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Cholinergic receptor nicotinic alpha 5 subunit polymorphisms are associated with smoking cessation success in women.

ABSTRACT: BACKGROUND:The identification of variants in the nicotinic acetylcholine receptor (nAChR) subunit genes associated with smoking phenotypes are increasingly important for prevention and treatment of nicotine dependence. In the context of personalized medicine, the aims of this study were to evaluate whether cholinergic receptor nicotinic alpha 2 (CHRNA2), cholinergic receptor nicotinic alpha 3 (CHRNA3), cholinergic receptor nicotinic alpha 5 (CHRNA5) and cholinergic receptor nicotinic beta 3 (CHRNB3) polymorphisms were associated with nicotine dependence severity, and to investigate possible pharmacogenetics markers of smoking cessation treatment. METHODS:This study cohort enrolled 1049 smoking patients who received pharmacological treatment (varenicline, varenicline plus bupropion, bupropion plus/or nicotine replacement therapy). Smoking cessation success was considered for patients who completed 6 months of continuous abstinence. Fagerström test for nicotine dependence (FTND) and Issa situational smoking scores (Issa score) were analyzed for nicotine dependence. CHRNA2 (rs2472553), CHRNA3 (rs1051730), CHRNA5 (rs16969968 and rs2036527) and CHRNB3 (rs6474413) polymorphisms were genotyped by high resolution melting analysis. RESULTS:Females with GA and AA genotypes for CHRNA5 rs16969968 and rs2036527 polymorphisms had higher success rate in smoking cessation treatment: 44.0% and 56.3% (rs16969968), 41.5% and 56.5% (rs2036527), respectively, compared with carriers of the GG genotypes: 35.7% (rs16969968), 34.8% (rs2036527), (P?=?0.03, n?=?389; P?=?0.01, n?=?391). The GA or AA genotypes for the rs16969968 and rs2036527 were associated with higher odds ratio for success in women (OR?=?1.63; 95% CI?=?1.04 to 2.54; P?=?0.03 and OR?=?1.59, 95% CI?=?1.02 to 2.48; P?=?0.04; respectively). We did not find association of these polymorphisms with nicotine dependence related scores. Polymorphisms in the CHRNA2, CHRNA3 and CHRNB3 genes were not associated with the phenotypes studied. CONCLUSION:CHRNA5 rs16969968 and rs2036527 were associated with higher success rate in the smoking cessation treatment in women. These findings might contribute to advances in personalized medicine.

SUBMITTER: Tomaz PRX

PROVIDER: S-EPMC5887212 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Cholinergic receptor nicotinic alpha 5 subunit polymorphisms are associated with smoking cessation success in women.

Tomaz Paulo Roberto Xavier PRX Santos Juliana Rocha JR Scholz Jaqueline J Abe Tânia Ogawa TO Gaya Patrícia Viviane PV Negrão André Brooking AB Krieger José Eduardo JE Pereira Alexandre Costa AC Santos Paulo Caleb Júnior Lima PCJL

BMC medical genetics 20180405 1

<h4>Background</h4>The identification of variants in the nicotinic acetylcholine receptor (nAChR) subunit genes associated with smoking phenotypes are increasingly important for prevention and treatment of nicotine dependence. In the context of personalized medicine, the aims of this study were to evaluate whether cholinergic receptor nicotinic alpha 2 (CHRNA2), cholinergic receptor nicotinic alpha 3 (CHRNA3), cholinergic receptor nicotinic alpha 5 (CHRNA5) and cholinergic receptor nicotinic bet ...[more]

PMID: 29621993

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Project description:Cigarette smoking leads to upregulation of nicotinic acetylcholine receptors (nAChRs) in the human brain, including the common ?4?2* nAChR subtype. While subjective aspects of tobacco dependence have been extensively examined as predictors of quitting smoking with treatment, no studies to our knowledge have yet reported the relationship between the extent of pretreatment upregulation of nAChRs and smoking cessation.To determine whether the degree of nAChR upregulation in smokers predicts quitting with a standard course of treatment.Eighty-one tobacco-dependent cigarette smokers (volunteer sample) underwent positron emission tomographic (PET) scanning of the brain with the radiotracer 2-FA followed by 10 weeks of double-blind, placebo-controlled treatment with nicotine patch (random assignment). Pretreatment specific binding volume of distribution (VS/fP) on PET images (a value that is proportional to ?4?2* nAChR availability) was determined for 8 brain regions of interest, and participant-reported ratings of nicotine dependence, craving, and self-efficacy were collected. Relationships between these pretreatment measures, treatment type, and outcome were then determined. The study took place at academic PET and clinical research centers.Posttreatment quit status after treatment, defined as a participant report of 7 or more days of continuous abstinence and an exhaled carbon monoxide level of 3 ppm or less.Smokers with lower pretreatment VS/fP values (a potential marker of less severe nAChR upregulation) across all brain regions studied were more likely to quit smoking (multivariate analysis of covariance, F8,69?=?4.5; P?<?.001), regardless of treatment group assignment. Furthermore, pretreatment average VS/fP values provided additional predictive power for likelihood of quitting beyond the self-report measures (stepwise binary logistic regression, likelihood ratio ?21?=?19.8; P?<?.001).Smokers with less upregulation of available ?4?2* nAChRs have a greater likelihood of quitting with treatment than smokers with more upregulation. In addition, the biological marker studied here provided additional predictive power beyond subjectively rated measures known to be associated with smoking cessation outcome. While the costly, time-consuming PET procedure used here is not likely to be used clinically, simpler methods for examining ?4?2* nAChR upregulation could be tested and applied in the future to help determine which smokers need more intensive and/or lengthier treatment.clinicaltrials.gov Identifier: NCT01526005.

Project description:Smoking is associated with an increased risk of total and cause-specific death, but the rate of mortality risk reduction after quitting compared with continuing to smoke is uncertain. There is inadequate or insufficient evidence to infer the presence or absence of a causal relationship between smoking and ovarian cancer and colorectal cancer.To assess the relationship between cigarette smoking and smoking cessation on total and cause-specific mortality in women.Prospective observational study of 104,519 female participants in the Nurses' Health Study with follow-up from 1980 to 2004.Hazard ratios (HRs) for total mortality, further categorized into vascular and respiratory diseases, lung cancer, other cancers, and other causes.A total of 12,483 deaths occurred in this cohort, 4485 (35.9%) among never smokers, 3602 (28.9%) among current smokers, and 4396 (35.2%) among past smokers. Compared with never smokers, current smokers had an increased risk of total mortality (HR, 2.81; 95% confidence interval [CI], 2.68-2.95) and all major cause-specific mortality. The HR for cancers classified by the 2004 surgeon general's report to be smoking-related was 7.25 (95% CI, 6.43-8.18) and 1.58 (95% CI, 1.45-1.73) for other cancers. Compared with never smokers, the HR for colorectal cancer was 1.63 (95% CI, 1.29-2.05) for current smokers and 1.23 (95% CI, 1.02-1.49) for former smokers. A significant association was not observed for ovarian cancer. Significant trends were observed for earlier age at initiation of smoking for total mortality (P = .003), respiratory disease mortality (P = .001), and all smoking-related cancer mortality (P = .001). The excess risk for all-cause mortality decreases to the level of a never smoker 20 years after quitting, with different time frames for risk reduction observed across outcomes. Approximately 64% of deaths among current smokers and 28% of deaths among former smokers were attributable to cigarette smoking.Most of the excess risk of vascular mortality due to smoking in women may be eliminated rapidly upon cessation and within 20 years for lung diseases. Postponing the age of smoking initiation reduces the risk of respiratory disease, lung cancer, and other smoking-related cancer deaths but has little effect on other cause-specific mortality. These data suggest that smoking is associated with an increased risk of colorectal cancer mortality but not ovarian cancer mortality.

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Cholinergic receptor nicotinic alpha 5 subunit polymorphisms are associated with smoking cessation success in women.

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Cholinergic receptor nicotinic alpha 5 subunit polymorphisms are associated with smoking cessation success in women.

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