Polymorphisms in the nicotinic acetylcholine receptor gene (CHRNA5/CHRNA3 locus) have been associated with several smoking related traits such as nicotine dependence, cigarette consumption, smoking cessation, lung cancer, and COPD. The aim of this candidate gene
study was to study the locus among the Finnish COPD patients and long-term smokers with regard to COPD risk, smoking behavior, cancer, and all-cause mortality. Genotyping of rs1051730, the locus tagging SNP was done in two longitudinal cohorts: Finnish COPD patients (N = 575, 74% men) and long-term smokers, all men (N = 1911). Finnish population sample (N = 1730) was used as controls. The analyses were done using logistic and Cox regression. The main findings were that the minor allele increased the risk of COPD when compared to the Finnish population at large (OR = 1.4, 95% CI 1.2-1.7, p = 3.2 × 10-5). Homozygosity for the risk allele was associated in both cohorts with all-cause mortality (crude HR 2.2, 95% CI 1.2-3.8 and 1.3, 95% CI 1.1-1.5, respectively), with any type of cancer (crude OR 2.3, 95% CI 1.0-5.1) among the COPD patients and with the number of pack-years (crude OR 1.4, 95% CI 1.1-1.9) among the male smokers. CHRNA5/CHRNA3 locus tagged by rs1051730, which has been previously associated with several smoking related diseases was now shown to be associated also with increased all-cause mortality among long-term smokers with or without clinical COPD further emphasizing the clinical importance of the finding.
He P, etal., Int J Mol Sci. 2014 Mar 28;15(4):5446-57. doi: 10.3390/ijms15045446.
Recent genome-wide association studies (GWASs) have identified 15q25.1 as a lung cancer susceptibility locus. Here, we sought to explore the direct carcinogenic effects of genetic variants in this region on the risk of developing lung adenocarcinoma (ADC). Five common SNPs (rs8034191, rs16969968, rs
1051730, rs938682, and rs8042374) spanning the 15q25.1 locus were assayed in a case-control study examining a cohort of 301 lung ADCs and 318 healthy controls. Stratification analysis by gender, smoking status, and tumor, node, metastasis (TNM) classification, was performed. In addition, sections from ADC tissue and normal tissue adjacent to tumors were stained with an anti-CHRNA3 (cholinergic receptor nicotinic α3) antibody by immunohistochemistry in 81 cases. Our results demonstrate that rs8042374, a variant of the CHRNA3 gene, is associated with an increased risk of ADC with an OR of 1.76 (95% CI: 1.17-2.65, p=0.024). This variant was linked to a greater risk of ADC in female nonsmokers (OR (95% CI): 1.81 (1.05-3.12), p=0.032) and female stage I+II cases (OR (95% CI): 1.92 (1.03-3.57), p=0.039). Although located within the same gene, rs938682 showed protective effects for smokers, stage III+IV cases, and male stage III+IV cases. Additionally, the CHRNA3 protein level in ADC tissue was slightly higher than in the surrounding normal lung tissue, based on immunohistochemical analysis. Our results suggest that the CHRNA3 polymorphism functions as a genetic modifier of the risk of developing lung ADC in the Chinese population, particularly in nonsmoking females.
Li Z, etal., Transl Oncol. 2012 Dec;5(6):448-52. doi: 10.1593/tlo.12304. Epub 2012 Dec 1.
AIM: To explore the potential association between single-nucleotide polymorphisms (SNPs) and haplotypes of the CHRNA5-CHRNA3-CHRNB4 gene cluster and the non-small cell lung cancer (NSCLC) susceptibility in never-smoking Chinese. METHODS: A c
ase-control study was conducted with 200 NSCLC patients and 200 healthy controls, matched on age and sex. Five SNPs distributed in CHRNA5-CHRNA3-CHRNB4 gene cluster were selected for genotyping. The association between genotype and lung cancer risk was evaluated by computing the odds ratio (OR) and 95% confidence interval (CI) from multivariate unconditional logistic regression analyses with adjustment for gender and age. RESULTS: For CHRNA3 rs578776 status, data were available in 199 NSCLC patients and 199 controls. The G/G homozygote in CHRNB4 rs7178270 had a reduced risk of developing NSCLC (OR = 0.553; 95% CI = 0.309-0.989; P = .0437), especially squamous cell carcinoma (SQC) (OR = 0.344; 95% CI = 0.161-0.732; P = .0043), compared with those who carry at least one C allele (C/C and C/G). The polymorphisms of rs578776, rs938682, rs17486278, and rs11637635 were not significantly different between controls and cases or between controls and histologic subgroups, adenocarcinoma and SQC, respectively. CONCLUSIONS: In our study, we found that the SNP of CHRNB4 rs7178270 is significantly associated with reduced risk of NSCLC, especially with reduced risk of SQC in never-smoking Chinese population.
Kaur-Knudsen D, etal., Eur Respir J. 2012 Dec;40(6):1538-44. doi: 10.1183/09031936.00176811. Epub 2012 Mar 22.
The CHRNA3 rs1051730 polymorphism has been associated to chronic obstructive pulmonary disease (COPD), lung cancer and nicotine dependence in case-control studies with high smoking exposure; however, its influence on lung function and COPD severity in the genera
l population is largely unknown. We genotyped 57,657 adult individuals from the Copenhagen General Population Study, of whom 34,592 were ever-smokers. Information on spirometry, hospital admissions, smoking behaviour and use of nicotinic replacement therapy was recorded. In homozygous (11%), heterozygous (44%) and noncarrier (45%) ever-smokers, forced expiratory volume in 1 s (FEV(1)) was 94.1% predicted, 95.3% pred and 96.5% pred, forced vital capacity (FVC) was 97.1% pred, 97.5% pred and 98.3% pred, and FEV(1)/FVC was 0.770, 0.773 and 0.777, respectively (all p<0.001 for trend). Smoking interacted with genotype on FEV(1) % pred and FEV(1)/FVC (both p<0.001). When adjusted for cumulative tobacco consumption, these associations remained significant. In ever-smokers, odds ratios for COPD in homozygotes versus noncarriers were 1.3 (95% CI 1.2-1.4) for Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages I-IV, 1.4 (95% CI 1.2-1.6) for GOLD II-IV and 1.7 (95% CI 1.3-2.1) for GOLD III-IV. The corresponding value for lung cancer was 1.8 (95% CI 1.2-2.6). Genotype was also associated with daily and cumulative tobacco consumption and with use of nicotinic replacement therapy in former smokers. In ever-smokers, the CHRNA3 rs1051730 genotype associated with reduced lung function and increased COPD severity.
Zhang Y, etal., PLoS One. 2016 Mar 4;11(3):e0149946. doi: 10.1371/journal.pone.0149946. eCollection 2016.
INTRODUCTION: Recently, genome-wide association studies (GWAS) in Caucasian populations have identified an association between single nucleotide polymorphisms (SNPs) in the CHRNA5-A3-B4 nicotinic acetylcholine receptor subunit gene cluster on chromosome 15q25, lung cancer risk and smoking behaviors.
However, these SNPs are rare in Asians, and there is currently no consensus on whether SNPs in CHRNA5-A3-B4 have a direct or indirect carcinogenic effect through smoking behaviors on lung cancer risk. Though some studies confirmed rs6495308 polymorphisms to be associated with smoking behaviors and lung cancer, no research was conducted in China. Using a case-control study, we decided to investigate the associations between CHRNA3 rs6495308, CHRNB4 rs11072768, smoking behaviors and lung cancer risk, as well as explore whether the two SNPs have a direct or indirect carcinogenic effect on lung cancer. METHODS: A total of 1025 males were interviewed using a structured questionnaire (204 male lung cancer patients and 821 healthy men) to acquire socio-demographic status and smoking behaviors. Venous blood samples were collected to measure rs6495308 and rs11072768 gene polymorphisms. All subjects were divided into 3 groups: non-smokers, light smokers (1-15 cigarettes per day) and heavy smokers (>15 cigarettes per day). RESULTS: Compared to wild genotype, rs6495308 and rs11072768 variant genotypes reported smoking more cigarettes per day and a higher pack-years of smoking (P<0.05). More importantly, among smokers, both rs6495308 CT/TT and rs11072768 GT/GG had a higher risk of lung cancer compared to wild genotype without adjusting for potential confounding factors (OR = 1.36, 95%CI = 1.09-1.95; OR = 1.11, 95%CI = 1.07-1.58 respectively). Furthermore, heavy smokers with rs6495308 or rs11072768 variant genotypes have a positive interactive effect on lung cancer after adjustment for potential confounding factors (OR = 1.13, 95%CI = 1.01-3.09; OR = 1.09, 95%CI = 1.01-3.41 respectively). However, No significant associations were found between lung cancer risk and both rs6495308 and rs11072768 genotypes among non-smokers and smokers after adjusting for age, occupation, and education. CONCLUSION: This study confirmed both rs6495308 and rs11072768 gene polymorphisms association with smoking behaviors and had an indirect link between gene polymorphisms and lung cancer risk.
Kim WJ, etal., Respiration. 2013;86(2):117-22. doi: 10.1159/000342976. Epub 2012 Nov 27.
BACKGROUND: Genome-wide association studies have identified CHRNA3 as a lung cancer and chronic obstructive pulmonary disease (COPD) candidate gene in non-Hispanic Caucasian cohorts. However, there are differences in minor allele frequencies among eth
nic groups, and limited data exists for Asian populations. OBJECTIVES: The aim of this case-control study was to determine whether there is an association between COPD and genetic variation in CHRNA3 in the Korean population. In addition, we investigated the association of CHRNA3 with intermediate disease phenotypes including emphysema and lung function in COPD subjects. METHODS: Two single-nucleotide polymorphisms (SNPs) in CHRNA3 (rs660652 and rs12910984) were genotyped in 219 COPD subjects registered in the Korean Obstructive Lung Disease cohort study and in 305 control subjects. Volumetric computed tomography was performed in all COPD subjects. Emphysema severity was measured quantitatively by determining the volume fraction of the lung below -950 Hounsfield units. Logistic regression analysis for case-control analysis and linear regression modeling for quantitative analysis were performed using SAS. RESULTS: This case-control analysis of 219 COPD patients and 305 control participants identified a significant association between an SNP of CHRNA3 (rs12910984) and COPD (p = 0.049). Analysis in COPD subjects revealed that genetic variations were not associated with FEV1. There was no association between SNPs and emphysema severity. However, both SNPs were significantly associated with DLCO. CONCLUSION: Genetic variations in CHRNA3 are associated with COPD in the Korean population.
Freathy RM, etal., Hum Mol Genet. 2009 Aug 1;18(15):2922-7. doi: 10.1093/hmg/ddp216. Epub 2009 May 9.
Maternal smoking during pregnancy is associated with low birth weight and adverse pregnancy outcomes. Women are more likely to quit smoking during pregnancy than at any other time in their lives, but some pregnant women continue to smoke. A recent genome-wide association study demonstrated an associ
ation between a common polymorphism (rs1051730) in the nicotinic acetylcholine receptor gene cluster (CHRNA5-CHRNA3-CHRNB4) and both smoking quantity and nicotine dependence. We aimed to test whether the same polymorphism that predisposes to greater cigarette consumption would also reduce the likelihood of smoking cessation in pregnancy. We studied 7845 pregnant women of European descent from the South-West of England. Using 2474 women who smoked regularly immediately pre-pregnancy, we analysed the association between the rs1051730 risk allele and both smoking cessation during pregnancy and smoking quantity. Each additional copy of the risk allele was associated with a 1.27-fold higher odds (95% CI 1.11-1.45) of continued smoking during pregnancy (P = 0.0006). Adjustment for pre-pregnancy smoking quantity weakened, but did not remove this association [odds ratio (OR) 1.20 (95% CI 1.03-1.39); P = 0.018]. The same risk allele was also associated with heavier smoking before pregnancy and in the first, but not the last, trimester [OR for smoking 10+ cigarettes/day versus 1-9/day in first trimester = 1.30 (95% CI 1.13-1.50); P = 0.0003]. To conclude, we have found strong evidence of association between the rs1051730 variant and an increased likelihood of continued smoking in pregnancy and have confirmed the previously observed association with smoking quantity. Our data support the role of genetic factors in influencing smoking cessation during pregnancy.
Ren JH, etal., J Huazhong Univ Sci Technolog Med Sci. 2013 Dec;33(6):897-901. doi: 10.1007/s11596-013-1218-4. Epub 2013 Dec 13.
Recent population-based genome wide association studies have revealed potential susceptibility loci of lung cancer at the region of chromosome 15q25.1 containing nicotinic acetylcholine receptor genes. The loci increasing lung cancer risk has been widely identified in Caucasians, but whether this as
sociation also exists in Asians and whether this association is a direct role or mediated via tobacco smoking indirectly has not been fully established. We conducted a case-control study comprising of 210 histologically confirmed lung cancer cases and 200 healthy controls to examine rs1051730 genotyping, a single nucleotide polymorphism receiving much attention recently, and its influence on lung cancer risk as well as nicotine dependence in a Chinese Han population. Our results showed that the heterozygous C/T genotype and minor allele T conferred a significant higher risk of lung cancer than the CC homozygotes and allele C (adjusted OR=2.25, 95% CI=1.04-4.89, P=0.040 and OR=2.18, 95% CI=1.02-4.67, P=0.045 respectively). However, no association between the smoking habit and the CHRNA3 rs1051730 polymorphism was observed in this study. The results suggested that the rs1051730 polymorphism may modify susceptibility to lung cancer via a smoking-independent manner among Chinese Han population. Additional studies in vitro and in vivo are warranted to further elucidate the impact of rs1051730 on lung cancer susceptibility.
A cluster of three nicotinic acetylcholine receptor genes on chromosome 15 (CHRNA5/CHRNA3/CHRNB4) has been shown to be associated with nicotine dependence and smoking quantity. The aim of this study was to clarify whether the variation at this locus regulates n
icotine intake among smokers by using the level of a metabolite of nicotine, cotinine, as an outcome. The number of cigarettes smoked per day (CPD) and immune-reactive serum cotinine level were determined in 516 daily smokers (age 30-75 years, 303 males) from the population-based Health2000 study. Association of 21 SNPs from a 100 kb region of chromosome 15 with cotinine and CPD was examined. SNP rs1051730 showed the strongest association to both measures. However, this SNP accounted for nearly a five-fold larger proportion of variance in cotinine levels than in CPD (R(2) 4.3% versus 0.9%). The effect size of the SNP was 0.30 for cotinine level, whereas it was 0.13 for CPD. Variation at CHRNA5/CHRNA3/CHRNB4 cluster influences nicotine level, measured as cotinine, more strongly than smoking quantity, measured by CPD, and appears thus to be involved in regulation of nicotine levels among smokers.
OBJECTIVE: Genetic variations are most likely an additional risk factor besides tobacco smoking per se for the risk of chronic obstructive pulmonary disease (COPD). In this study, we compared genetic variants influencing the effect of smoking on COPD, that is, the effect of the well-known splicing d
efect polymorphism, CYP3A5*3 (rs776746), identified before genome-wide association studies, with the genome-wide association studies identified CHRNA3 (rs1051730) polymorphism on the risk of decreased lung function and COPD. MATERIALS AND METHODS: In all, 10 605 participants from the general population were genotyped. Information on spirometry, hospital admissions and smoking behaviour was recorded. Endpoints were lung function and COPD. RESULTS: For CHRNA3, the percentage of forced expiratory volume in 1 s (FEV1%) predicted was 89.3, 90.6 and 92.4% in homozygous, heterozygous and noncarrier ever-smokers (P-trend<0.001). The corresponding values for forced vital capacity percentage (FVC%) predicted were 94.5, 95.2 and 96.7% (P-trend<0.001), and for FEV1/FVC ratio, the values were 0.753, 0.760 and 0.764 (P-trend=0.008). The odds ratio for COPD in homozygous versus noncarrier ever-smokers was 1.5 [95% confidence interval (CI) 1.3-1.9] for COPD hospitalization, 1.3 (95% CI 1.1-1.6) for COPD defined as FEV1/FVC less than lower limit of normal, 1.3 (95% CI 1.0-1.5) for the Global Initiative for Chronic Obstructive Lung Disease category 1-4 (GOLD 1-4), 1.2 (95% CI 1.0-1.5) for GOLD 2-4 and 1.5 (95% CI 1.1-2.2) for GOLD 3-4. This association could not be found in never-smokers. No association was found for CYP3A5*3. CONCLUSION: The CHRNA3 genotype is associated with decreased lung function and risk of COPD among ever-smokers, whereas this was not the case for CYP3A5*3.
BACKGROUND AND PURPOSE: Smoking is a major public health problem worldwide. Polymorphisms in CHRNA3, CHRNA5, and CHRNB4 receptors play a critical role in nicotine dependence, lung cancer (LC) risk, and chronic obstructive pulmonary disease (COPD). Thi
s study characterized the CHRNA3 rs1051730 and CHRNA5 rs16969968 polymorphisms in a Mexican population and its association with nicotine dependence, LC, and COPD. METHODS: The study included 312 healthy individuals, 74 LC cases and 117 COPD cases. Genotyping was performed using TaqMan probes, and the data were analyzed using logistic regression adjusted for covariates. RESULTS: The polymorphism CHRNA3 rs1051730 and CHRNA5 rs16969968 were in the Hardy-Weinberg equilibrium and the allelic frequency of the A allele was 0.15, for both polymorphisms. The smokers were stratified in heavy smokers and moderate/light smokers, and we found in A alleles an OR = 2.86 (P = 0.01) to CHRNA3 rs1051730 and OR = 3.12 (P = 0.03) to CHRNA5 rs16969968. In addition, the A alleles in CHRNA3 rs1051730 and CHRNA5 rs16969968 were associated with the risk for LC (OR = 1.66, P = 0.07 and OR = 1.57, P = 0.1, respectively) and for COPD (OR = 2.04, P = 0.01 and OR = 1.91, P = 0.02, respectively). CONCLUSION: CHRNA3/5 polymorphisms are associated with nicotine dependence, LC, and COPD in Mexicans.
Wu XY, etal., Int J Environ Res Public Health. 2015 Apr 14;12(4):4156-69. doi: 10.3390/ijerph120404156.
Cigarette smoking is an important risk factor for hypertension. However, the effects on hypertension of the interaction between smoking and the genotype of the nicotinic acetylcholine receptor gene are unclear. The purpose of this study is to determine whether the CHRNA3
NA3 rs6495308 genotype affects the association between daily cigarette consumption and hypertension. We recruited 947 male smokers in southern China and used a questionnaire administered in face to face interviews to obtain information on their socio-demographic characteristics and smoking behavior. Blood samples were collected to test for CHRNA3 rs6495308 genotype variations. Three blood-pressure measurements were taken for each participant, and the average values recorded. We found that, compared with light smoking (<15 cigarettes per day), heavy smoking (>/=15 cigarettes per day) yielded a greater risk of hypertension. We also observed that the interaction between daily cigarette consumption and the CHRNA3 rs6495308 genotype may affect hypertension. Heavy smokers with the homozygous mutant CHRNA3 rs6495308 genotype exhibited a significantly greater risk of hypertension than light smokers with wild-type CHRNA3 rs6495308 genotypes. The positive interaction between heavy smoking and the homozygous mutant CHRNA3 rs6495308 genotype was found to affect the likelihood of hypertension in Chinese male smokers.
Both environmental and genetic factors participate in the pathogenesis of lung cancer. The aim of this study was to explore the association between CHRNA3 polymorphisms of the nicotinic acetylcholine receptor gene and lung cancer risk
in a hospital-based, case-controlled study. Single nucleotide polymorphisms (SNPs) in CHRNA3 rs3743073 (A>G) were determined using the TaqMan-MGB probe technique in 600 lung cancer cases and 600 normal controls. The differences in genotype and allele frequency were compared between groups and their association with lung cancer. The genotype frequency of rs3743073 (A>G) demonstrated Hardy-Weinberg equilibrium (P<0.05). The genotype and allele frequencies were significantly different between the cancer and control groups (P<0.05). Compared with patients with the TT genotype, lung cancer incidence was increased in patients with the TG and GG genotypes (OR=1.68; 95% CI, 1.30-2.19; P<0.05; OR=1.30; 95% CI, 1.05-1.61; P<0.05, respectively). Patients with rs3743073G variant alleles (TG and GG) were at greater risk (OR=0.65; 95% CI, 0.50-0.84; P<0.05) of developing lung cancer. Increased risk associated with rs3743073G variant alleles was observed in male smokers over the age of 60 (P<0.05). In this cohort, the CHRNA3 gene rs3743073G variant genotype significantly increased lung cancer risk, especially in male smokers over the age of 60.
BACKGROUND: Several single nucleotide polymorphisms (SNPs) in an alpha-neuronal nicotinic acetylcholine receptor subunit (CHRNA3/5) were identified to be associated with chronic obstructive pulmonary disease (COPD) in a study based on a Norwegian population. Ho
wever, results from subsequent studies have been controversial, particularly in studies recruiting Asians. In the present study, we conducted a comprehensive search and meta-analyses to identify susceptibility SNPs for COPD in the CHRNA3/5 locus. METHODS: A comprehensive literature search was conducted to find studies that have reported an association between SNPs in the CHRNA3/5 locus and COPD risk. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) for each SNP were calculated with the major allele or genotype as the reference group. The influence of individual studies on pooled measures was assessed, in addition to publication bias. RESULTS: A total of 12 articles with 14 eligible studies were included in this analysis. Association between 4 SNPs in the CHRNA3/5 locus and COPD was evaluated and included rs1051730, rs8034191, rs6495309, and rs16969968. Significant associations between the 4 SNPs and COPD were identified under allele (rs1051730: OR = 1.14, 95%CI = 1.10-1.18; rs8034191: OR = 1.29, 95%CI = 1.18-1.41; rs6495309: OR = 1.26, 95%CI = 1.09-1.45; rs16969968: OR = 1.27, 95%CI = 1.17-1.39) and genotype models. Subgroup analysis conducted for rs1051730 showed a significant association between this SNP and COPD risk in non-Asians (OR = 1.14, 95%CI = 1.10-1.18), but not Asians (OR = 1.23, 95%CI = 0.91-1.67). Rs1051730 and rs6495309 were also significantly associated with COPD after adjusting for multiple variables, including age and smoking status. CONCLUSION: Our results indicate that 4 SNPs in the CHRNA3/5 locus are associated with COPD risk. Rs1051730 was particularly associated with COPD in non-Asians, but its role in Asians still needs to be verified. Additional studies will be necessary to assess the effect of rs6495309 on COPD. Although rs1051730 and rs6495309 were shown to be independent risk factors for COPD, validation studies should be performed.
Yang L, etal., PLoS One. 2012;7(10):e46071. doi: 10.1371/journal.pone.0046071. Epub 2012 Oct 3.
Recently, several genome-wide association studies (GWAS) have identified many susceptible single nucleotide polymorphisms (SNPs) for chronic obstructive pulmonary disease (COPD) and lung cancer which are two closely related diseases. Among those SNPs, some of them are shared by both the diseases, re
flecting there is possible genetic similarity between the diseases. Here we tested the hypothesis that whether those shared SNPs are common predictor for risks or prognosis of COPD and lung cancer. Two SNPs (rs6495309 and rs1051730) located in nicotinic acetylcholine receptor alpha 3 (CHRNA3) gene were genotyped in 1511 patients with COPD, 1559 lung cancer cases and 1677 controls in southern and eastern Chinese populations. We found that the rs6495309CC and rs6495309CT/CC variant genotypes were associated with increased risks of COPD (OR = 1.32, 95% C.I. = 1.14-1.54) and lung cancer (OR = 1.57; 95% CI = 1.31-1.87), respectively. The rs6495309CC genotype contributed to more rapid decline of annual Forced expiratory volume in one second (FEV1) in both COPD cases and controls (P<0.05), and it was associated with advanced stages of COPD (P = 0.033); the rs6495309CT/CC genotypes conferred a poor survival for lung cancer (HR = 1.41, 95%CI = 1.13-1.75). The luciferase assays further showed that nicotine and other tobacco chemicals had diverse effects on the luciferase activity of the rs6495309C or T alleles. However, none of these effects were found for another SNP, rs1051730G>A. The data show a statistical association and suggest biological plausibility that the rs6495309T>C polymorphism contributed to increased risks and poor prognosis of both COPD and lung cancer.
BACKGROUND: Genetic 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. OBJECTIVES: To 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 Malmo Diet and Cancer study, a population-based prospective cohort study. METHODS: At 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. RESULTS: Amongst 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. CONCLUSION: Our 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.
Previous findings have demonstrated that variants in nicotinic receptor genes are associated with nicotine, alcohol and cocaine dependence. Because of the substantial comorbidity, it has often been unclear whether a variant is associated with multiple substances or whether the association is actuall
y with a single substance. To investigate the possible contribution of rare variants to the development of substance dependencies other than nicotine dependence, specifically alcohol and cocaine dependence, we undertook pooled sequencing of the coding regions and flanking sequence of CHRNA5, CHRNA3, CHRNB4, CHRNA6 and CHRNB3 in 287 African American and 1028 European American individuals from the Collaborative Study of the Genetics of Alcoholism (COGA). All members of families for whom any individual was sequenced (2504 African Americans and 7318 European Americans) were then genotyped for all variants identified by sequencing. For each gene, we then tested for association using FamSKAT. For European Americans, we find increased DSM-IV cocaine dependence symptoms (FamSKAT P = 2 × 10(-4)) and increased DSM-IV alcohol dependence symptoms (FamSKAT P = 5 × 10(-4)) among carriers of missense variants in CHRNB3. Additionally, one variant (rs149775276; H329Y) shows association with both cocaine dependence symptoms (P = 7.4 × 10(-5), β = 2.04) and alcohol dependence symptoms (P = 2.6 × 10(-4), β = 2.04). For African Americans, we find decreased cocaine dependence symptoms among carriers of missense variants in CHRNA3 (FamSKAT P = 0.005). Replication in an independent sample supports the role of rare variants in CHRNB3 and alcohol dependence (P = 0.006). These are the first results to implicate rare variants in CHRNB3 or CHRNA3 in risk for alcohol dependence or cocaine dependence.
Wassenaar CA, etal., J Natl Cancer Inst. 2011 Sep 7;103(17):1342-6. doi: 10.1093/jnci/djr237. Epub 2011 Jul 11.
Genetic variations in the CYP2A6 nicotine metabolic gene and the CHRNA5-CHRNA3-CHRNB4 (CHRNA5-A3-B4) nicotinic gene cluster have been independently associated with lung cancer. With genotype data from ever-smokers of European ancestry (417 lung cancer patients a
nd 443 control subjects), we investigated the relative and combined associations of polymorphisms in these two genes with smoking behavior and lung cancer risk. Kruskal-Wallis tests were used to compare smoking variables among the different genotype groups, and odds ratios (ORs) for cancer risk were estimated using logistic regression analysis. All statistical tests were two-sided. Cigarette consumption (P < .001) and nicotine dependence (P = .036) were the highest in the combined CYP2A6 normal metabolizers and CHRNA5-A3-B4 AA (tag single-nucleotide polymorphism rs1051730 G>A) risk group. The combined risk group also exhibited the greatest lung cancer risk (OR = 2.03; 95% confidence interval [CI] = 1.21 to 3.40), which was even higher among those who smoked 20 or fewer cigarettes per day (OR = 3.03; 95% CI = 1.38 to 6.66). Variation in CYP2A6 and CHRNA5-A3-B4 was independently and additively associated with increased cigarette consumption, nicotine dependence, and lung cancer risk. CYP2A6 and CHRNA5-A3-B4 appear to be more strongly associated with smoking behaviors and lung cancer risk, respectively.
Winterer G, etal., Am J Med Genet B Neuropsychiatr Genet. 2010 Dec 5;153B(8):1448-58. doi: 10.1002/ajmg.b.31126. Epub 2010 Sep 30.
Recent studies strongly support an association of the nicotinic acetylcholine receptor gene cluster CHRNA5-CHRNA3-CHRNB4 with nicotine dependence (ND). However, the precise genotype-phenotype relationship is still unknown. Clinical and epidemiological data on sm
oking behavior raise the possibility that the relevant gene variants may indirectly contribute to the development of ND by affecting cognitive performance in some smokers who consume nicotine for reasons of "cognition enhancement." Here, we tested seven single nucleotide polymorphisms (SNPs) rs684513, rs637137, rs16969968, rs578776, rs1051730, rs3743078, rs3813567 from the CHRNA5-CHRNA3-CHRNB4 gene cluster for association with ND, measures of cognitive performance and gene expression. As expected, we found all SNPs being associated with ND in three independent cohorts (KORA, NCOOP, ESTHER) comprising 5,561 individuals. In an overlapping sample of 2,186 subjects we found three SNPs (rs16969968, rs1051730, rs3743078) being associated with cognitive domains from the Wechsler-Adult-Intelligence Scale (WAIS-R)-most notably in the performance subtest "object assembly" and the verbal subtest "similarities." In a refined analysis of a subsample of 485 subjects, two of these three SNPs (rs16969968, rs1051730) were associated with n-back task performance/Continuous Performance Test. Furthermore, two CHRNA5 risk alleles (rs684513, rs637137) were associated with CHRNA5 mRNA expression levels in whole blood in a subgroup of 190 subjects. We here report for the first time an association of CHRNA5-CHRNA3-CHRNB4 gene variants with cognition possibly mediating in part risk for developing ND. The observed phenotype-genotype associations may depend on altered levels of gene expression. (c) 2010 Wiley-Liss, Inc.
Wang Y, etal., Carcinogenesis. 2010 Feb;31(2):234-8. doi: 10.1093/carcin/bgp287. Epub 2009 Dec 2.
Genome-wide association studies have provided evidence that common variation at 5p15.33 (TERT-CLPTM1L), 6p21.33 and 15q25.1 (CHRNA5-CHRNA3) influences lung cancer risk. To examine if variation at any of these loci influences the risk of lung cancer in never-smok
ers, we compared 5p15.33-TERT (rs2736100), 5p15.33-CLPTM1L (rs4975616), 6p21.33-BAT3 (rs3117582), 15q25.1-CHRNA3 (rs8042374) and 15q25.1-CHRNA3 (rs12914385) genotypes in a series of 239 never-smoker lung cancer cases and 553 never-smoker controls. A statistically significant association between lung cancer risk and 5p15.33 genotypes was found: rs2736100 (odds ratio = 0.78, 95% confidence interval: 0.63-0.97; P = 0.02), rs4975616 (odds ratio = 0.69, 95% confidence interval: 0.55-0.85; P = 7.95 x 10(-4)), primarily for adenocarcinoma. There was no evidence of association between 6p21.33 or 15q25.1 variation and risk of lung cancer. This analysis provides evidence that TERT-CLPTM1L variants may influence the risk of lung cancer outside the context of tobacco smoking.
Sun Y, etal., Oncotarget. 2017 Dec 20;9(2):2435-2444. doi: 10.18632/oncotarget.23459. eCollection 2018 Jan 5.
CHRNA5/CHRNA3/CHRNB4 gene cluster is located on chromosome 15q25.1 and was reported to be associated with risk of lung cancer. So far, the effect of three single nucleotide polymorphisms rs6495309, rs8040868, rs1948 in this gene cluster was unclear about lung ca
ncer risk. The aim of the present study was to evaluate the associations of rs6495309, rs8040868, rs1948 polymorphism, smoking exposure and the interaction with non-small cell lung cancer risk in Chinese population. In this hospital-based case-control study, 306 lung cancer patients and 306 cancer-free controls were interviewed to collect demographic data and exposure status of smoking, and then donate 2ml venous blood which was used to be genotyped by Taqman allelic discrimination method. Our study found that subjects carrying rs1948 CT genotype stated to be a risk factor in Chinese Han population (adjusted OR = 1.594, 95% CI = 1.066-2.383, P = 0.023) and in non-smoking population (adjusted OR = 1.896, 95%CI = 1.069-3.362, P = 0.029). rs8040868 CC genotype indicated a higher risk for lung cancer in non-smokers in a recessive model (adjusted OR = 2.496, 95%CI = 1.044-5.965, P = 0.040) and in age-based stratified analysis (age <= 60, adjusted OR = 4.213, 95%CI = 1.062-16.708, P = 0.041). All smoking interaction were positive in the multiplicative interaction of the SNPs and smoking status (-/+) compared with recessive model. Overall, these finding suggested that rs1948(C > T) and rs8040868(T > C) could be meaningful as genetic markers for lung cancer risk in Chinese Han population.
Saccone NL, etal., Cancer Res. 2009 Sep 1;69(17):6848-56. doi: 10.1158/0008-5472.CAN-09-0786. Epub 2009 Aug 25.
Genetic association studies have shown the importance of variants in the CHRNA5-CHRNA3-CHRNB4 cholinergic nicotinic receptor subunit gene cluster on chromosome 15q24-25.1 for the risk of nicotine dependence, smoking, and lung cancer in populations of European de
scent. We have carried out a detailed study of this region using dense genotyping in both European-Americans and African-Americans. We genotyped 75 known single nucleotide polymorphisms (SNPs) and one sequencing-discovered SNP in an African-American sample (N = 710) and in a European-American sample (N = 2,062). Cases were nicotine-dependent and controls were nondependent smokers. The nonsynonymous CHRNA5 SNP rs16969968 is the most significant SNP associated with nicotine dependence in the full sample of 2,772 subjects [P = 4.49 x 10(-8); odds ratio (OR), 1.42; 95% confidence interval (CI), 1.25-1.61] as well as in African-Americans only (P = 0.015; OR, 2.04; 1.15-3.62) and in European-Americans only (P = 4.14 x 10(-7); OR, 1.40; 1.23-1.59). Other SNPs that have been shown to affect the mRNA levels of CHRNA5 in European-Americans are associated with nicotine dependence in African-Americans but not in European-Americans. The CHRNA3 SNP rs578776, which has a low correlation with rs16969968, is associated with nicotine dependence in European-Americans but not in African-Americans. Less common SNPs (frequency
BACKGROUND: CHRNA5-CHRNA3-CHRNB4 and TTC12-ANKK1-DRD2 gene-clusters influence smoking behavior. Our aim was to test developmental changes in their effects as well as the interplays between them and with nongenetic factors. METHODS: Participa
nts included 4762 subjects from a general population-based, prospective Northern Finland 1966 Birth Cohort (NFBC 1966). Smoking behavior was collected at age 14 and 31 years. Information on maternal smoking, socioeconomic status, and novelty seeking were also collected. Structural equation modeling was used to construct an integrative etiologic model including genetic and nongenetic factors. RESULTS: Several single nucleotide polymorphisms in both gene-clusters were significantly associated with smoking. The most significant were in CHRNA3 (rs1051730, p = 1.1 × 10(-5)) and in TTC12 (rs10502172, p = 9.1 × 10(-6)). CHRNA3-rs1051730[A] was more common among heavy/regular smokers than nonsmokers with similar effect-sizes at age 14 years (odds ratio [95% CI]: 1.27 [1.06-1.52]) and 31 years (1.28 [1.13-1.44]). TTC12-rs10502172[G] was more common among smokers than nonsmokers with stronger association at 14 years (1.33 [1.11-1.60]) than 31 years (1.14 [1.02-1.28]). In adolescence, carriers of three-four risk alleles at either CHRNA3-rs1051730 or TTC12-rs10502172 had almost threefold odds of smoking regularly than subjects with no risk alleles. TTC12-rs10502172 effect on smoking in adulthood was mediated by its effect on smoking in adolescence and via novelty seeking. Effect of CHRNA3-rs1051730 on smoking in adulthood was direct. CONCLUSIONS: TTC12-ANKK1-DRD2s seemed to influence smoking behavior mainly in adolescence, and its effect is partially mediated by personality characteristics promoting drug-seeking behavior. In contrast, CHRNA5-CHRNA3-CHRNB4 is involved in the transition toward heavy smoking in mid-adulthood and in smoking persistence. Factors related to familial and social disadvantages were strong independent predictors of smoking.
