CHRNA5 Rs16969968 Research Articles

Does High Tobacco Consumption Cause Psychological Distress? A Mendelian Randomization Study.

Increasing evidence suggests that smoking influences mental health negatively. This study investigated whether high tobacco consumption is causally related to psychological distress in a Mendelian randomization design, using a variant in the nicotine acetylcholine receptor gene CHRNA3-known to influence individual tobacco consumption-as instrumental variable for tobacco consumption. Data from 90 108 participants in the Copenhagen General Population Study was used. Exposures included self-reported cigarettes/day and pack years and the CHRNA3 rs1051730 genotype as instrumental variable for tobacco consumption. Three dimensions of psychological distress were studied: Stress, fatigue, and hopelessness. Analyses with the CHRNA3 genotype were stratified by smoking status. Self-reported amount of smoking was associated with all three dimensions of psychological distress. For instance among participants smoking 30 cigarettes/day or more, the odds ratio (OR) for stress was 1.67 (95% confidence interval [CI] 1.47-1.89) compared to never-smokers. Corresponding ORs for fatigue and hopelessness were 2.18 (95% CI 1.92-2.47) and 3.08 (95% CI 2.62-3.62). Among current smokers, homozygotes and heterozygotes for the CHRNA3 genotype had higher tobacco consumption than noncarriers. Nevertheless, the CHRNA3 genotype was not associated with psychological distress neither in current nor in former or never-smokers. For instance among current smokers, the OR for stress was 1.02 (95% CI 0.91-1.15) among homozygotes compared to noncarriers of the CHRNA3 genotype. Though a strong association between tobacco consumption and psychological distress was found, there was no clear evidence that high tobacco consumption was causally related to psychological distress. Smoking is associated with several mental health outcomes and smoking cessation is associated with improved mental health. Causality in the association between smoking and mental health is difficult to establish using observational data. Using a genotype known to influence tobacco consumption as instrumental variable for amount of smoking, we found no clear evidence of a direct causal path between high tobacco consumption and psychological distress. Whatever causes the strong association between tobacco consumption and psychological distress, the co-occurrence is important to consider both in interventions for smoking prevention and cessation.

Association Between CHRNA3 and CHRNA5 Nicotine Receptor Subunit Gene Variants and Nicotine Dependence in an Isolated Populationof Kashubians in Poland

BackgroundGenome-wide and allelic association studies have shown the contribution of CHRNA5-A3-B4 nicotinic receptor subunit gene cluster within chromosome 15 to nicotine dependence (ND). While an association between several single-nucleotide polymorphisms (SNPs) at that locus and smoking quantity (cigarettes per day; CPD) has been well recognized, there are some inconsistencies in demonstrating the influence of these SNPs on other ND phenotypes. This uncertainty motivated us to examine the association of 3 selected SNPs (CHRNA3 rs1051730, rs6495308, and CHRNA5 rs55853898) with ND in an isolated population of Kashubians from Poland.Material/MethodsThe study sample consisted of 788 current daily smokers. ND was assessed by CPD, the Fagerstrom Test for Nicotine Dependence (FTND), its brief version - Heavy Smoking Index (HSI), and time to first cigarette after waking (TTF). The correlation between studied SNPs and dichotomized values of ND measures was assessed in the regression analysis. Bonferroni corrected p-value of 0.017 was set for a type 1 error.ResultsWe found a robust association between risk allele A of rs1051730 and CPD >10 (odds ratio (OR)=1.77, 95% confidence interval (CI): 1.20–2.59, p=0.004), and a weak association, which did not survive correction for multiple testing, with FTND ≥4. No associations between studied SNPs and HSI or TTF were demonstrated.ConclusionsOur findings confirm that rs1051730 influences ND phenotype, as defined by CPD.

Different effects of the three polymorphisms on 15q25.1 onlung cancer risk: Evidence from published literatures.

Genetic studies have shown a significant association between lung cancer risk and single nucleotide polymorphisms on chromosome 15q25.1. The potential association of three polymorphisms in the CHRNA3 (rs1051730(G > A)), CHRNA5 (rs16969968(G > A)), and AGPHD1 (rs8034191(A > G)) with the lung cancer risk has been widely investigated, but the results are inconsistent. The aim of meta-analysis was toclarify the link between three polymorphisms and susceptibility to lung cancer. All the relevant data were retrieved by Embase, PubMed, and Web of Science, and then 38 eligible studies were chosen in this meta-analysis. There was no association of rs16969968 polymorphism with cancer risk in the overall pooled analysis. For the rs1051730 and rs8034191 polymorphisms, the results revealed that the five models were significantlyassociated with elevated risk of cancer. Further stratified analysis indicated that increased risk for lung cancer was foundinthe Caucasian, African American, and Asian population. In summary, CHRNA3 rs1051730 (G > A) and AGPHD1 rs8034191 (A > G) were more susceptible to lung cancers than noncarriers.

Replication of the association between CHRNA4 rs1044396 and harm avoidance in a large population-based sample

Harm avoidance is a personality trait characterized by excessive worrying and fear of uncertainty, which has repeatedly been related to anxiety disorders. Converging lines of research in rodents and humans point towards an involvement of the nicotinic cholinergic system in the modulation of anxiety. Most notably, the rs1044396 polymorphism in the CHRNA4 gene, which codes for the α4 subunit of the nicotinic acetylcholine receptor, has been linked to negative emotionality traits including harm avoidance in a recent study. Against this background, we investigated the association between harm avoidance and the rs1044396 polymorphism using data from N=1673 healthy subjects, which were collected in the context of the German multi-centre study ׳Genetics of Nicotine Dependence and Neurobiological Phenotypes׳. Homozygous carriers of the C-allele showed significantly higher levels of harm avoidance than homozygous T-allele carriers, with heterozygous subjects exhibiting intermediate scores. The effect was neither modulated by age or gender nor by smoking status. By replicating previous findings in a large population-based sample for the first time, the present study adds to the growing evidence suggesting an involvement of nicotinic cholinergic mechanism in anxiety and negative emotionality, which may pose an effective target for medical treatment.

CHRNA5 rs16969968 Polymorphism Association with Risk of Lung Cancer--Evidence from 17,962 Lung Cancer Cases and 77,216 Control Subjects.

Genetic studies have shown a possible relationship between the rs16969968 polymorphism in CHRNA5 and the risk of lung cancer. However, the results have been conflicting. Thus we rigorously conducted a meta-analysis to clarify any association. A total of 10 case-control studies involving 17,962 lung cancer cases and 77,216 control subjects were analysed. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to measure the strength of the association. We found the CHRNA5 rs16969968 polymorphism to be associated with the risk of lung cancer (AA vs GG: OR=1.60, 95%CI=1.51-1.71). On stratified analysis by smoking status, a statistically significant increased risk was observed in the smoking group (AA vs GG: OR=1.80, 95%CI=1.61-2.01). However, this polymorphism was not associated with lung cancer risk in Asians (AA vs GG: OR=0.95, 95%CI=0.35-2.59), whereas it was linked to increased risk of lung cancer among Caucasians (AA vs GG: OR=1.65, 95%CI=1.55-1.76). Our meta-analysis provided statistical evidence for a strong association between rs16969968 polymorphism and the risk of lung cancer, especially in smokers and Caucasians. Application of this relationship may contribute to identification of individuals at high risk of lung cancer and indicate a chemoprevention target.

Genetic variation (CHRNA5), medication (combination nicotine replacement therapy vs. varenicline), and smoking cessation

ObjectiveRecent evidence suggests that the efficacy of smoking cessation pharmacotherapy can vary across patients based on their genotypes. This study tests whether the coding variant rs16969968 in the CHRNA5 nicotinic receptor gene predicts the effects of combination nicotine replacement therapy (cNRT) and varenicline on treatment outcomes. MethodIn two randomized smoking cessation trials comparing cNRT vs. placebo, and varenicline vs. placebo, we used logistic regression to model associations between CHRNA5 rs16969968 and abstinence at end of treatment. ResultsFor abstinence at end of treatment, there was an interaction between cNRT and rs16969968 (X2=8.15, df=2, omnibus-p=0.017 for the interaction); individuals with the high-risk AA genotype were more likely to benefit from cNRT. In contrast, varenicline increased abstinence, but its effect did not vary with CHRNA5. However, the genetic effects differed between the placebo control groups across two trials (wald=3.94, df=1, p=0.047), this non-replication can alter the interpretation of pharmacogenetic findings. ConclusionsResults from two complementary smoking cessation trials demonstrate inconsistent genetic results in the placebo arms. This evidence highlights the need to compare the most effective pharmacotherapies with the same placebo control to establish pharmacogenetic evidence to aid decisions on medication choice for patients trying to quit smoking.

Crucial role of nicotinic α5 subunit variants for Ca2+ fluxes in ventral midbrain neurons.

Neuronal nicotinic acetylcholine receptors (nAChRs) containing the α5 subunit modulate nicotine consumption, and the human CHRNA5 rs16969968 polymorphism, causing the replacement of the aspartic acid residue at position 398 with an asparagine (α5DN), has recently been associated with increased use of tobacco and higher incidence of lung cancer. We show that in ventral midbrain neurons, the α5 subunit is essential for heteromeric nAChR-induced intracellular-free Ca(2+) concentration elevations and that in α5(-/-) mice, a class of large-amplitude nicotine-evoked currents is lost. Furthermore, the expression of the α5DN subunit is not able to restore nicotinic responses, indicating a loss of function by this subunit in native neurons. To understand how α5DN impairs heteromeric nAChR functions, we coexpressed α4, α5, or α5DN subunits with a dimeric concatemer (β2α4) in a heterologous system, to obtain nAChRs with fixed stoichiometry. Both α5(β2α4)2 and α5DN(β2α4)2 nAChRs yielded similar levels of functional expression and Ca(2+) permeability, measured as fractional Ca(2+) currents (8.2 ± 0.7% and 8.0 ± 1.9%, respectively), 2-fold higher than α4(β2α4)2. Our results indicate that the loss of function of nicotinic responses observed in α5DN-expressing ventral midbrain neurons is neither due to an intrinsic inability of this subunit to form functional nAChRs nor to an altered Ca(2+) permeability but likely to intracellular modulation.

CHRNA5 risk variant predicts delayed smoking cessation and earlier lung cancer diagnosis--a meta-analysis.

Recent meta-analyses show strong evidence of associations among genetic variants in CHRNA5 on chromosome 15q25, smoking quantity, and lung cancer. This meta-analysis tests whether the CHRNA5 variant rs16969968 predicts age of smoking cessation and age of lung cancer diagnosis. Meta-analyses examined associations between rs16969968, age of quitting smoking, and age of lung cancer diagnosis in 24 studies of European ancestry (n = 29 072). In each dataset, we used Cox regression models to evaluate the association between rs16969968 and the two primary phenotypes (age of smoking cessation among ever smokers and age of lung cancer diagnosis among lung cancer case patients) and the secondary phenotype of smoking duration. Heterogeneity across studies was assessed with the Cochran Q test. All statistical tests were two-sided. The rs16969968 allele (A) was associated with a lower likelihood of smoking cessation (hazard ratio [HR] = 0.95, 95% confidence interval [CI] = 0.91 to 0.98, P = .0042), and the AA genotype was associated with a four-year delay in median age of quitting compared with the GG genotype. Among smokers with lung cancer diagnoses, the rs16969968 genotype (AA) was associated with a four-year earlier median age of diagnosis compared with the low-risk genotype (GG) (HR = 1.08, 95% CI = 1.04 to 1.12, P = 1.1*10(-5)). These data support the clinical significance of the CHRNA5 variant rs16969968. It predicts delayed smoking cessation and an earlier age of lung cancer diagnosis in this meta-analysis. Given the existing evidence that this CHRNA5 variant predicts favorable response to cessation pharmacotherapy, these findings underscore the potential clinical and public health importance of rs16969968 in CHRNA5 in relation to smoking cessation success and lung cancer risk.

High tobacco consumption lowers body weight: a Mendelian randomization study of the Copenhagen General Population Study.

Conflicting evidence has been found regarding the association between high tobacco consumption and body weight among smokers. We tested the hypothesis that high tobacco consumption is causally associated with low body weight. We conducted a Mendelian randomization study with a genetic variant in CHRNA3 (rs1051730) as proxy for high tobacco consumption. The cohort consisted of 80,342 participants from the Copenhagen General Population Study, with details on body weight, smoking habits and CHRNA3 genotype, including 15,220 current smokers. In observational analyses, high tobacco consumption was associated with high body weight, body mass index, waist circumference, hip circumference and waist-hip ratio. In multivariable adjusted models a 1-cigarette/day higher tobacco consumption was associated with 0.05 kg (95% confidence interval 0.02; 0.08) higher body weight, 0.02 kg/m(2) (0.01; 0.02) higher body mass index, 0.10 cm (0.07; 0.12) higher waist circumference and 0.02 cm (0.001; 0.03) higher hip circumference. In contrast, the per-allele increase inCHRNA3 rs1051730 associated with high tobacco consumption was associated with 0.59 kg (0.96; 0.22) lower body weight, 0.23 kg/m(2) (0.33; 0.13) lower body mass index, 0.32 cm (0.74; 0.003) lower waist circumference and 0.45 cm (0.66; 0.24) lower hip circumference. No association was found between tobacco consumption and waist-hip ratio in genetic analysis, or among CHRNA3 genotype and any of the outcome variables in former or never smokers. High tobacco consumption causes lower body weight among current smokers. However, smoking does not seem to affect body shape or fat distribution causally. The lack of association between CHRNA3 genotype and body weight among former smokers and never smokers favours smoking as the causal factor for the observed associations.

Are genetic variants for tobacco smoking associated with cannabis involvement?

BackgroundCannabis users are highly likely to also be tobacco cigarette smokers and a proportion of this comorbidity is attributable to shared genetic influences. Three large meta-analyses of genomewide association studies (GWAS) of tobacco smoking have identified multiple genomewide significant (p<5×10−8) single nucleotide polymorphisms (SNPs). We examine whether these SNPs are associated with tobacco smoking and with cannabis involvement in an independent sample. MethodEleven SNPs associated with cigarettes per day (CPD), ever versus never smoking and current smoking/smoking cessation at p<5×10−8 were selected from three published meta-analyses. Association analyses were conducted with similar tobacco smoking measures in 2716 European-American subjects from the Study of Addictions Genes and Environment (SAGE) and with lifetime and current cannabis use and DSM-IV cannabis abuse/dependence. ResultsCannabis use and tobacco smoking correlated at 0.54. Rs16969968 in CHRNA5 (and its proxy, rs1051730 in CHRNA3) and rs1451240, a proxy for rs13280604 in CHRNB3, were associated with CPD after Bonferroni correction (p<0.006). rs1451240 was also associated with DSM-IV cannabis abuse/dependence. Rs6265 in BDNF was associated with smoking initiation, as in the original meta-analysis and also with lifetime cannabis use. Associations with cannabis involvement were no longer significant upon adjustment for the tobacco smoking measures. ConclusionsThe modest associations between cannabis involvement and SNPs for tobacco smoking were not independent of the comorbidity between tobacco and cannabis involvement. Larger samples of individuals might be required to articulate the specific genetic architecture of cannabis involvement.

CHRNA4 rs1044396 is associated with smoking cessation in varenicline therapy.

Background: The large individual variability in response to drugs for smoking cessation suggests that specific treatments can be more effective in particular subgroups of smokers. In the context of personalized medicine, the main aim of the present study was to evaluate whether the CHRNA4 and CHRNB2 polymorphisms are associated with response to smoking cessation therapies in patients from a smoker assistance program.Methods: This cohort study enrolled 483 smoking patients who received behavioral counseling and drug treatment (varenicline, bupropion, and/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 were analyzed for nicotine dependence. The CHRNA4 (rs1044396 and rs2236196) and CHRNB2 (rs2072660 and rs2072661) polymorphisms were genotyped by high resolution melting analysis.Results: Patients with rs1044396 CC genotype had lower success rate in treatment with varenicline (29.5%) compared with carriers of CT or TT genotypes (50.9%; p = 0.007, n = 167). The CT or TT genotypes were associated with higher odds ratio for success (OR = 1.67, 95% CI = 1.10–2.53, p = 0.02), in a multivariate model. We did not observe significant differences in the FTND and Issa scores according to the studied polymorphisms.Conclusion: The CHRNA4 rs1044396 is associated with smoking cessation in individuals on varenicline therapy. We suggest that this polymorphism influences the varenicline response, but replications of this finding are needed.

Nicotine dependence in an isolated population of Kashubians from North Poland: a population survey.

BackgroundTobacco use is a complex, multistage behaviour. The particular stages of this behaviour, including nicotine dependence (ND), are influenced by both genetics and the environment. Surveys on factors influencing tobacco use and ND, conducted in ethnically homogenous populations, can provide results less influenced by genetic and cultural heterogeneity. We aimed to assess ND in a sample of current smokers, derived from the geographically and culturally isolated population of Kashubians from North Poland, and evaluate its potential association with age, sex, and self-reported comorbidities. In addition, we attempted to replicate - for the first time in this population - previous findings on the association between ND and several variants within the CHRNA5A3-A5-B4 nicotine receptor subunit gene cluster.MethodsThe study sample consisted of 969 unrelated subjects who were all current smokers. ND was evaluated using four measures: the Fagerstrom Test for Nicotine Dependence (FTND), the Heavy Smoking Index (HSI), the number of cigarettes per day (CPD) and the time to first cigarette after waking (TTF). All subjects underwent genotyping for CHRNA5 rs16969968, CHRNA3 rs578776, and CHRNB4 rs12914008 variants. Multivariate regression analysis was used for the assessment of the studied correlations. A significance level of 0.05 with the Bonferroni correction for multiple testing was set for a type 1 error in the analyses.ResultsThe mean CPD, FTND and HSI scores in the study sample were 17.3 ± 7.7, 3.9 ± 2.3 and 2.6 ± 1.5, respectively. No association between ND defined by FTND, HSI or TTF and age was found. In turn, heavy smoking was significantly associated with older age (odds ratio (OR) = 1.72, 95% confidence interval (CI): 1.14-2.59, p = 0.009), and men were more likely than women to be heavy smokers (OR = 1.70, 95% CI: 1.09-2.65, p = 0.018). Chronic comorbidity did not significantly influence ND. An analysis of association of studied polymorphisms with ND showed a borderline association of rs16969968 with CPD (OR = 1.63, 95% CI: 1.09–2.45, p = 0.017).ConclusionOur study showed a low to moderate level of ND in the Kashubians, influenced by age, sex, as well as the CHRNA5 rs16969968 variant.

Individual response speed is modulated by variants of the gene encoding the alpha 4 sub-unit of the nicotinic acetylcholine receptor (CHRNA4)

Acetylcholine (ACh) is a known modulator of several domains of cognition, among them attention, memory and learning. The neurotransmitter also influences the speed of information processing, particularly the detection of targets and the selection of suitable responses. We examined the effect of the rs1044396 (C/T) polymorphism of the gene encoding the nicotinic acetylcholine receptor α4-subunit (CHRNA4) on response speed and selective visual attention. To this end, we administered a Stroop task, a Negative priming task and an exogenous Posner-Cuing task to healthy participants (n=157). We found that the CHRNA4 rs1044396 polymorphism modulated the average reaction times (RTs) across all three tasks. Dependent on the C allele dosage, the RTs linearly increased. Homozygous T allele carriers were always fastest, while homozygous C allele carriers were always slowest. We did not observe effects of this polymorphism on selective attention. In sum, we conclude that naturally occurring variations within the cholinergic system influence an important factor of information processing. This effect might possibly be produced by the neuromodulator system rather than the deterministic system of cortical ACh.

CHRNA3 rs1051730 polymorphism and lung cancer susceptibility in Asian population: a meta-analysis.

Many studies have examined the association between the CHRNA3 rs1051730 polymorphism gene polymorphisms and lung cancer risk in various populations, but their results have been inconsistent. The PubMed was searched for case-control studies published up to Jan 01, 2015. Data were extracted and pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. In this meta-analysis, we assessed four published studies involving comprising 2,890 lung cancer cases and 2,521 controls of the association between CHRNA3 rs1051730 polymorphism and lung cancer risk. For the T allele carriers (C/T + T/T) and the homozygote T/T, the pooled ORs for all studies combined 2,890 cases and 2,521 controls were 1.93 (95% CI =1.48-2.53, P=0.34 for heterogeneity) and 1.63 (95% CI =1.27-1.99, P=0.46 for heterogeneity), when compared with the homozygous wild-type genotype (C/C). There was no observable publication bias for both polymorphisms. These results from the meta-analysis suggest that CHRNA3 rs1051730 polymorphism contributes to risk of lung cancer among Asian population.

Association of CHRNA4 gene rs1044396 and rs1044397 polymorphisms with Parkinson's disease symptoms and smoking.

We assessed the CHRNA4 exon 5 rs1044396 and rs1044397 polymorphisms and investigated their relationship with Parkinson's disease (PD) severity and several non-motor symptoms. Ninety-seven patients with primary PD and 108 controls were recruited, and their smoking history identified. Patients with PD were assessed using the unified PD rating scale (UPDRS), Hoehn & Yahr (H&Y) grade, Hamilton depression rating scale (HAMD), visual analogue 10-points scale (VAS), and the Pittsburgh sleep quality index (PSQI). Polymerase chain reaction amplification and direct sequencing was performed on genomic DNA to identify polymorphic variants. Statistical analysis demonstrated that there were no gender differences in rs1044396(C→T) and rs1044397(G→A) frequencies. More smokers were identified among carriers of rs1044396 CT/TT genotypes. We also found no differences between PD and control groups in frequencies of either polymorphism. However, in women, PD onset was latest in rs1044397 GA/AA (P = 0.015). rs1044396 CT/TT genotype carriers and rs1044397 GG genotype patients with PD had higher VAS scores. No differences were found on the course of PD, H&Y grade, or UPDRS-II or -III scores between various genotypes, nor were differences found on scores of HAMD, nocturia, or PSQI in PD patients. Our results suggested that the CHRNA4 rs1044396 CT/TT genotype is related to cigarette smoking, that the rs1044397 polymorphism may associate with PD age of onset in women, and that rs1044396 and rs1044397 may relate to pain in PD patients, but not to the course or severity of disease, or to depression or nocturnal or sleeping disorders.

Association of cancer susceptibility variants with risk of multiple primary cancers: The population architecture using genomics and epidemiology study.

Multiple primary cancers account for approximately 16% of all incident cancers in the United States. Although genome-wide association studies (GWAS) have identified many common genetic variants associated with various cancer sites, no study has examined the association of these genetic variants with risk of multiple primary cancers (MPC). As part of the National Human Genome Research Institute (NHGRI) Population Architecture using Genomics and Epidemiology (PAGE) study, we used data from the Multiethnic Cohort (MEC) and Women's Health Initiative (WHI). Incident MPC (IMPC) cases (n = 1,385) were defined as participants diagnosed with more than one incident cancer after cohort entry. Participants diagnosed with only one incident cancer after cohort entry with follow-up equal to or longer than IMPC cases served as controls (single-index cancer controls; n = 9,626). Fixed-effects meta-analyses of unconditional logistic regression analyses were used to evaluate the associations between 188 cancer risk variants and IMPC risk. To account for multiple comparisons, we used the false-positive report probability (FPRP) to determine statistical significance. A nicotine dependence-associated and lung cancer variant, CHRNA3 rs578776 [OR, 1.16; 95% confidence interval (CI), 1.05-1.26; P = 0.004], and two breast cancer variants, EMBP1 rs11249433 and TOX3 rs3803662 (OR, 1.16; 95% CI, 1.04-1.28; P = 0.005 and OR, 1.13; 95% CI, 1.03-1.23; P = 0.006), were significantly associated with risk of IMPC. The associations for rs578776 and rs11249433 remained (P < 0.05) after removing subjects who had lung or breast cancers, respectively (P ≤ 0.046). These associations did not show significant heterogeneity by smoking status (Pheterogeneity ≥ 0.53). Our study has identified rs578776 and rs11249433 as risk variants for IMPC. These findings may help to identify genetic regions associated with IMPC risk.

Association of genes involved in nicotine and tobacco smoke toxicant metabolism (CHRNA3/5, CYP2A6, and NQO1) and DNA repair (XRCC1, XRCC3, XPC, and XPA) with chronic obstructive pulmonary disease

Polymorphisms of the CHRNA5/A3, CYP2A6, NQO1, XPC, XRCC1, CRCC3, XPD, and XPA genes were tested for association with the development and progression of chronic obstructive pulmonary disease (COPD) in ethnic Tatars. CHRNA5 (rs16969968) (P = 0.0001, OR = 2.24) and CHRNA3 (rs1051730) (P = 0.0001, OR = 2.72) polymorphisms were associated with COPD development in the recessive model. The nondeletion variant of CYP2A6 (del) was associated with COPD risk (P = 0.00001, OR = 2.77). NQO1 (rs113341), XRCC1 (rs25487), XRCC3 (rs86539), XPC (rs2228001), and XPA (rs1800975) were associated with COPD in the additive model (P = 0.000001, OR = 2.67; P = 0.00001, OR = 0.51; P = 0.0003, OR = 1.76; P = 0.0004, OR = 0.54; and P = 0.007, OR = 0.74, respectively). A gene-by-environment interaction was observed for XPA (rs1800975) and the smoking status (P interact = 0.002), and the rs16969968 and rs1051730 polymorphisms of the CHRNA3/5 gene cluster showed an association with COPD only in smokers. Carriers of the CYP2A6 deletion (CYP2A6*4) had a lower smoking index (P = 0.0019). XRCC3 (rs861539) genotype TT was characterized by lower indices of pulmonary function, including vital capacity (VC) (P = 0.0487), forced vital capacity (FVC) (P = 0.0032), and forced expiratory volume in 1 second (FEV1) (P = 0.02). FVC was found to depend on the genotype at XPA (rs1800975) (P = 0.0028).

CHRNA5 variants moderate the effect of nicotine deprivation on a neural index of cognitive control.

Individuals with reduced attention and memory cognitive control-related processes may be motivated to smoke as a result of the cognitive enhancing effects of nicotine. Further, nicotine deprivation-induced reductions in cognitive control may negatively reinforce smoking. Minor allele carriers at rs16969968 in the nicotinic acetylcholine receptor α5 subunit gene (CHRNA5) have been shown to exhibit both reduced cognitive control and greater nicotine dependence. It is therefore of interest to see if variants in this gene moderate the influence of nicotine deprivation on cognitive control. P3b and P3a components of the event-related brain potential waveform evoked by a three-stimulus visual oddball task are widely viewed as positive indices of cognitive control-related processes. We tested the hypothesis that individuals possessing at least one minor allele at rs16969968 in CHRNA5 would show greater nicotine deprivation-induced reductions in P3b and P3a amplitude. The sample included 72 non-Hispanic, Caucasian heavy smokers (54 men and 18 women) with a mean age of 36.11 years (SD = 11.57). Participants completed the visual oddball task during counterbalanced nicotine and placebo smoking sessions. Findings indicated that rs16969968 status did not moderate nicotine effects on P3b or P3a, whereas variation in other CHRNA5 polymorphisms, which are not as well characterized and are not in linkage disequilibrium with rs16969968, predicted nicotine deprivation-induced reduction of P3a amplitude: rs588765 (F1,68 = 7.74, P = 0.007) and rs17408276 (F1,67 = 7.34, P = 0.009). Findings are interpreted in the context of vulnerability alleles that may predict nicotine effects on cognitive control.

High tobacco consumption is causally associated with increased all-cause mortality in a general population sample of 55,568 individuals, but not with short telomeres: a Mendelian randomization study.

High cumulative tobacco consumption is associated with short telomeres and with increased all-cause mortality. We tested the hypothesis that high tobacco consumption is causally associated with short telomeres and with increased all-cause mortality. We studied 55,568 individuals including 32,823 ever smokers from the Danish general population, of whom 3430 died during 10 years of follow-up. All had telomere length measured, detailed information on smoking history, and CHRNA3 rs1051730 genotype, which is associated with tobacco consumption, determined. In a Mendelian randomization study, we conducted observational, genetic, and mediation analyses. First, tobacco consumption was 21.1 pack-years in non-carriers, 22.8 in heterozygotes and 24.8 in homozygotes (P-trend<0.001). Second, the observational multivariable adjusted hazard ratio for all-cause mortality was 1.12 [95% confidence interval (CI): 1.09, 1.15] per doubling in tobacco consumption. In Mendelian randomization analysis, the hazard ratio was 1.08 (1.02, 1.14) per minor CHRNA3 allele in ever smokers. Third, in observational analysis telomeres shortened with -13 base pairs (-18, -8) per doubling in tobacco consumption. In Mendelian randomization analysis, the estimate was +3 base pairs (-10, +15) per minor CHRNA3 allele. Finally, individuals with the shortest vs longest telomeres had a multivariable adjusted hazard ratio of 1.30 (1.13, 1.50) for all-cause mortality; however, in mediation analysis short telomeres explained only +0.4% (-3.5%, +4.3%) of the association between high tobacco consumption and increased all-cause mortality. High tobacco consumption is causally associated with increased all-cause mortality. High cumulative tobacco consumption is associated with short telomeres observationally, but there is no clear genetic association.

ANALYSIS OF BRONCHIAL ASTHMA-PREDISPOSING INTERGENIC AND GENE-ENVIRONMENTAL CORRELATIONS

Aim. The objective of the study was to assess the contribution of associated exposure of genetic and environmental (tobacco smoke) factors on the development of bronchial asthma. Materials and methods. 104 adolescents aged 12-18, ill with bronchial asthma including 49 smokers (45 - with mild degree of severity and 4 - with moderate one) and 55 nonsmokers were examined. Molecular-genetic studies were carried out at the Laboratory of Epidemiological Genetics of Medicogenetic Scientific Center of RAMS ((MGSC). Results. Bronchial asthma in smoking patients is associated with GSDMB (rs7216389), NOS3 (VNTR) and ADRB2 (Gln27Glu) genes, in nonsmoking patients - with GSDMB (rs7216389), CHRNA5 (rs16969968), ADRB2 (Gln27Glu) and THOI (STR) genes. Alleles and genotypes of increased BA-forming risk were detected, additional genetic attributive risk confirming and objectivizing the role of tobacco-smoking in BA development was determined. Differences were revealed in the structure and character of correlations between gene locuses predisposing to BA development in smokers and non-smokers. Conclusion. Analysis of intergenic correlations permitted to state a complicated character of correlations between genes-candidates of BA development and genes-candidates of predisposition to tobacco-smoking, conditioning the possible pathogenetic differences in the exposure of environmental risk factor (tobacco-smoking).