Meta-analysis and imputation refines the association of 15q25 with smoking quantity

Department of Statistics, University of Oxford, Oxford, UK.
Nature Genetics (Impact Factor: 29.35). 05/2010; 42(5):436-40. DOI: 10.1038/ng.572
Source: PubMed


Smoking is a leading global cause of disease and mortality. We established the Oxford-GlaxoSmithKline study (Ox-GSK) to perform a genome-wide meta-analysis of SNP association with smoking-related behavioral traits. Our final data set included 41,150 individuals drawn from 20 disease, population and control cohorts. Our analysis confirmed an effect on smoking quantity at a locus on 15q25 (P = 9.45 x 10(-19)) that includes CHRNA5, CHRNA3 and CHRNB4, three genes encoding neuronal nicotinic acetylcholine receptor subunits. We used data from the 1000 Genomes project to investigate the region using imputation, which allowed for analysis of virtually all common SNPs in the region and offered a fivefold increase in marker density over HapMap2 (ref. 2) as an imputation reference panel. Our fine-mapping approach identified a SNP showing the highest significance, rs55853698, located within the promoter region of CHRNA5. Conditional analysis also identified a secondary locus (rs6495308) in CHRNA3.

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Available from: Arne S Schaefer, Mar 16, 2015
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    • "The International Lung Cancer Consortium was established in 2004 and coordinates genotyping activities and ongoing genome-wide association studies (GWAS) [9]. Recent association findings for smokingrelated diseases implicate genetically derived individual differences [10] [11] [12] [13] [14]. "

    Full-text · Dataset · Oct 2013
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    • "The International Lung Cancer Consortium was established in 2004 and coordinates genotyping activities and ongoing genome-wide association studies (GWAS) [9]. Recent association findings for smokingrelated diseases implicate genetically derived individual differences [10] [11] [12] [13] [14]. "
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    ABSTRACT: Recent genome-wide association studies have identified several lung cancer susceptibility loci. We previously carried out a replication study in male Japanese smokers that focused on chromosome 5p15 (telomerase reverse transcriptase) and 3q28 (tumor protein p63) (Shimizu et al., Journal of Cancer Therapy, Vol. 2, No. 5, 2011, pp. 690-696). The cur-rent study was performed to confirm the association of traditional susceptibility loci [i.e., alcohol dehydrogenase 1C (ADH1C) and aldehyde dehydrogenase 2 (ALDH2)] in 1039 male Japanese smokers (573 lung cancer patients and 466 healthy control subjects) who were previously enrolled in a study to investigate the low odds ratio for lung cancer risk associated with functionally impaired and deletion polymorphisms in cytochrome P450 2A6 (CYP2A6). The minor al-lele frequency of rs671 in ALDH2 (0.304) was significantly higher in lung cancer cases than in controls (0.226), with an odds ratio of 1.42 [95% confidence interval (CI) of 1.12 -1.80, p = 0.0033]. No significant association of rs698 in ADH1C with lung cancer risk was found in this population of male Japanese smokers. For light smokers categorized according to the 50th percentile Brinkman index value among the control subjects (620 daily cigarettes × years) and for the CYP2A6*1 wild-type non-carrier sub-population, significantly high odds ratios of 1.98 and 1.68 (95% CI of 1.28 -3.06, p = 0.0022, and 1.07 -2.66, p = 0.025), respectively, were observed for rs671 in ALDH2. The present results sup-port the association of ALDH2 loci with lung cancers and suggest a specific effect of ALDH2 loci resulting in a higher risk of lung cancer in light smokers. CYP2A6 polymorphisms, including copy number polymorphisms, may lower the risk of heavy tobacco use-related lung cancer.
    Full-text · Article · Aug 2013 · Journal of Cancer Therapy
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    • "Initial genome-wide associations in lung cancer robustly implicated SNPs (Table 1) spanning the chromosome 15q25 region encoding the gene cluster of nicotinic receptors, CHRNA3/A5/B4[9-12]. Subsequent multi-investigator consortia analyses confirmed the association of SNPs spanning this region with heavy smoking, nicotine dependence, craving and related endophenotypes [11,13,14]. Saccone et al. [13] conducted a meta-analysis across 34 datasets of European-ancestry participants (Table 1), including a diverse group of 38,617 smokers, and demonstrated that rs16969968, a nonsynonymous coding polymorphism of the CHRNA5 gene, correlated highly significantly with smoking behavior (odds ratio = 1.33, "
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    ABSTRACT: Lung cancer is the leading cause of cancer death worldwide in part due to our inability to identify which smokers are at highest risk and the lack of effective tools to detect the disease at its earliest and potentially curable stage. Recent results from the National Lung Screening Trial have shown that annual screening of high-risk smokers with low-dose helical computed tomography of the chest can reduce lung cancer mortality. However, molecular biomarkers are needed to identify which current and former smokers would benefit most from annual computed tomography scan screening in order to reduce the costs and morbidity associated with this procedure. Additionally, there is an urgent clinical need to develop biomarkers that can distinguish benign from malignant lesions found on computed tomography of the chest given its very high false positive rate. This review highlights recent genetic, transcriptomic and epigenomic biomarkers that are emerging as tools for the early detection of lung cancer both in the diagnostic and screening setting.
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