Dataset Information

A CHRNA5 Smoking Risk Variant Decreases the Aversive Effects of Nicotine in Humans.

ABSTRACT: Genome-wide association studies have implicated the CHRNA5-CHRNA3-CHRNB4 gene cluster in risk for heavy smoking and several smoking-related disorders. The heavy smoking risk allele might reduce the aversive effects of nicotine, but this hypothesis has not been tested in humans. We evaluated the effects of a candidate causal variant in CHRNA5, rs16969968, on the acute response to nicotine in European American (EA) and African American (AA) smokers (n=192; 50% AA; 73% male). Following overnight abstinence from nicotine, participants completed a protocol that included an intravenous (IV) dose of saline and two escalating IV doses of nicotine. The outcomes evaluated were the aversive, pleasurable, and stimulatory ratings of nicotine's effects, cardiovascular reactivity to nicotine, withdrawal severity, and cognitive performance before and after the nicotine administration session. The heavy smoking risk allele (rs16969968*A; frequency=28% (EA) and 6% (AA)) was associated with lower ratings of aversive effects (P<5 × 10(-8)) with marked specificity. This effect was evident in EA and AA subjects analyzed as separate groups and was most robust at the highest nicotine dose. Rs16969968*A was also associated with greater improvement on a measure of cognitive control (Stroop Task) following nicotine administration. These findings support differential aversive response to nicotine as one likely mechanism for the association of CHRNA5-CHRNA3-CHRNB4 with heavy smoking.

SUBMITTER: Jensen KP

PROVIDER: S-EPMC4864657 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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A CHRNA5 Smoking Risk Variant Decreases the Aversive Effects of Nicotine in Humans.

Jensen Kevin P KP DeVito Elise E EE Herman Aryeh I AI Valentine Gerald W GW Gelernter Joel J Sofuoglu Mehmet M

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20150507 12

Genome-wide association studies have implicated the CHRNA5-CHRNA3-CHRNB4 gene cluster in risk for heavy smoking and several smoking-related disorders. The heavy smoking risk allele might reduce the aversive effects of nicotine, but this hypothesis has not been tested in humans. We evaluated the effects of a candidate causal variant in CHRNA5, rs16969968, on the acute response to nicotine in European American (EA) and African American (AA) smokers (n=192; 50% AA; 73% male). Following overnight ab ...[more]

PMID: 25948103

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Project description:A mediation model explores the direct and indirect effects between an independent variable and a dependent variable by including other variables (or mediators). Mediation analysis has recently been used to dissect the direct and indirect effects of genetic variants on complex diseases using case-control studies. However, bias could arise in the estimations of the genetic variant-mediator association because the presence or absence of the mediator in the study samples is not sampled following the principles of case-control study design. In this case, the mediation analysis using data from case-control studies might lead to biased estimates of coefficients and indirect effects. In this article, we investigated a multiple-mediation model involving a three-path mediating effect through two mediators using case-control study data. We propose an approach to correct bias in coefficients and provide accurate estimates of the specific indirect effects. Our approach can also be used when the original case-control study is frequency matched on one of the mediators. We employed bootstrapping to assess the significance of indirect effects. We conducted simulation studies to investigate the performance of the proposed approach, and showed that it provides more accurate estimates of the indirect effects as well as the percent mediated than standard regressions. We then applied this approach to study the mediating effects of both smoking and chronic obstructive pulmonary disease (COPD) on the association between the CHRNA5-A3 gene locus and lung cancer risk using data from a lung cancer case-control study. The results showed that the genetic variant influences lung cancer risk indirectly through all three different pathways. The percent of genetic association mediated was 18.3% through smoking alone, 30.2% through COPD alone, and 20.6% through the path including both smoking and COPD, and the total genetic variant-lung cancer association explained by the two mediators was 69.1%.

Project description:BackgroundRecent meta-analyses show that individuals with high risk variants in CHRNA5 on chromosome 15q25 are likely to develop lung cancer earlier than those with low-risk genotypes. The same high-risk genetic variants also predict nicotine dependence and delayed smoking cessation. It is unclear whether smoking cessation confers the same benefits in terms of lung cancer risk reduction for those who possess CHRNA5 risk variants versus those who do not.MethodsMeta-analyses examined the association between smoking cessation and lung cancer risk in 15 studies of individuals with European ancestry who possessed varying rs16969968 genotypes (N=12,690 ever smokers, including 6988 cases of lung cancer and 5702 controls) in the International Lung Cancer Consortium.ResultsSmoking cessation (former vs. current smokers) was associated with a lower likelihood of lung cancer (OR=0.48, 95%CI=0.30-0.75, p=0.0015). Among lung cancer patients, smoking cessation was associated with a 7-year delay in median age of lung cancer diagnosis (HR=0.68, 95%CI=0.61-0.77, p=4.9∗10-10). The CHRNA5 rs16969968 risk genotype (AA) was associated with increased risk and earlier diagnosis for lung cancer, but the beneficial effects of smoking cessation were very similar in those with and without the risk genotype.ConclusionWe demonstrate that quitting smoking is highly beneficial in reducing lung cancer risks for smokers regardless of their CHRNA5 rs16969968 genetic risk status. Smokers with high-risk CHRNA5 genotypes, on average, can largely eliminate their elevated genetic risk for lung cancer by quitting smoking- cutting their risk of lung cancer in half and delaying its onset by 7years for those who develop it. These results: 1) underscore the potential value of smoking cessation for all smokers, 2) suggest that CHRNA5 rs16969968 genotype affects lung cancer diagnosis through its effects on smoking, and 3) have potential value for framing preventive interventions for those who smoke.

Dataset Information

A CHRNA5 Smoking Risk Variant Decreases the Aversive Effects of Nicotine in Humans.

Publications

A CHRNA5 Smoking Risk Variant Decreases the Aversive Effects of Nicotine in Humans.

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