Familial Aggregation of Common Sequence Variants on 15q24-25.1 in Lung Cancer

Liu, Pengyuan; Vikis, Haris G.; Wang, Daolong; Lü, Yan; Wang, Yian; Schwartz, Ann G.; Pinney, Susan M.; Yang, Ping; Andrade, Mariza de; Petersen, Gloria M.; Wiest, Jonathan S.; Fain, Pamela R.; Gazdar, Adi F.; Gaba, Colette; Rothschild, Henry; Mandal, Diptasri; Coons, Teresa; Lee, Juwon; Kupert, Elena; Seminara, Daniela; Minna, John D.; Bailey-Wilson, Joan E.; Wu, Xifeng; Spitz, Margaret R.; Eisen, Timothy; Houlston, Richard S.; Amos, Christopher I.; Anderson, Marshall W.; You, Ming

doi:10.1093/jnci/djn268

Cited by 137 publications

(99 citation statements)

References 20 publications

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“…A systematic and comprehensive description of all the observations is beyond the scope of this review, which focuses on the role of nAChRs in ND. It is noted that the association of the rs8034191 and rs1051730 SNPs with familial LC was described by Liu et al 102 in the context of GWAS performed on a 194 familial LC patients and 219 control individuals sample (adjusted for age, sex and pack-years of cigarette exposure). However, data regarding ND in terms of FTND scores were unavailable.…”

Section: Chrna5-chrna3-chrnb4 and Lcmentioning

confidence: 89%

“…However, data regarding ND in terms of FTND scores were unavailable. 102 In a very recent follow-up publication to the GWAS of Amos et al 101 Spitz et al 103 combined the discovery and one of the replication samples and observed that the highly correlated rs1051370 and rs8034191 are significant risk factors for both LC and ND, contrary to the initial conclusions of Amos et al 103 (Supplementary Table 1). Two ND-related phenotypes were found to be significantly associated: CPD and FTND, but not other phenotypes such as age of SI.…”

Section: Chrna5-chrna3-chrnb4 and Lcmentioning

confidence: 97%

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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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Section: Chrna5-chrna3-chrnb4 and Lcmentioning

confidence: 89%

Section: Chrna5-chrna3-chrnb4 and Lcmentioning

confidence: 97%

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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“…The replicated nicotine dependence loci tagged by rs16969968 (96,(100)(101)(102) and rs578776 (101,103) have also been reported to influence lung cancer risk in several genomewide association studies. This is an exciting convergence of findings for nicotine dependence risk loci and lung cancer risk loci.…”

Section: Origins Of Cellular and Subcellular Selectivitymentioning

confidence: 90%

Nicotine is a Selective Pharmacological Chaperone of Acetylcholine Receptor Number and Stoichiometry. Implications for Drug Discovery

Lester

Xia

Srinivasan

et al. 2009

AAPS J

144

167

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Abstract. The acronym SePhaChARNS, for "selective pharmacological chaperoning of acetylcholine receptor number and stoichiometry," is introduced. We hypothesize that SePhaChARNS underlies classical observations that chronic exposure to nicotine causes "upregulation" of nicotinic receptors (nAChRs). If the hypothesis is proven, (1) SePhaChARNS is the molecular mechanism of the first step in neuroadaptation to chronic nicotine; and (2) nicotine addiction is partially a disease of excessive chaperoning. The chaperone is a pharmacological one, nicotine; and the chaperoned molecules are α4β2* nAChRs. SePhaChARNS may also underlie two inadvertent therapeutic effects of tobacco use: (1) the inverse correlation between tobacco use and Parkinson's disease; and (2) the suppression of seizures by nicotine in autosomal dominant nocturnal frontal lobe epilepsy. SePhaChARNS arises from the thermodynamics of pharmacological chaperoning: ligand binding, especially at subunit interfaces, stabilizes AChRs during assembly and maturation, and this stabilization is most pronounced for the highest-affinity subunit compositions, stoichiometries, and functional states of receptors. Several chemical and pharmacokinetic characteristics render exogenous nicotine a more potent pharmacological chaperone than endogenous acetylcholine. SePhaChARNS is modified by desensitized states of nAChRs, by acid trapping of nicotine in organelles, and by other aspects of proteostasis. SePhaChARNS is selective at the cellular, and possibly subcellular, levels because of variations in the detailed nAChR subunit composition, as well as in expression of auxiliary proteins such as lynx. One important implication of the SePhaChARNS hypothesis is that therapeutically relevant nicotinic receptor drugs could be discovered by studying events in intracellular compartments rather than exclusively at the surface membrane.

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“…Several GWAS have identified a region of 15q25.1, containing nicotinic acetylcholine receptor subunit genes CHRNA3 and CHRNA5, associated with lung cancer, nicotine addiction, cigarettes smoked per day, COPD, FEV 1 , and emphysema (59)(60)(61)(62)(63)(64)(65)(66)(67)(68). Additional regions of interest identified in lung cancer GWAS are on 3q29, 5p15, 6p21, 10q25, and 15q15 (69)(70)(71).…”

Section: Gwasmentioning

confidence: 99%

Genetic Epidemiology of Cigarette Smoke–Induced Lung Disease

Schwartz

2012

Proc Am Thorac Soc

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Chronic obstructive pulmonary disease (COPD) and lung cancer represent two diseases that share a strong risk factor in smoking, and COPD increases risk of lung cancer even after adjusting for the effects of smoking. These diseases not only occur jointly within an individual but also there is evidence of shared occurrence within families. Understanding the genetic contributions to these diseases, both individually and jointly, is needed to identify the highest risk group for screening and targeted prevention, as well as aiding in the development of targeted treatments. The chromosomal regions that have been identified as being associated either jointly or independently with lung cancer, COPD, nicotine addiction, and lung function are presented. Studies jointly measuring genetic variation in lung cancer and COPD have been limited by the lack of detailed COPD diagnosis and severity data in lung cancer populations, the lack of lung cancer-specific phenotypes (histology and tumor markers) in COPD populations, and the lack of inclusion of minorities. African Americans, who smoke fewer cigarettes per day and have different linkage disequilibrium and disease patterns than whites, and Asians, also with different patterns of exposure to lung carcinogens and linkage patterns, will provide invaluable information to better understand shared and independent genetic contributions to lung cancer and COPD to more fully define the highest risk group of individuals who will most benefit from screening and to develop molecular signatures to aid in targeted treatment and prevention efforts.

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Familial Aggregation of Common Sequence Variants on 15q24-25.1 in Lung Cancer

Cited by 137 publications

References 20 publications

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

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

Nicotine is a Selective Pharmacological Chaperone of Acetylcholine Receptor Number and Stoichiometry. Implications for Drug Discovery

Genetic Epidemiology of Cigarette Smoke–Induced Lung Disease

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