Intermediacy and Gene–Environment Interaction: The Example of CHRNA5-A3 Region, Smoking, Nicotine Dependence, and Lung Cancer

Wacholder, Sholom; Chatterjee, Nilanjan; Caporaso, Neil

doi:10.1093/jnci/djn380

Cited by 22 publications

(17 citation statements)

References 43 publications

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“…Rigorous environmental factors such as smoking are risk of lung cancer and gene-environment interaction is well known involved in the etiology of lung cancer [23], but here we found that the 97906A variant may influence the development of lung cancer mostly due to autochthonous inherited effect. As shown, 97906C>A is more significant in young individuals, in nonsmokers and in nondrinkers.…”

Section: Discussionmentioning

confidence: 51%

A Common Genetic Variant (97906C>A) of DAB2IP/AIP1 Is Associated with an Increased Risk and Early Onset of Lung Cancer in Chinese Males

Yang

Ling

et al. 2011

PLoS ONE

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DOC-2/DAB2 interactive protein (DAB2IP) is a novel identified tumor suppressor gene that inhibits cell growth and facilitates cell apoptosis. One genetic variant in DAB2IP gene was reported to be associated with an increased risk of aggressive prostate cancer recently. Since DAB2IP involves in the development of lung cancer and low expression of DAB2IP are observed in lung cancer, we hypothesized that the variations in DAB2IP gene can increase the genetic susceptibility to lung cancer. In a case-control study of 1056 lung cancer cases and 1056 sex and age frequency-matched cancer-free controls, we investigated the association between two common polymorphisms in DAB2IP gene (−1420T>G, rs7042542; 97906C>A, rs1571801) and the risk of lung cancer. We found that compared with the 97906CC genotypes, carriers of variant genotypes (97906AC+AA) had a significant increased risk of lung cancer (adjusted odds ratio [OR] = 1.33, 95%CI = 1.04–1.70, P = 0.023) and the number of variant (risk) allele worked in a dose-response manner (P trend = 0.0158). Further stratification analysis showed that the risk association was more pronounced in subjects aged less than 60 years old, males, non-smokers, non-drinkers, overweight groups and in those with family cancer history in first or second-degree relatives, and the 97906A interacted with overweight on lung cancer risk. We further found the number of risk alleles (97906A allele) were negatively correlated with early diagnosis age of lung cancer in male patients (P = 0.003). However, no significant association was observed on the −1420T>G polymorphism. Our data suggested that the 97906A variant genotypes are associated with the increased risk and early onset of lung cancer, particularly in males.

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Section: Discussionmentioning

confidence: 51%

A Common Genetic Variant (97906C>A) of DAB2IP/AIP1 Is Associated with an Increased Risk and Early Onset of Lung Cancer in Chinese Males

Yang

Ling

et al. 2011

PLoS ONE

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“…A third option is that these same loci are involved independently in the pathophysiology of both states. 107 If so, combination of high nicotine consumption and higher LC susceptibility would be synergistic. These controversial findings underscore the challenge of defining and measuring behavioral phenotypes (although some ND-related phenotypes seem at first glance quite simple to define; for example, CPD).…”

Section: Chrna5-chrna3-chrnb4 and Lcmentioning

confidence: 99%

Differential contribution of genetic variation in multiple brain nicotinic cholinergic receptors to nicotine dependence: recent progress and emerging open questions

Greenbaum¹,

Lerer²

2009

Mol Psychiatry

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Nicotine dependence (ND), a major public health challenge, is a complex, multifactorial behavior, in which both genetic and environmental factors have a role. Brain nicotinic acetylcholine receptor (nAChR)-encoding genes are among the most prominent candidate genes studied in the context of ND, because of their biological relevance as binding sites for nicotine. Until recently, most research on the role of nAChRs in ND has focused on two of these genes (encoding the a4-and b2-subunits) and not much attention has been paid to the possible contribution of the other nine brain nAChR subunit genes (a2-a3, a5-a7, a9-a10, b3-b4) to the pathophysiology and genetics of ND. This situation has changed dramatically in the last 2 years during which intensive research had addressed the issue, mainly from the genetics perspective, and has shown the importance of the CHRNA5-CHRNA3-CHRNB4 and CHRNA6-CHRNB3 loci in ND-related phenotypes. In this review, we highlight recent findings regarding the contribution of non-a4/b2-subunit containing nAChRs to ND, based on several lines of evidence: (1) human genetics studies (including linkage analysis, candidate-gene association studies and whole-genome association studies) of several ND-related phenotypes; (2) differential pharmacological and biochemical properties of receptors containing these subunits; (3) evidence from genetically manipulated mice; and (4) the contribution of nAChR genes to ND-related personality traits and neurocognitive profiles. Combining neurobiological genetic and behavioral perspectives, we suggest that genetic susceptibility to ND is not linked to one or two specific nAChR subtype genes but to several. In particular, the a3, a5-6 and b3-4 nAChR subunit-encoding genes may play a much more pivotal role in the neurobiology and genetics of ND than was appreciated earlier. At the functional level, variants in these subunit genes (most likely regulatory) may have independent as well as interactive contributions to the ND phenotype spectrum. We address methodological challenges in the field, highlight open questions and suggest possible pathways for future research.

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“…Thus, there is a debate about whether the genetic variants have an impact on lung cancer risk directly or exert their effect largely through the profound effect of the variants on smoking intensity [20]–[22] or COPD [23]. Further work investigating this association concluded that there are dual pathways between the genetic variant and lung cancer association, independently via a direct effect on lung carcinogenesis and through smoking behavior [6], [7], [15], [24]–[26]. More recent studies of current smokers have shown that the genetic variants on CHRNA5-A3 gene cluster have a stronger association with cotinine levels than with self-reported smoking behavior, and suggested that the effect of the genetic variants on lung cancer risk, is largely, if not exclusively, through their effect on smoking intensity [27]–[29].…”

Section: Introductionmentioning

confidence: 99%

Method for Evaluating Multiple Mediators: Mediating Effects of Smoking and COPD on the Association between the CHRNA5-A3 Variant and Lung Cancer Risk

et al. 2012

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A mediation model explores the direct and indirect effects between an independent variable and a dependent variable by including other variables (or mediators). Mediation analysis has recently been used to dissect the direct and indirect effects of genetic variants on complex diseases using case-control studies. However, bias could arise in the estimations of the genetic variant-mediator association because the presence or absence of the mediator in the study samples is not sampled following the principles of case-control study design. In this case, the mediation analysis using data from case-control studies might lead to biased estimates of coefficients and indirect effects. In this article, we investigated a multiple-mediation model involving a three-path mediating effect through two mediators using case-control study data. We propose an approach to correct bias in coefficients and provide accurate estimates of the specific indirect effects. Our approach can also be used when the original case-control study is frequency matched on one of the mediators. We employed bootstrapping to assess the significance of indirect effects. We conducted simulation studies to investigate the performance of the proposed approach, and showed that it provides more accurate estimates of the indirect effects as well as the percent mediated than standard regressions. We then applied this approach to study the mediating effects of both smoking and chronic obstructive pulmonary disease (COPD) on the association between the CHRNA5-A3 gene locus and lung cancer risk using data from a lung cancer case-control study. The results showed that the genetic variant influences lung cancer risk indirectly through all three different pathways. The percent of genetic association mediated was 18.3% through smoking alone, 30.2% through COPD alone, and 20.6% through the path including both smoking and COPD, and the total genetic variant-lung cancer association explained by the two mediators was 69.1%.

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Intermediacy and Gene–Environment Interaction: The Example of CHRNA5-A3 Region, Smoking, Nicotine Dependence, and Lung Cancer

Cited by 22 publications

References 43 publications

A Common Genetic Variant (97906C>A) of DAB2IP/AIP1 Is Associated with an Increased Risk and Early Onset of Lung Cancer in Chinese Males

A Common Genetic Variant (97906C>A) of DAB2IP/AIP1 Is Associated with an Increased Risk and Early Onset of Lung Cancer in Chinese Males

Differential contribution of genetic variation in multiple brain nicotinic cholinergic receptors to nicotine dependence: recent progress and emerging open questions

Method for Evaluating Multiple Mediators: Mediating Effects of Smoking and COPD on the Association between the CHRNA5-A3 Variant and Lung Cancer Risk

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