CHRNA3

Gene Summary

Gene:CHRNA3; cholinergic receptor nicotinic alpha 3 subunit
Aliases: LNCR2, PAOD2, NACHRA3
Location:15q25.1
Summary:This locus encodes a member of the nicotinic acetylcholine receptor family of proteins. Members of this family of proteins form pentameric complexes comprised of both alpha and beta subunits. This locus encodes an alpha-type subunit, as it contains characteristic adjacent cysteine residues. The encoded protein is a ligand-gated ion channel that likely plays a role in neurotransmission. Polymorphisms in this gene have been associated with an increased risk of smoking initiation and an increased susceptibility to lung cancer. Alternatively spliced transcript variants have been described. [provided by RefSeq, Nov 2009]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:neuronal acetylcholine receptor subunit alpha-3
Source:NCBIAccessed: 11 March, 2017

Ontology:

What does this gene/protein do?
Show (29)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • European Continental Ancestry Group
  • Genetic Variation
  • Alleles
  • Genotype
  • Nerve Tissue Proteins
  • Polymerase Chain Reaction
  • Single Nucleotide Polymorphism
  • Haplotypes
  • Smoking
  • Staging
  • p53 Protein
  • Case-Control Studies
  • Lung Cancer
  • Genetic Association Studies
  • Polymorphism
  • Asian Continental Ancestry Group
  • Squamous Cell Carcinoma
  • Phenotype
  • Genome-Wide Association Study
  • Non-Small Cell Lung Cancer
  • Genetic Predisposition
  • Tobacco Use Disorder
  • Cytochrome P-450 CYP2A6
  • Cancer DNA
  • Proteasome Endopeptidase Complex
  • Adenocarcinoma
  • Surveys and Questionnaires
  • Odds Ratio
  • Sex Factors
  • DNA Methylation
  • Chromosome 15
  • Alcohol Drinking
  • Risk Assessment
  • Incidence
  • Adolescents
  • African Americans
  • China
  • Pulmonary Disease, Chronic Obstructive
  • Cohort Studies
Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (2)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: CHRNA3 (cancer-related)

Zhang Y, Jiang M, Li Q, et al.
Chromosome 15q25 (CHRNA3-CHRNB4) Variation Indirectly Impacts Lung Cancer Risk in Chinese Males.
PLoS One. 2016; 11(3):e0149946 [PubMed] Free Access to Full Article Related Publications
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.

Qu X, Wang K, Dong W, et al.
Association between two CHRNA3 variants and susceptibility of lung cancer: a meta-analysis.
Sci Rep. 2016; 6:20149 [PubMed] Free Access to Full Article Related Publications
Genome-wide association studies (GWAS) have identified two CHRNA3 polymorphisms (rs578776 and rs938682) associated with lung cancer risk. Furthermore, these polymorphisms were investigated and genotyped by PCR analysis. All eligible case-control studies published up to Mar 1st 2015 were identified by searching Pubmed and Embase database. Negative association between rs578776-T allele and risk of lung cancer was obtained without obvious heterogeneity (OR: 0.83, 95% CI: 0.79-0.86; p = 0.898 for Q test). Rs938682-C allele carriers had a 12% to 28% decreased risk. Genotype model analysis showed results of dominant model for rs578776 (OR with 95% CI: 0.839(0.718-0.981)), dominant model for rs938682 (OR with 95% CI: 0.778(0.663-0.912)) and homozygous model for rs938682 (OR with 95% CI: 0.767(0.708-0.831)) were statistically significant. Subgroup analysis indicated rs578776-T variant had protective effect in Smokers, Caucasians, two histology subgroups, and two match subgroups. Meanwhile, rs938682-C allele was associated with decreased risk in Smokers, Caucasians, Lung cancer, and two match subgroups. Meta-regression suggested ethnicity might be the major source of heterogeneity in allele model and homozygous model for rs938682. Moreover, smoking status might contribute to part of heterogeneity under allele model. In summary, this meta-analysis suggested both rs578776 and rs938682 were significantly associated with the susceptibility of lung cancer.

Halldén S, Sjögren M, Hedblad B, et al.
Gene variance in the nicotinic receptor cluster (CHRNA5-CHRNA3-CHRNB4) predicts death from cardiopulmonary disease and cancer in smokers.
J Intern Med. 2016; 279(4):388-98 [PubMed] Free Access to Full Article Related Publications
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 Malmö 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.

Zhou W, Geng T, Wang H, et al.
CHRNA3 genetic polymorphism and the risk of lung cancer in the Chinese Han smoking population.
Tumour Biol. 2015; 36(7):4987-92 [PubMed] Related Publications
Lung cancer is the leading cause of cancer-related deaths worldwide that result from the combined effected of smoking exposure and genetic susceptibility. CHRNA3, a nicotinic acetylcholine receptor gene, was associated with lung cancer risk. The aim of this study was to identify whether CHRNA3 polymorphisms increase lung cancer risk directly or indirectly through smoking behavior in the Chinese Han individuals. We conducted a case-control study including 228 individuals with lung cancer and 301 healthy individuals. Seventeen known SNPs within CHRNA3 were selected for genotyping. Odds ratios (OR) and 95 % confidence interval (CI) were calculated by unconditional logistic regression with adjustment for gender and age. Two SNPs (rs8042059 and rs7177514) showed a 1.54-fold (p = 0.036; 95 % CI = 1.03-2.32) and 1.52-fold (p = 0.043; 95 % CI = 1.01-2.27) increased risk for lung cancer in smokers, respectively. Rs8042059 also showed a significant association for variant genotypes (CA/AA) compared with the wild-type genotype (CC), with an OR = 1.84 (p = 0.042; 95 % CI, 1.02-3.33) in the dominant model. In addition, the haplotype analysis found that the haplotypes "TCAC" and "CTGT," composed of rs938682, rs12914385, rs11637630, and rs2869546, were associated with a 1.79-fold and 501-fold increased lung cancer risk, respectively. However, the polymorphisms of all SNPs were not significantly different between controls and cases among general or nonsmokers population. Rs8042059 and rs7177514 may increase lung cancer risk indirectly through smoking behavior in the Chinese Han population.

Lou G, Zhang Y, Bao W, Deng D
Association between polymorphisms in CHRNA3 and PHACTR2 gene and environment and NSCLC risk in Chinese population.
Acta Biochim Pol. 2014; 61(4):765-8 [PubMed] Related Publications
Aims. This study aimed to investigate CHRNA3 (rs8040868) and PHACTR2 (rs9390123) single-nucleotide polymorphisms (SNPs) for association with non-small-cell lung cancer (NSCLC) risk in a Chinese population, and whether the environment affects the genetic polymorphisms. Methods. This case and control study included 500 NSCLC patients and 500 age-matched healthy controls. CHRNA3 (rs8040868) and PHACTR2 (rs9390123) SNPs were genotyped and associated for NSCLC risk by computing the odds ratio and 95% confidence interval from multivariate unconditional logistic regression analyses with adjustment of age. Results. The minor allele frequency (MAF) of CHRNA3 (rs8040868) and PHACTR2 (rs9390123) was 0.350 (C) and 0.397 (C), respectively. The frequencies of genotype and allele in CHRNA3 (rs8040868) and PHACTR2 (rs9390123) were not significantly different between the cases and controls, or between either of the subgroups. Conclusion. Although rs8040868 and rs9390123 SNPs are not associated with NSCLC risk in Chinese population, the results strongly suggest that geographical agents interact with human genetic polymorphism independent of ethnic background.

Xiao M, Chen L, Wu X, Wen F
The association between the rs6495309 polymorphism in CHRNA3 gene and lung cancer risk in Chinese: a meta-analysis.
Sci Rep. 2014; 4:6372 [PubMed] Free Access to Full Article Related Publications
The association between the rs6495309 polymorphism in CHRNA3 gene and lung cancer risk has been studied in Chinese by several number case-control control studies with small number of cases and controls, and these studies might be underpowered to reveal the true association. Thus we sought to investigate the association with the risk of lung cancer by performing a comprehensive meta-analysis on the polymorphism. Five case-control studies were extracted from 3 articles on the polymorphism involving 4608 lung cancer cases and 4617 controls. The results of meta-analysis showed that significant increased risk were found for the polymorphism with the risk of lung cancer in Chinese: OR = 1.47, 95%CI = 1.33-1.63, P < 0.00001 for CC + TC vs. TT; OR = 1.24, 95%CI = 1.07-1.44, P = 0.005 for CC vs. TT + TC; OR = 1.62, 95%CI = 1.32-2.00, P < 0.00001 for CC vs. TT; OR = 1.42, 95%CI = 1.26-1.61, P < 0.00001 for CT vs. TT; OR = 1.42, 95%CI = 1.26-1.61, P < 0.00001. No significant publication bias was found for the five genetic models. Our findings demonstrated that CHRNA3 gene rs6495309 polymorphism might be a risk factor for the development of lung cancer in Chinese.

Tseng TS, Park JY, Zabaleta J, et al.
Role of nicotine dependence on the relationship between variants in the nicotinic receptor genes and risk of lung adenocarcinoma.
PLoS One. 2014; 9(9):e107268 [PubMed] Free Access to Full Article Related Publications
Several variations in the nicotinic receptor genes have been identified to be associated with both lung cancer risk and smoking in the genome-wide association (GWA) studies. However, the relationships among these three factors (genetic variants, nicotine dependence, and lung cancer) remain unclear. In an attempt to elucidate these relationships, we applied mediation analysis to quantify the impact of nicotine dependence on the association between the nicotinic receptor genetic variants and lung adenocarcinoma risk. We evaluated 23 single nucleotide polymorphisms (SNPs) in the five nicotinic receptor related genes (CHRNB3, CHRNA6, and CHRNA5/A3/B4) previously reported to be associated with lung cancer risk and smoking behavior and 14 SNPs in the four 'control' genes (TERT, CLPTM1L, CYP1A1, and TP53), which were not reported in the smoking GWA studies. A total of 661 lung adenocarcinoma cases and 1,347 controls with a smoking history, obtained from the Environment and Genetics in Lung Cancer Etiology case-control study, were included in the study. Results show that nicotine dependence is a mediator of the association between lung adenocarcinoma and gene variations in the regions of CHRNA5/A3/B4 and accounts for approximately 15% of this relationship. The top two CHRNA3 SNPs associated with the risk for lung adenocarcinoma were rs1051730 and rs12914385 (p-value = 1.9×10(-10) and 1.1×10(-10), respectively). Also, these two SNPs had significant indirect effects on lung adenocarcinoma risk through nicotine dependence (p = 0.003 and 0.007). Gene variations rs2736100 and rs2853676 in TERT and rs401681 and rs31489 in CLPTM1L had significant direct associations on lung adenocarcinoma without indirect effects through nicotine dependence. Our findings suggest that nicotine dependence plays an important role between genetic variants in the CHRNA5/A3/B4 region, especially CHRNA3, and lung adenocarcinoma. This may provide valuable information for understanding the pathogenesis of lung adenocarcinoma and for conducting personalized smoking cessation interventions.

He P, Yang XX, He XQ, et al.
CHRNA3 polymorphism modifies lung adenocarcinoma risk in the Chinese Han population.
Int J Mol Sci. 2014; 15(4):5446-57 [PubMed] Free Access to Full Article Related Publications
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, rs1051730, 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.

Zhao Y, Zhou W, Xue L, et al.
Nicotine activates YAP1 through nAChRs mediated signaling in esophageal squamous cell cancer (ESCC).
PLoS One. 2014; 9(3):e90836 [PubMed] Free Access to Full Article Related Publications
Cigarette smoking is an established risk factor for esophageal cancers. Yes-associated protein 1 (YAP1), the key transcription factor of the mammalian Hippo pathway, has been reported to be an oncogenic factor for many cancers. In this study, we find nicotine administration can induce nuclear translocation and activation of YAP1 in ESCC. Consistently, we observed nuclear translocation and activation of YAP1 by knockdown of CHRNA3, which is a negative regulator of nicotine signaling in bronchial and esophageal cancer cells. Nicotine administration or CHRNA3 depletion substantially increased proliferation and migration in esophageal cancer cells. Interestingly, we find that YAP1 physically interacts with nAChRs, and nAChRs-signaling dissociates YAP1 from its negative regulatory complex composed with α-catenin, β-catenin and 14-3-3 in the cytoplasm, leading to upregulation and nuclear translocation of YAP1. This process likely requires PKC activation, as PKC specific inhibitor Enzastaurin can block nicotine induced YAP1 activation. In addition, we find nicotine signaling also inhibits the interaction of YAP1 with P63, which contributes to the inhibitory effect of nicotine on apoptosis. Using immunohistochemistry analysis we observed upregulation of YAP1 in a significant portion of esophageal cancer samples. Consistently, we have found a significant association between YAP1 upregulation and cigarette smoking in the clinical esophageal cancer samples. Together, these findings suggest that the nicotine activated nAChRs signaling pathway which further activates YAP1 plays an important role in the development of esophageal cancer, and this mechanism may be of a general significance for the carcinogenesis of smoking related cancers.

Anantharaman D, Chabrier A, Gaborieau V, et al.
Genetic variants in nicotine addiction and alcohol metabolism genes, oral cancer risk and the propensity to smoke and drink alcohol: a replication study in India.
PLoS One. 2014; 9(2):e88240 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Genetic variants in nicotinic acetylcholine receptor and alcohol metabolism genes have been associated with propensity to smoke tobacco and drink alcohol, respectively, and also implicated in genetic susceptibility to head and neck cancer. In addition to smoking and alcohol, tobacco chewing is an important oral cancer risk factor in India. It is not known if these genetic variants influence propensity or oral cancer susceptibility in the context of this distinct etiology.
METHODS: We examined 639 oral and pharyngeal cancer cases and 791 controls from two case-control studies conducted in India. We investigated six variants known to influence nicotine addiction or alcohol metabolism, including rs16969968 (CHRNA5), rs578776 (CHRNA3), rs1229984 (ADH1B), rs698 (ADH1C), rs1573496 (ADH7), and rs4767364 (ALDH2).
RESULTS: The CHRN variants were associated with the number of chewing events per day, including in those who chewed tobacco but never smoked (P =  0.003, P =  0.01 for rs16969968 and rs578776 respectively). Presence of the variant allele contributed to approximately 13% difference in chewing frequency compared to non-carriers. While no association was observed between rs16969968 and oral cancer risk (OR =  1.01, 95% CI =  0.83- 1.22), rs578776 was modestly associated with a 16% decreased risk of oral cancer (OR =  0.84, 95% CI =  0.72- 0.98). There was little evidence for association between polymorphisms in genes encoding alcohol metabolism and oral cancer in this population.
CONCLUSION: The association between rs16969968 and number of chewing events implies that the effect on smoking propensity conferred by this gene variant extends to the use of smokeless tobacco.

Li R, Qian J, Wang YY, et al.
Long noncoding RNA profiles reveal three molecular subtypes in glioma.
CNS Neurosci Ther. 2014; 20(4):339-43 [PubMed] Related Publications
BACKGROUND: Gliomas are the most lethal type of primary brain tumor in adult. Long noncoding RNAs (lncRNAs), which are involved in the progression of various cancers, may offer a potential gene therapy target in glioma.
METHODS AND FINDINGS: We first classified gliomas into three molecular subtypes (namely LncR1, LncR2 and LncR3) in Rembrandt dataset using consensus clustering. Survival analysis indicated that LncR3 had the best prognosis, while the LncR1 subtype showed the poorest overall survival rate. The results were further validated in an independent glioma dataset GSE16011. Additionally, we collected and merged data of the two databases (Rembrandt and GSE16011 dataset) and analyzed prognosis of each subtype in WHO II, III and IV gliomas. The similar results were obtained. Gene Set Variation Analysis (GSVA) demonstrated that LncR1 subtype enriched cultured astroglia's gene signature, while LncR2 subtype was characterized by neuronal gene signature. Oligodendrocytic was rich in LncR3. In addition, IDH1 mutation and 1p/19q LOH were found rich with LncR3, and EGFR amplification showed high percentage in LncR1 in GSE16011 dataset.
CONCLUSIONS: We report a novel molecular classification of glioma based on lncRNA expression profiles and believe that it would provide a potential platform for future studies on gene treatment for glioma and lead to more individualized therapies to improve survival rates.

Ren JH, Jin M, He WS, et al.
Association between CHRNA3 rs1051730 genotype and lung cancer risk in Chinese Han population: a case-control study.
J Huazhong Univ Sci Technolog Med Sci. 2013; 33(6):897-901 [PubMed] Related Publications
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 association 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.

Wassenaar CA, Dong Q, Amos CI, et al.
Pilot study of CYP2B6 genetic variation to explore the contribution of nitrosamine activation to lung carcinogenesis.
Int J Mol Sci. 2013; 14(4):8381-92 [PubMed] Free Access to Full Article Related Publications
We explored the contribution of nitrosamine metabolism to lung cancer in a pilot investigation of genetic variation in CYP2B6, a high-affinity enzymatic activator of tobacco-specific nitrosamines with a negligible role in nicotine metabolism. Previously we found that variation in CYP2A6 and CHRNA5-CHRNA3-CHRNB4 combined to increase lung cancer risk in a case-control study in European American ever-smokers (n = 860). However, these genes are involved in the pharmacology of both nicotine, through which they alter smoking behaviours, and carcinogenic nitrosamines. Herein, we separated participants by CYP2B6 genotype into a high- vs. low-risk group (*1/*1 + *1/*6 vs. *6/*6). Odds ratios estimated through logistic regression modeling were 1.25 (95% CI 0.68-2.30), 1.27 (95% CI 0.89-1.79) and 1.56 (95% CI 1.04-2.31) for CYP2B6, CYP2A6 and CHRNA5-CHRNA3-CHRNB4, respectively, with negligible differences when all genes were evaluated concurrently. Modeling the combined impact of high-risk genotypes yielded odds ratios that rose from 2.05 (95% CI 0.39-10.9) to 2.43 (95% CI 0.47-12.7) to 3.94 (95% CI 0.72-21.5) for those with 1, 2 and 3 vs. 0 high-risk genotypes, respectively. Findings from this pilot point to genetic variation in CYP2B6 as a lung cancer risk factor supporting a role for nitrosamine metabolic activation in the molecular mechanism of lung carcinogenesis.

Hartomo TB, Kozaki A, Hasegawa D, et al.
Minimal residual disease monitoring in neuroblastoma patients based on the expression of a set of real-time RT-PCR markers in tumor-initiating cells.
Oncol Rep. 2013; 29(4):1629-36 [PubMed] Related Publications
Minimal residual disease (MRD) is derived from tumor-initiating cells (TICs) and is responsible for tumor relapse. Neuroblastoma is characterized by extreme tumor heterogeneity, and more than half of high-risk patients experience tumor relapse. To overcome tumor heterogeneity and achieve more sensitive detection of MRD, several sets of real-time RT-PCR markers have been reported for MRD monitoring in neuroblastoma patients from different centers. However, these markers vary across centers and are still being validated. In the present study, we validated the ability of 14 commonly used real-time RT-PCR markers to detect MRD based on their expression in neuroblastoma TICs, and we developed a novel MRD detection protocol, which scored the samples as MRD-positive when the expression of one of the 11 real-time RT-PCR markers (CHRNA3, CRMP1, DBH, DCX, DDC, GABRB3, GAP43, ISL1, KIF1A, PHOX2B and TH) exceeded the normal range. By using this protocol, we prospectively monitored MRD in 73 bone marrow (BM), 12 peripheral blood stem cell and 8 peripheral blood samples from 14 neuroblastoma patients treated at a single center. We scored 100, 56, 56 and 57% BM cytology-positive, elevated vanillylmandelic acid (VMA), elevated homovanillic acid (HVA) and elevated neuron-specific enolase (NSE) samples as MRD-positive, respectively. MRD was also positive in 48, 45, 46 and 43% of the BM cytology-negative and normal VMA, normal HVA and normal NSE samples, respectively. These results suggest that the present MRD detection protocol based on the expression of a set of 11 real-time RT-PCR markers in neuroblastoma TICs achieves sensitive MRD monitoring in neuroblastoma patients.

Kim WJ, Oh YM, Kim TH, et al.
CHRNA3 variant for lung cancer is associated with chronic obstructive pulmonary disease in Korea.
Respiration. 2013; 86(2):117-22 [PubMed] Related Publications
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 ethnic 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.

Li Y, Huang J, Amos CI
Genetic association analysis of complex diseases incorporating intermediate phenotype information.
PLoS One. 2012; 7(10):e46612 [PubMed] Free Access to Full Article Related Publications
Genetic researchers often collect disease related quantitative traits in addition to disease status because they are interested in understanding the pathophysiology of disease processes. In genome-wide association (GWA) studies, these quantitative phenotypes may be relevant to disease development and serve as intermediate phenotypes or they could be behavioral or other risk factors that predict disease risk. Statistical tests combining both disease status and quantitative risk factors should be more powerful than case-control studies, as the former incorporates more information about the disease. In this paper, we proposed a modified inverse-variance weighted meta-analysis method to combine disease status and quantitative intermediate phenotype information. The simulation results showed that when an intermediate phenotype was available, the inverse-variance weighted method had more power than did a case-control study of complex diseases, especially in identifying susceptibility loci having minor effects. We further applied this modified meta-analysis to a study of imputed lung cancer genotypes with smoking data in 1154 cases and 1137 matched controls. The most significant SNPs came from the CHRNA3-CHRNA5-CHRNB4 region on chromosome 15q24-25.1, which has been replicated in many other studies. Our results confirm that this CHRNA region is associated with both lung cancer development and smoking behavior. We also detected three significant SNPs--rs1800469, rs1982072, and rs2241714--in the promoter region of the TGFB1 gene on chromosome 19 (p = 1.46×10(-5), 1.18×10(-5), and 6.57×10(-6), respectively). The SNP rs1800469 is reported to be associated with chronic obstructive pulmonary disease and lung cancer in cigarette smokers. The present study is the first GWA study to replicate this result. Signals in the 3q26 region were also identified in the meta-analysis. We demonstrate the intermediate phenotype can potentially enhance the power of complex disease association analysis and the modified meta-analysis method is robust to incorporate intermediate phenotype or other quantitative risk factor in the analysis.

Fachiroh J, Sangrajrang S, Johansson M, et al.
Tobacco consumption and genetic susceptibility to nasopharyngeal carcinoma (NPC) in Thailand.
Cancer Causes Control. 2012; 23(12):1995-2002 [PubMed] Related Publications
BACKGROUND: The incidence of nasopharyngeal carcinoma (NPC) varies substantially worldwide, with an endemic pocket in Southeast Asia.
METHOD: We assessed lifestyle and genetic factors in relation to NPC risk among 681 NPC cases and 1,078 controls from Thailand. Evaluated lifestyle factors included traditionally preserved foods, tobacco smoking, betel quid chewing, and alcohol consumption. Genetic factors included six variants implicated in a previous a genome-wide association study (GWAS) of NPC and three variants residing near the CHRNA3 and TERT genes that were linked to lung cancer risk in Asian populations. Odds ratios (OR) and 95 % confidence intervals (95 % CI) were estimated using unconditional logistic regression.
RESULTS: Frequent consumption of fermented vegetables was associated with increased NPC risk (OR of consumption ≥weekly vs. ≤rare 1.78, 95 % CI 1.24-2.55, p (trend) = 0.005), as was tobacco smoking (p (trend) < 0.001), former and current smokers displaying OR of 1.57 (95 % CI 1.10-2.30) and 2.00 (95 % CI 1.48-2.71) compared to never smokers, respectively. Four out of six genetic variants implicated in the recent NPC GWAS were associated with NPC risk (p (trend) ≤ 0.03), as well as two variants (rs402710 and rs2736098) on the TERT locus at 5p15.33 (p = 0.004 and p = 0.04, respectively).
CONCLUSIONS: These results strengthen our previous observation that tobacco smoking is an important risk factor of NPC in this population. Four out of six genetic variants identified in a recent NPC GWAS were confirmed, and the association noted with variants on 5p15.33 suggests that this locus is involved in NPC susceptibility, representing a novel finding in NPC epidemiology.

Yang L, Qiu F, Lu X, et al.
Functional polymorphisms of CHRNA3 predict risks of chronic obstructive pulmonary disease and lung cancer in Chinese.
PLoS One. 2012; 7(10):e46071 [PubMed] Free Access to Full Article Related Publications
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, reflecting 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.

Shen B, Shi MQ, Zheng MQ, et al.
Correlation between polymorphisms of nicotine acetylcholine acceptor subunit CHRNA3 and lung cancer susceptibility.
Mol Med Rep. 2012; 6(6):1389-92 [PubMed] Related Publications
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.

Tekpli X, Landvik NE, Skaug V, et al.
Functional effect of polymorphisms in 15q25 locus on CHRNA5 mRNA, bulky DNA adducts and TP53 mutations.
Int J Cancer. 2013; 132(8):1811-20 [PubMed] Related Publications
Genome-wide association studies have demonstrated that genetic polymorphisms influence the risk of developing lung cancer. Nicotinic acetylcholine receptor alpha3, alpha5 and beta4 genes (CHRNA3, CHRNA5 and CHRNB4) cluster at the 15q25.1 lung cancer susceptibility locus. We genotyped 310 patients with non-small cell lung cancer and a control group of 348 cancer-free individuals for seven sequence variants located in CHRNA3 and CHRNA5 genes. Two of the polymorphisms (rs3829787 and rs3841324) statistically influenced the risk of developing lung cancer. We found that four of the variants (rs3829787, rs3841324, rs588765 and rs3743073) were associated with differential levels of genetic alterations measured as the levels of hydrophobic DNA adducts in the adjacent histologically normal tissue of the lung cancer patients and as TP53 mutations in their lung tumors. The seven sequence variants formed three haplotypes with a frequency above 5%. The two most frequent haplotypes were associated with the risk of developing lung cancer and with smoking-related DNA alterations. We also found an association between CHRNA5 mRNA levels and the sequence variants or haplotypes. In conclusion, our results showed that several of the polymorphisms and their haplotypes in CHRNA5/CHRNA3 genes may have functional effects on (i) CHRNA5 mRNA levels, (ii) polycyclic aromatic hydrocarbon-DNA adduct levels, (iii) TP53 mutations and (iv) susceptibility to lung cancer.

Scherf DB, Sarkisyan N, Jacobsson H, et al.
Epigenetic screen identifies genotype-specific promoter DNA methylation and oncogenic potential of CHRNB4.
Oncogene. 2013; 32(28):3329-38 [PubMed] Free Access to Full Article Related Publications
Genome-wide association studies have highlighted three major lung cancer susceptibility regions at 15q25.1, 5p15.33 and 6p21.33. To gain insight into the possible mechanistic relevance of the genes in these regions, we investigated the regulation of candidate susceptibility gene expression by epigenetic alterations in healthy and lung tumor tissues. For genes up or downregulated in lung tumors, the influence of genetic variants on DNA methylation was investigated and in vitro studies were performed. We analyzed 394 CpG units within 19 CpG islands in the susceptibility regions in a screening set of 34 patients. Significant findings were validated in an independent patient set (n=50) with available DNA and RNA. The most consistent overall DNA methylation difference between tumor and adjacent normal tissue on 15q25 was tumor hypomethylation in the promoter region of CHRNB4 with a median difference of 8% (P<0.001), which resulted in overexpression of the transcript in tumors (P<0.001). Confirming previous studies, we also found hypermethylation in CHRNA3 and telomerase reverse transcriptase (TERT) with significant expression changes. Decitabine treatment of H1299 cells resulted in reduced methylation levels in gene promoters, elevated transcript levels of CHRNB4 and CHRNA3, and a slight downregulation of TERT demonstrating epigenetic regulation of lung cancer cells. Single-nucleotide polymorphisms rs421629 on 5p15.33 and rs1948, rs660652, rs8040868 and rs2036527 on 15q25.1, previously identified as lung cancer risk or nicotine-addiction modifiers, were associated with tumor DNA methylation levels in the promoters of TERT and CHRNB4 (P<0.001), respectively, in two independent sample sets (n=82; n=150). In addition, CHRNB4 knockdown in two different cell lines (A549 and H1299) resulted in reduced proliferation (PA549<0.05;PH1299<0.001) and propensity to form colonies in H1299 cells. These results suggest epigenetic deregulation of nicotinic acetylcholine receptor subunit (nAChR) genes which in the case of CHRNB4 is strongly associated with genetic lung cancer susceptibility variants and a functional impact on tumorigenic potential.

Jin G, Bae EY, Yang E, et al.
A functional polymorphism on chromosome 15q25 associated with survival of early stage non-small-cell lung cancer.
J Thorac Oncol. 2012; 7(5):808-14 [PubMed] Related Publications
INTRODUCTION: The 15q25 region has been associated with lung-cancer risk and might also be associated with the prognosis of lung cancer. This study was conducted to determine the impact of a functional polymorphism in the CHRNA3 gene on chromosome 15q25 in the survival of patients with early-stage non-small-cell lung cancer (NSCLC).
METHODS: Five hundred and eighty-three consecutive patients with surgically resected NSCLC were enrolled. The rs6495309C > T polymorphism in the promoter of the CHRNA3 gene was investigated. The association between genotype and overall survival (OS) and disease-free survival (DFS) was analyzed.
RESULTS: Patients with the rs6495309 CT or TT genotype had a significantly better OS and DFS than the rs6495309 CC genotype (adjusted hazard ratio for OS = 0.56, 95% confidence interval = 0.41-0.75, p = 0.0001; and adjusted hazard ratio for DFS = 0.61, 95% confidence interval = 0.48-0.79, p = 0.0001). An association between the rs6495309C > T polymorphism and survival outcome was demonstrated in smokers and never-smokers, and in squamous-cell carcinomas and adenocarcinomas.
CONCLUSION: The CHRNA3 rs6495309C > T polymorphism may affect survival in patients with early-stage NSCLC. Analysis of the rs6495309C > T polymorphism can help identify patients at high risk of a poor disease outcome.

Gu M, Dong X, Zhang X, et al.
Strong association between two polymorphisms on 15q25.1 and lung cancer risk: a meta-analysis.
PLoS One. 2012; 7(6):e37970 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The association between polymorphisms on 15q25.1 and lung cancer has been widely evaluated; however, the studies have yielded contradictory results. We sought to investigate this inconsistency by performing a comprehensive meta-analysis on two polymorphisms (CHRNA3 gene: rs1051730 and AGPHD1 gene: rs8034191) on 15q25.1.
METHODS: Data were extracted from 15 and 14 studies on polymorphisms rs1051730 and rs8034191 involving 12301/14000 and 14075/12873 lung cancer cases/controls, respectively. The random-effects model was applied, addressing heterogeneity and publication bias.
RESULTS: The two polymorphisms followed Hardy-Weinberg equilibrium for all studies (P>0.05). For rs1051730-G/A, carriers of A allele had a 36% increased risk for lung cancer (95% confidence interval [CI]: 1.27-1.46; P<0.0005), without heterogeneity (P = 0.258) or publication bias (P(Egger) = 0.462). For rs8034191-T/C, the allelic contrast indicated that C allele conferred a 23% increased risk for lung cancer (95% CI: 1.08-1.4; P = 0.002), with significant heterogeneity (P<0.0005), without publication bias (P(Egger) = 0.682). Subgroup analyses suggested that the between-study heterogeneity was derived from ethnicity, study design, matched information, and lung cancer subtypes. For example, the association of polymorphisms rs1051730 and rs8034191 with lung cancer was heterogeneous between Caucasians (OR = 1.32 and 1.22; 95% CI: 1.25-1.44 and 1.05-1.42; P<0.0005 and 0.008, respectively) and East Asians (OR = 1.51 and 1.03; 95% CI: 0.76-3 and 0.47-2.27; P = 0.237 and 0.934, respectively) under the allelic model, and this association was relatively strengthened under the dominant model. There was no observable publication bias for both polymorphisms.
CONCLUSIONS: Our findings demonstrated that CHRNA3 gene rs1051730-A allele and AGPHD1 gene rs8034191-T allele might be risk-conferring factors for the development of lung cancer in Caucasians, but not in East-Asians.

Ware JJ, van den Bree M, Munafò MR
From men to mice: CHRNA5/CHRNA3, smoking behavior and disease.
Nicotine Tob Res. 2012; 14(11):1291-9 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: The nicotinic acetylcholine receptor (nAChR) gene cluster CHRNA5-A3-B4 on chromosome 15 has been the subject of a considerable body of research over recent years. Two highly correlated single nucleotide polymorphisms (SNPs) within this region--rs16969968 in CHRNA5 and rs1051730 in CHRNA3--have generated particular interest.
METHODS: We reviewed the literature relating to SNPs rs16969968 and rs1051730 and smoking-related phenotypes, and clinical and preclinical studies, which shed light on the mechanisms underlying these associations.
RESULTS: Following the initial discovery of an association between this locus and smoking behavior, further associations with numerous phenotypes have been subsequently identified, including smoking-related behaviors, diseases, and cognitive phenotypes. Potential mechanisms thought to underlie these have also been described, as well as possible gene × environment interaction effects.
CONCLUSIONS: Perhaps counter to the usual route of scientific inquiry, these initial findings, based exclusively on human samples and strengthened by their identification through agnostic genome-wide methods, have led to preclinical research focused on determining the mechanism underlying these associations. Progress has been made using knockout mouse models, highlighting the importance of α5 nAChR subunits in regulating nicotine intake, particularly those localized to the habenula-interpeduncular nucleus pathway. Translational research seeking to evaluate the effect of nicotine challenge on brain activation as a function of rs16969968 genotype using neuroimaging technologies is now called for, which may point to new targets for novel smoking cessation therapies.

Chen LS, Saccone NL, Culverhouse RC, et al.
Smoking and genetic risk variation across populations of European, Asian, and African American ancestry--a meta-analysis of chromosome 15q25.
Genet Epidemiol. 2012; 36(4):340-51 [PubMed] Free Access to Full Article Related Publications
Recent meta-analyses of European ancestry subjects show strong evidence for association between smoking quantity and multiple genetic variants on chromosome 15q25. This meta-analysis extends the examination of association between distinct genes in the CHRNA5-CHRNA3-CHRNB4 region and smoking quantity to Asian and African American populations to confirm and refine specific reported associations. Association results for a dichotomized cigarettes smoked per day phenotype in 27 datasets (European ancestry (N = 14,786), Asian (N = 6,889), and African American (N = 10,912) for a total of 32,587 smokers) were meta-analyzed by population and results were compared across all three populations. We demonstrate association between smoking quantity and markers in the chromosome 15q25 region across all three populations, and narrow the region of association. Of the variants tested, only rs16969968 is associated with smoking (P < 0.01) in each of these three populations (odds ratio [OR] = 1.33, 95% CI = 1.25-1.42, P = 1.1 × 10(-17) in meta-analysis across all population samples). Additional variants displayed a consistent signal in both European ancestry and Asian datasets, but not in African Americans. The observed consistent association of rs16969968 with heavy smoking across multiple populations, combined with its known biological significance, suggests rs16969968 is most likely a functional variant that alters risk for heavy smoking. We interpret additional association results that differ across populations as providing evidence for additional functional variants, but we are unable to further localize the source of this association. Using the cross-population study paradigm provides valuable insights to narrow regions of interest and inform future biological experiments.

Mani S, Szymańska K, Cuenin C, et al.
DNA methylation changes associated with risk factors in tumors of the upper aerodigestive tract.
Epigenetics. 2012; 7(3):270-7 [PubMed] Free Access to Full Article Related Publications
Cancers of the upper aerodigestive tract (UADT) are common forms of malignancy associated with tobacco and alcohol exposures, although human papillomavirus and nutritional deficiency are also important risk factors. While somatically acquired DNA methylation changes have been associated with UADT cancers, what triggers these events and precise epigenetic targets are poorly understood. In this study, we applied quantitative profiling of DNA methylation states in a panel of cancer-associated genes to a case-control study of UADT cancers. Our analyses revealed a high frequency of aberrant hypermethylation of several genes, including MYOD1, CHRNA3 and MTHFR in UADT tumors, whereas CDKN2A was moderately hypermethylated. Among differentially methylated genes, we identified a new gene (the nicotinic acetycholine receptor gene) as target of aberrant hypermethylation in UADT cancers, suggesting that epigenetic deregulation of nicotinic acetycholine receptors in non-neuronal tissues may promote the development of UADT cancers. Importantly, we found that sex and age is strongly associated with the methylation states, whereas tobacco smoking and alcohol intake may also influence the methylation levels in specific genes. This study identifies aberrant DNA methylation patterns in UADT cancers and suggests a potential mechanism by which environmental factors may deregulate key cellular genes involved in tumor suppression and contribute to UADT cancers.

Fehringer G, Liu G, Briollais L, et al.
Comparison of pathway analysis approaches using lung cancer GWAS data sets.
PLoS One. 2012; 7(2):e31816 [PubMed] Free Access to Full Article Related Publications
Pathway analysis has been proposed as a complement to single SNP analyses in GWAS. This study compared pathway analysis methods using two lung cancer GWAS data sets based on four studies: one a combined data set from Central Europe and Toronto (CETO); the other a combined data set from Germany and MD Anderson (GRMD). We searched the literature for pathway analysis methods that were widely used, representative of other methods, and had available software for performing analysis. We selected the programs EASE, which uses a modified Fishers Exact calculation to test for pathway associations, GenGen (a version of Gene Set Enrichment Analysis (GSEA)), which uses a Kolmogorov-Smirnov-like running sum statistic as the test statistic, and SLAT, which uses a p-value combination approach. We also included a modified version of the SUMSTAT method (mSUMSTAT), which tests for association by averaging χ(2) statistics from genotype association tests. There were nearly 18000 genes available for analysis, following mapping of more than 300,000 SNPs from each data set. These were mapped to 421 GO level 4 gene sets for pathway analysis. Among the methods designed to be robust to biases related to gene size and pathway SNP correlation (GenGen, mSUMSTAT and SLAT), the mSUMSTAT approach identified the most significant pathways (8 in CETO and 1 in GRMD). This included a highly plausible association for the acetylcholine receptor activity pathway in both CETO (FDR≤0.001) and GRMD (FDR = 0.009), although two strong association signals at a single gene cluster (CHRNA3-CHRNA5-CHRNB4) drive this result, complicating its interpretation. Few other replicated associations were found using any of these methods. Difficulty in replicating associations hindered our comparison, but results suggest mSUMSTAT has advantages over the other approaches, and may be a useful pathway analysis tool to use alongside other methods such as the commonly used GSEA (GenGen) approach.

Chikova A, Bernard HU, Shchepotin IB, Grando SA
New associations of the genetic polymorphisms in nicotinic receptor genes with the risk of lung cancer.
Life Sci. 2012; 91(21-22):1103-8 [PubMed] Free Access to Full Article Related Publications
AIMS: Previous studies revealed association of lung cancer risk with single nucleotide polymorphisms (SNPs) in chromosome 15q25 region containing CHRNA5-CHRNA3-CHRNB4 nicotinic acetylcholine receptor (nAChR) subunit gene cluster. The genetic variations in other lung nAChRs remained unknown. In this study, we perform case-control analysis of CHRNA9 and CHRNA3 genes using 340 non-small cell lung cancer cases and 435 controls.
MAIN METHODS: All exons, 3'UTR, intron 1 and parts of other introns surrounding exons 2-5 of CHRNA9 gene as well as exons 2, 3 of CHRNA3 gene and parts of surrounding intronic regions were sequenced. The study was controlled for gender, age and ethnicity related differences. Each SNP in analyzed groups was assessed by allele frequency, genotype distribution and haplotype analysis.
KEY FINDINGS: The case-control analysis revealed that an increased risk is associated with two SNPs in CHRNA9, rs56159866 and rs6819385, and one in CHRNA3, rs8040868. The risk was reduced for three SNPs in CHRNA9, rs55998310, rs56291234, and newly discovered rs182073550, and also in carriers of the haplotype NP_060051.2 containing ancestral N442 variant of α9.
SIGNIFICANCE: The nonsynonymous substitutions can produce receptors exhibiting unique ligand-binding and downstream signaling characteristics, synonymous as well all intronic SNPs may affect protein production at the transcriptional and/or translational levels, or just manifest association with cancer by genetic linkage to other alleles. Elucidation of the mechanisms by which individual genetic variations in α9 affect predisposition to lung cancer may lead to development of personalized approaches to cancer prevention and treatment as well as protection against tobacco consumption.

Ware JJ, van den Bree MB, Munafò MR
Association of the CHRNA5-A3-B4 gene cluster with heaviness of smoking: a meta-analysis.
Nicotine Tob Res. 2011; 13(12):1167-75 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Variation in the CHRNA5-A3-B4 gene cluster is a promising candidate region for smoking behavior and has been linked to multiple smoking-related phenotypes (e.g., nicotine dependence) and diseases (e.g., lung cancer). Two single nucleotide polymorphisms (SNPs), rs16969968 in CHRNA5 and rs1051730 in CHRNA3, have generated particular interest.
METHODS: We evaluated the published evidence for association between rs16969968 (k = 27 samples) and rs1051730 (k = 44 samples) SNPs with heaviness of smoking using meta-analytic techniques. We explored which SNP provided a stronger genetic signal and investigated study-level characteristics (i.e., ancestry, disease state) to establish whether the strength of association differed across populations. We additionally tested for small study bias and explored the impact of year of publication.
RESULTS AND CONCLUSIONS: Meta-analysis indicated compelling evidence of an association between the rs1051730/rs16966968 variants and daily cigarette consumption (fixed effects: B = 0.91, 95% CI = 0.77, 1.06, p < .001; random effects: B = 1.01, 95% CI = 0.81, 1.22, p < .001), equivalent to a per-allele effect of approximately 1 cigarette/day. SNP rs1051730 was found to provide a stronger signal than rs16966968 in stratified analyses (p(diff) = .028), although this difference was only qualitatively observed in the subset of samples that provided data on both SNPs. While the functional relevance of rs1051730 is unknown, it may be a strong tagging SNP for functional haplotypes in this region.

Timofeeva MN, McKay JD, Smith GD, et al.
Genetic polymorphisms in 15q25 and 19q13 loci, cotinine levels, and risk of lung cancer in EPIC.
Cancer Epidemiol Biomarkers Prev. 2011; 20(10):2250-61 [PubMed] Related Publications
BACKGROUNDS: Multiple polymorphisms affecting smoking behavior have been identified through genome-wide association studies. Circulating levels of the nicotine metabolite cotinine is a marker of recent smoking exposure. Hence, genetic variants influencing smoking behavior are expected to be associated with cotinine levels.
METHODS: We conducted an analysis in a lung cancer case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. We investigated the effects of single-nucleotide polymorphisms (SNP) previously associated with smoking behavior on (i) circulating cotinine and (ii) lung cancer risk. A total of 894 cases and 1,805 controls were analyzed for cotinine and genotyped for 10 polymorphisms on 7p14, 8p11, 10q23, 15q25, and 19q13.
RESULTS: Two variants in the nicotinic acetylcholine receptor subunit genes CHRNA5 and CHRNA3 on 15q25, rs16969968 and rs578776, were associated with cotinine (P = 0.001 and 0.03, respectively) in current smokers and with lung cancer risk (P < 0.001 and P = 0.001, respectively). Two 19q13 variants, rs7937 and rs4105144, were associated with increased cotinine (P = 0.003 and P < 0.001, respectively) but decreased lung cancer risk (P = 0.01 for both, after adjusting for cotinine). Variants in 7p14, 8p11, and 10q23 were not associated with cotinine or lung cancer risk.
CONCLUSIONS: 15q25 and 19q13 SNPs were associated with circulating cotinine. The directions of association for 15q25 variants with cotinine were in accordance with that expected of lung cancer risk, whereas SNPs on 19q13 displayed contrasting associations of cotinine and lung cancer that require further investigation.
IMPACT: This study is the largest to date investigating the effects of polymorphisms affecting smoking behavior on lung cancer risk using circulating cotinine measures as proxies for recent smoking behavior.

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