Smokers with the<i>CHRNA</i>Lung Cancer–Associated Variants Are Exposed to Higher Levels of Nicotine Equivalents and a Carcinogenic Tobacco-Specific Nitrosamine

Marchand, Loı̈c Le; Derby, Kiersten S.; Murphy, Sharon E.; Hecht, Stephen S.; Hatsukami, Dorothy K.; Carmella, Steven G.; Tiirikainen, Maarit; Wang, Hansong

doi:10.1158/0008-5472.can-08-2271

Cited by 185 publications

(118 citation statements)

References 14 publications

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“…While we failed to demonstrate an association with cigarette smoking behavior and rs7937 within our case or control groups, both the 15q25 and 19q13 loci have been associated with cotinine levels in other studies that did not find an association with cigarettes per day (44,45), suggesting that standard measures of smoking behavior are incomplete. Issues with measuring the complexity of cigarette smoke exposure such as recall bias (46), as well as differential intensity of smoking per cigarette and effects of cigarette metabolism, may be responsible for the lack of association with pack-years or cigarettes per day in our case and control groups.…”

Section: Discussioncontrasting

confidence: 93%

A Genome-Wide Association Study In COPD Identifies A Susceptibility Locus On Chromosome 19q13

Cho

Castaldi

Hersh

et al. 2011

A95. Cutting Edge Insights to the Pathobiology of Copd and Interstitial Lung Disease

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The genetic risk factors for chronic obstructive pulmonary disease (COPD) are still largely unknown. To date, genome-wide association studies (GWASs) of limited size have identified several novel risk loci for COPD at CHRNA3/CHRNA5/IREB2, HHIP and FAM13A; additional loci may be identified through larger studies. We performed a GWAS using a total of 3499 cases and 1922 control subjects from four cohorts: the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE); the Normative Aging Study (NAS) and National Emphysema Treatment Trial (NETT); Bergen, Norway (GenKOLS); and the COPDGene study. Genotyping was performed on Illumina platforms with additional markers imputed using 1000 Genomes data; results were summarized using fixed-effect meta-analysis. We identified a new genomewide significant locus on chromosome 19q13 (rs7937, OR 5 0.74, P 5 2.9 3 10 29 ). Genotyping this single * Molecular Genetics, 2012, Vol. 21, No. 4 947-957 doi:10.1093/hmg/ddr524 Advance Access published on November 11, 2011nucleotide polymorphism (SNP) and another nearby SNP in linkage disequilibrium (rs2604894) in 2859 subjects from the family-based International COPD Genetics Network study (ICGN) demonstrated supportive evidence for association for COPD (P 5 0.28 and 0.11 for rs7937 and rs2604894), pre-bronchodilator FEV 1 (P 5 0.08 and 0.04) and severe (GOLD 3&4) COPD (P 5 0.09 and 0.017). This region includes RAB4B, EGLN2, MIA and CYP2A6, and has previously been identified in association with cigarette smoking behavior.

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Section: Discussioncontrasting

confidence: 93%

A Genome-Wide Association Study In COPD Identifies A Susceptibility Locus On Chromosome 19q13

Cho

Castaldi

Hersh

et al. 2011

A95. Cutting Edge Insights to the Pathobiology of Copd and Interstitial Lung Disease

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“…Thus, using cigarettes per day and self-reported nicotine dependence as measures for smokingrelated toxin and carcinogen exposure do not fully capture the health risks associated with smoking. This evidence builds on prior findings that showed a strong association between the CHRNA5-CHRNA3-CHRNB4 locus and another smoking biomarker, cotinine, a metabolite of nicotine (7,38,39). Each biomarker has its advantages.…”

Section: Original Researchsupporting

confidence: 69%

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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“…The unique finding here is that psychiatric illnesses affect the same circuit independently from and in addition to the α5 genetic effect. 398Asn has repeatedly shown a signal for smoking (5,7,37,(50)(51)(52)(53)(54) but, thus far, not for increased smoking in other psychiatric diagnoses (36,37). Because the sample sizes for psychiatric diagnoses in the present and many of these previous samples are relatively small, these disorders might potentially show a signal with still larger sample sizes.…”

Section: Discussionmentioning

confidence: 92%

A genetically modulated, intrinsic cingulate circuit supports human nicotine addiction

Hong

Hodgkinson

Yang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

156

131

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Whole-genome searches have identified nicotinic acetylcholine receptor α5-α3-β4 subunit gene variants that are associated with smoking. How genes support this addictive and high-risk behavior through their expression in the brain remains poorly understood. Here we show that a key α5 gene variant Asp398Asn is associated with a dorsal anterior cingulate-ventral striatum/extended amygdala circuit, such that the "risk allele" decreases the intrinsic resting functional connectivity strength in this circuit. Importantly, this effect is observed independently in nonsmokers and smokers, although the circuit strength distinguishes smokers from nonsmokers, predicts addiction severity in smokers, and is not secondary to smoking per se, thus representing a trait-like circuitry biomarker. This same circuit is further impaired in people with mental illnesses, who have the highest rate of smoking. Identifying where and how brain circuits link genes to smoking provides practical neural circuitry targets for new treatment development.genetics | imaging | smoking | functional connectivity | nAChR S moking is influenced by both genetic and environmental factors, although the major factors associated with persistent smoking are genetics [heritability at 75% with minimal shared environmental contribution (1, 2)] and mental illnesses [smoking rate at 50-80% in many mental illnesses (3, 4)]. The brain mechanisms linking these factors to smoking behavior are not clear. In this context, the recent discovery of several polymorphisms at the 15q nicotinic acetylcholine receptor (nAChR) α5-α3-β4 gene cluster is important because they were found based on genomewide searches (5-7), have been replicated a considerable number of times (SI Methods), and provide a starting point to dissect the neurobiological pathways leading to persistent smoking. The most replicated functional marker associated with smoking, and secondarily to lung cancer, is the α5 subunit gene (CHRNA5) rs16969968 or Asp398Asn polymorphism that changes aspartic acid (Asp) to asparagine (Asn) (5-7), with the Asn risk allele reducing α4β2α5 receptor function (6). The α4β2 nAChR is a key regulator of nicotine addiction (8-10), and the participation of the α5 subunit substantially impacts α4β2 function (11).Identifying relevant genes is only the first step in finding more effective therapeutic agents. Identifying the brain circuit(s) linking the "risk alleles" to smoking is an important next step. Brain regions consistently associated with smoking-related behaviors and nicotine actions are the cingulate, striatum, orbitofrontal and prefrontal cortex, insula, and thalamus (12-16). The extant literature suggests that the α5 subunit is expressed cortically mainly in the cingulate; its mRNA expression is found in layer VIb in rats, with the highest concentration in the cingulate (17) and the cortical expression pattern of α5 seen in the cingulate and retrosplenial cortex (18). Subcortically, the α5 subunit is expressed in striatum, thalamus, hippocampus, and amygdala (SI Methods) (17,...

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Smokers with theCHRNALung Cancer–Associated Variants Are Exposed to Higher Levels of Nicotine Equivalents and a Carcinogenic Tobacco-Specific Nitrosamine

Cited by 185 publications

References 14 publications

A Genome-Wide Association Study In COPD Identifies A Susceptibility Locus On Chromosome 19q13

A Genome-Wide Association Study In COPD Identifies A Susceptibility Locus On Chromosome 19q13

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

A genetically modulated, intrinsic cingulate circuit supports human nicotine addiction

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