased COPD risk (≥4-copy vs 2/3-copy: OR = 1.44, 95% CI = 1.23-1.68) and caused poor lung function, and it similarly augmented risk (OR = 1.49, 95% CI = 1.29-1.73) and worsened prognosis (hazard ratio (HR) = 1.25, 95% CI = 1.07-1.45) of lung cancer. The ≥ 4-copy was estimated to account for 1.56% of COPD heritability and 1.87% of lung cancer heritability, respectively. Phenotypic analysis further showed that the ≥ 4-copy of CNV-3956 improved CHRNA7 expression in vivo and increased the carriers' smoking amount. The CNV-3956 of CHRNA7 contributed to increased risks and poor prognoses of both COPD and lung cancer, and this may be a genetic biomarker of the two diseases.

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Sequence variants at CHRNB3–CHRNA6 and CYP2A6 affect smoking behavior

Cited by 644 publications

References 35 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

Beyond Cigarettes Per Day. A Genome-Wide Association Study of the Biomarker Carbon Monoxide

Duplicated copy of CHRNA7 increases risk and worsens prognosis of COPD and lung cancer

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