Alternative titles; symbols
Other entities represented in this entry:
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 15q25.1 | {Nicotine dependence, susceptibility to} | 612052 | 3 | CHRNA5 | 118505 | |
| 15q25.1 | {Lung cancer susceptibility 2} | 612052 | 3 | CHRNA5 | 118505 | |
| 15q25.1 | {Lung cancer susceptibility 2} | 612052 | 3 | CHRNA3 | 118503 |
A number sign (#) is used with this entry because single-nucleotide polymorphisms (SNPs) in the nicotinic acetylcholine receptor gene cluster on chromosome 15q25.1, represented by SNPs in the CHRNA3 (118503) and CHRNA5 (118505) genes, have been associated with susceptibility to smoking-related behavioral traits and lung cancer.
For a discussion of genetic influences on smoking behavior, see 188890. For a phenotypic description and a discussion of genetic heterogeneity of lung cancer, see 211980.
Lung cancer is caused predominantly by tobacco smoking. Hung et al. (2008) noted that independent biologic data suggested that nicotinic acetylcholine receptors could be involved in lung cancer through mechanisms other than smoking. It has been suggested that N-prime-nitrosonornicotine and nitrosamines may facilitate neoplastic transformation by stimulating angiogenesis and tumor growth mediated through their interaction with nicotinic acetylcholine receptors. The expression of these receptors can also be inhibited by nicotine receptor antagonists, which, if confirmed to be involved in disease etiology through such a mechanism, would suggest possible chemoprevention opportunities for lung cancer.
Three genomewide association studies on smoking quantity were reported simultaneously and in partnership in 2010. Liu et al. (2010) performed a genomewide association study of smoking quantity, as measured by cigarettes per day (CPD) in a final database set of 41,150 individuals from 20 disease, population, and control cohorts. The single most significant locus was with the A allele of rs1051730 on chromosome 15q25 (p = 9.45 x 10(-19)). A repeat of the analysis using more SNPs in this region found a significant association with rs55853698 (p = 1.31 x 10(-16)); this SNP's location in the 5-prime untranslated region of the CHRNA5 gene makes it a candidate for affecting transcription. Another SNP in this region (rs16969968) also showed significance (p = 1.64 x 10(-18)).
Simultaneously, The Tobacco and Genetics Consortium (2010) reported their findings of genomewide association studies for number of cigarettes smoked per day among 38,181 individuals from multiple different cohorts. The most significant association was with rs12914385 in CHRNA3 (p = 4.2 x 10(-35)), followed by rs1051730 (p = 8.0 x 10(-33)), which was noted to be a synonymous SNP in the CHRNA3 gene. Significant association was also found with the G allele of rs16969968 (p = 4.48 x 10(-33)), also in the CHRNA3 gene. Thorgeirsson et al. (2010) found that the most significant association with number of cigarettes smoked per day in their study of 31,266 individuals was with the A allele of rs1051730 (p = 2.1 x 10(-33)). Each of the studies provided p value estimates for the combined effect of rs1051730 with smoking behavior from all 3 studies, including about 75,000 individuals: 1.71 x 10(-66) (Liu et al., 2010); 2.75 x 10(-73) (The Tobacco and Genetics Consortium, 2010), and 2.4 x 10(-69) (Thorgeirsson et al., 2010). Liu et al. (2010) and The Tobacco and Genetics Consortium (2010) also found significant association with the G allele of rs16969968 across all 3 studies (p = 4.29 x 10(-65) and 5.57 x 10(-72), respectively).
To identify genetic factors that modify disease risk, Hung et al. (2008) conducted a genomewide association study by analyzing 317,139 SNPs in 1,989 lung cancer cases and 2,625 controls from 6 central European countries. Hung et al. (2008) identified a locus in chromosome region 15q25 that was strongly associated with lung cancer (P = 9 x 10(-10)). This locus was replicated in 5 separate lung cancer cases comprising an additional 2,513 lung cancer cases and 4,752 controls (P = 5 x 10(-20) overall), and it was found to account for 14% (attributable risk) of lung cancer cases. In an examination of the association in different smoking categories, increased risks were seen for former smokers (P = 4 x 10(-7)) and current smokers (P = 3 x 10(-10)), as well as a potential increased risk for people who had never smoked (P = 0.013). The locus was not associated with smoking-related head and neck cancers. The association region contains several genes, including 3 that encode nicotinic acetylcholine receptor subunits (CHRNA5, 118505; CHRNA3, 118503; and CHRNB4, 118509). Such subunits are expressed in neurons and other tissues, in particular alveolar epithelial cells, pulmonary neuroendocrine cells, and lung cancer cell lines, and they bind to N-prime-nitrosonornicotine and potential lung carcinogens. A nonsynonymous variant in CHRNA5, rs16969968, that induces an amino acid substitution (D398N; 118505.0001) at a highly conserved site in the second intracellular loop of the protein was among the markers with the strongest disease association. Hung et al. (2008) concluded that their results provided compelling evidence of a locus at chromosome 15q25 predisposing to lung cancer, and reinforced interest in nicotinic acetylcholine receptors as potential disease candidates and chemopreventative targets.
Thorgeirsson et al. (2008) identified a common variant, rs1051730, in the nicotinic acetylcholine receptor gene cluster on chromosome 15q24 with an effect on smoking quantity, nicotine dependence, and the risk of 2 smoking-related diseases (lung cancer and peripheral artery disease) in populations of European descent. The SNP rs1051730, which resides in the CHRNA3 gene (118503.0001), was strongly associated with smoking quantity (P = 5 x 10(-16)). The same variant was associated with nicotine dependence in a previous genomewide association study that used low-quantity smokers as controls (Saccone et al., 2007; Bierut et al., 2007). With a similar approach, Thorgeirsson et al. (2008) observed a highly significant association with nicotine dependence. Thorgeirsson et al. (2008) studied the effect of the rs1051730 variant on lung cancer and peripheral artery disease risk directly, including indirect effects through smoking quantity and nicotine dependence. The lung cancer study included 1,024 cases and 32,244 controls from Iceland, Spain, and the Netherlands; the peripheral artery disease study was based on 2,738 cases and 29,964 controls from 5 Caucasian populations (Iceland, New Zealand, Austria, Sweden, and Italy). Significant association was found with both diseases. Combining the results from all 3 groups in the lung cancer study gave an odds ratio (OR) of 1.31 (P = 10(-8)). Combining results from all 5 peripheral artery disease study groups yielded an OR of 1.19 (P = 1.4 x 10(-7)). Thorgeirsson et al. (2008) concluded that their findings provided a case study of a gene-environment interaction, highlighting the role of nicotine addiction in the pathology of other serious diseases.
Both Hung et al. (2008) and Thorgeirsson et al. (2008) noted that rs1051730 and rs16969968 are in strong linkage disequilibrium; Hung et al. (2008) gave the squared correlation coefficient (r(2)) between the 2 variants as 0.99, while Thorgeirsson et al. (2008) cited r(2) = 0.90 for the 2 in the HapMap project.
To identify risk variants for nonsmall cell lung cancer, Amos et al. (2008) conducted a multistage genomewide association study. In the discovery phase, the authors analyzed 315,450 tagging SNPS in 1,154 current and former (ever) smoking cases of European ancestry with nonsmall cell lung cancer versus 1,137 frequency-matched, ever-smoking controls from Houston, Texas. For replication, Amos et al. (2008) evaluated 10 SNPs most significantly associated with lung cancer in an additional 711 cases and 632 controls from Texas and 2,013 cases and 3,062 controls from the UK. Two SNPs, rs1051730 (118503.0001) and rs8034191, mapping to a region of strong linkage disequilibrium within 15q25.1 containing the PSMA4 (176846) and the nicotinic acetylcholine receptor unit genes CHRNA3 (118503.0001) and CHRNA5 (118505), were significantly associated with risk in both replication sets. Combined analysis yielded odds ratios of 1.32 (P less than 1 x 10(-17)) for both SNPs. Haplotype analysis was consistent with there being a single risk variant in this region. Amos et al. (2008) concluded that variation in a region of 15q25.1 containing nicotinic acetylcholine receptor genes contributes to lung cancer risk. The SNP rs8034191 lies within the LOC123688 gene. The SNPs rs1051730 and rs8034191 are separated by 88 kb, and the genotypes are highly correlated (r(2) = 0.88 in the discovery set and 0.81 in HapMap for the population of European ancestry).
In a genomewide association study pooling data from 3 studies including 5,095 patients with lung cancer and 5,200 controls, Wang et al. (2008) found a significant association between susceptibility to lung cancer and rs8042374 on chromosome 15q25.1 (p = 7.75 x 10(-12)), confirming previous reports.
Keskitalo et al. (2009) measured the number of cigarettes smoked per day (CPD) and immune-reactive serum cotinine level (a nicotine metabolite) in 516 daily smokers (aged 30-75 years; 303 males and 213 females) from an adult Finnish population. Association of 21 SNPs from a 100-kb region of chromosome 15q25.1 with cotinine and CPD were examined. The SNP rs1051730 showed the strongest association to both measures. However, this SNP accounted for nearly a 5-fold larger proportion of variance in cotinine levels than in CPD (r(2) 4.3% vs 0.9%). The effect size of the SNP was 0.30 for cotinine level, whereas it was 0.13 for CPD. Keskitalo et al. (2009) concluded that variation at the CHRNA5/CHRNA3/CHRNB4 cluster influences nicotine level, measured as cotinine, more strongly than smoking quantity, measured by CPD, and appears thus to be involved in regulation of nicotine levels among smokers.
Amos, C. I., Wu, X., Broderick, P., Gorlov, I. P., Gu, J., Eisen, T., Dong, Q., Zhang, Q., Gu, X., Vijayakrishnan, J., Sullivan, K., Matakidou, A., Wang, Y., Mills, G., Doheny, K., Tsai, Y.-Y., Chen, W. V., Shete, S., Spitz, M. R., Houlston, R. S. Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nature Genet. 40: 616-622, 2008. [PubMed: 18385676] [Full Text: https://doi.org/10.1038/ng.109]
Bierut, L. J., Madden, P. A., Breslau, N., Johnson, E. O., Hatsukami, D., Pomerleau, O. F., Swan, G. E., Rutter, J., Bertelsen, S., Fox, L., Fugman, D., Goate, A. M., and 10 others. Novel genes identified in a high-density genome wide association study for nicotine dependence. Hum. Molec. Genet. 16: 24-35, 2007. [PubMed: 17158188] [Full Text: https://doi.org/10.1093/hmg/ddl441]
Hung, R. J., McKay, J. D., Gaborieau, V., Boffetta, P., Hashibe, M., Zaridze, D., Mukeria, A., Szeszenia-Dabrowska, N., Lissowska, J., Rudnai, P., Fabianova, E., Mates, D., and 53 others. A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25. Nature 452: 633-637, 2008. [PubMed: 18385738] [Full Text: https://doi.org/10.1038/nature06885]
Keskitalo, K., Broms, U., Heliovaara, M., Ripatti, S., Surakka, I., Perola, M., Pitkaniemi, J., Peltonen, L., Aromaa, A., Kaprio, J. Association of serum cotinine level with a cluster of three nicotinic acetylcholine receptor genes (CHRNA3/CHRNA5/CHRNB4) on chromosome 15. Hum. Molec. Genet. 18: 4007-4012, 2009. [PubMed: 19628476] [Full Text: https://doi.org/10.1093/hmg/ddp322]
Liu, J. Z., Tozzi, F., Waterworth, D. M., Pillai, S. G., Muglia, P., Middleton, L., Berrettini, W., Knouff, C. W., Yuan, X., Waeber, G., Vollenweider, P., Preisig, M., and 95 others. Meta-analysis and imputation refines the association of 15q25 with smoking quantity. (Letter) Nature Genet. 42: 436-440, 2010. [PubMed: 20418889] [Full Text: https://doi.org/10.1038/ng.572]
Saccone, S. F., Hinrichs, A. L., Saccone, N. L., Chase, G. A., Konvicka, K., Madden, P. A., Breslau, N., Johnson, E. O., Hatsukami, D., Pomerleau, O., Swan, G. E., Goate, A. M., and 10 others. Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs. Hum. Molec. Genet. 16: 36-49, 2007. [PubMed: 17135278] [Full Text: https://doi.org/10.1093/hmg/ddl438]
The Tobacco and Genetics Consortium. Genome-wide meta-analyses identify multiple loci associated with smoking behavior. (Letter) Nature Genet. 42: 441-447, 2010. [PubMed: 20418890] [Full Text: https://doi.org/10.1038/ng.571]
Thorgeirsson, T. E., Geller, F., Sulem, P., Rafnar, T., Wiste, A., Magnusson, K. P., Manolescu, A., Thorleifsson, G., Stefansson, H., Ingason, A., Stacey, S. N., Bergthorsson, J. T., and 45 others. A variant associated with nicotine dependence, lung cancer and peripheral arterial disease. Nature 452: 638-641, 2008. [PubMed: 18385739] [Full Text: https://doi.org/10.1038/nature06846]
Thorgeirsson, T. E., Gudbjartsson, D. F., Surakka, I., Vink, J. M., Amin, N., Geller, F., Sulem, P., Rafnar, T., Esko, T., Walter, S., Gieger, C., Rawal, R., and 83 others. Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior. Nature Genet. 42: 448-453, 2010. [PubMed: 20418888] [Full Text: https://doi.org/10.1038/ng.573]
Wang, Y., Broderick, P., Webb, E., Wu, X., Vijayakrishnan, J., Matakidou, A., Qureshi, M., Dong, Q., Gu, X., Chen, W. V., Spitz, M. R., Eisen, T., Amos, C. I., Houlston, R. S. Common 5p15.33 and 6p21.33 variants influence lung cancer risk. Nature Genet. 40: 1407-1409, 2008. [PubMed: 18978787] [Full Text: https://doi.org/10.1038/ng.273]