Dissecting the genetic overlap of smoking behaviors, lung cancer, and chronic obstructive pulmonary disease: A focus on nicotinic receptors and nicotine metabolizing enzyme (original) (raw)
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PloS one, 2014
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...
A variant associated with nicotine dependence, lung cancer and peripheral arterial disease
Nature, 2008
Smoking is a leading cause of preventable death, causing about 5 million premature deaths worldwide each year 1,2 . Evidence for genetic influence on smoking behaviour and nicotine dependence (ND) 3-8 has prompted a search for susceptibility genes. Furthermore, assessing the impact of sequence variants on smokingrelated diseases is important to public health 9,10 . Smoking is the major risk factor for lung cancer (LC) 11-14 and is one of the main risk factors for peripheral arterial disease (PAD) 15-17 . Here we identify a common variant in the nicotinic acetylcholine receptor gene cluster on chromosome 15q24 with an effect on smoking quantity, ND and the risk of two smoking-related diseases in populations of European descent. The variant has an effect on the number of cigarettes smoked per day in our sample of smokers. The same variant was associated with ND in a previous genomewide association study that used low-quantity smokers as controls , and with a similar approach we observe a highly significant association with ND. A comparison of cases of LC and PAD with population controls each showed that the variant confers risk of LC and PAD. The findings provide a case study of a gene-environment interaction 20 , highlighting the role of nicotine addiction in the pathology of other serious diseases.
Nicotinic Receptor Gene Variants Influence Susceptibility to Heavy Smoking
Cancer Epidemiology, Biomarkers & Prevention, 2008
Heavy smoking is a strong predictor of nicotine dependence, which is a major impediment to smoking cessation. Although both heavy smoking and nicotine dependence are highly heritable, previous attempts to identify genes influencing these phenotypes have been largely unsuccessful until very recently. We studied 1,452 heavy smokers (defined as smoking at least 30 cigarettes per day for at least 5 years) and 1,395 light smokers (defined as smoking <5 cigarettes per day for at least 1 year) to investigate the association of common variants in nicotinic receptor subunit genes with smoking behavior. Compared with the most common allele, two separate groups of single nucleotide polymorphisms (SNP) in the CHRNA5-CHRNA3-CHRNB4 gene cluster were associated with heavy smoking with a very high statistical significance. One group of eight SNPs, which included a nonsynonymous SNP in the CHRNA5 gene, was in strong linkage disequilibrium and associated with increased risk of heavy smoking. A sec...