Chromosome 15q25 (CHRNA3-CHRNB4) Variation Indirectly Impacts Lung Cancer Risk in Chinese Males

Abstract

IntroductionRecently, genome-wide association studies (GWAS) in Caucasian populations have identified an association between single nucleotide polymorphisms (SNPs) in the CHRNA5-A3-B4 nicotinic acetylcholine receptor subunit gene cluster on chromosome 15q25, lung cancer risk and smoking behaviors. However, these SNPs are rare in Asians, and there is currently no consensus on whether SNPs in CHRNA5-A3-B4 have a direct or indirect carcinogenic effect through smoking behaviors on lung cancer risk. Though some studies confirmed rs6495308 polymorphisms to be associated with smoking behaviors and lung cancer, no research was conducted in China. Using a case-control study, we decided to investigate the associations between CHRNA3 rs6495308, CHRNB4 rs11072768, smoking behaviors and lung cancer risk, as well as explore whether the two SNPs have a direct or indirect carcinogenic effect on lung cancer.MethodsA total of 1025 males were interviewed using a structured questionnaire (204 male lung cancer patients and 821 healthy men) to acquire socio-demographic status and smoking behaviors. Venous blood samples were collected to measure rs6495308 and rs11072768 gene polymorphisms. All subjects were divided into 3 groups: non-smokers, light smokers (1–15 cigarettes per day) and heavy smokers (>15 cigarettes per day).ResultsCompared to wild genotype, rs6495308 and rs11072768 variant genotypes reported smoking more cigarettes per day and a higher pack-years of smoking (P<0.05). More importantly, among smokers, both rs6495308 CT/TT and rs11072768 GT/GG had a higher risk of lung cancer compared to wild genotype without adjusting for potential confounding factors (OR = 1.36, 95%CI = 1.09–1.95; OR = 1.11, 95%CI = 1.07–1.58 respectively). Furthermore, heavy smokers with rs6495308 or rs11072768 variant genotypes have a positive interactive effect on lung cancer after adjustment for potential confounding factors (OR = 1.13, 95%CI = 1.01–3.09; OR = 1.09, 95%CI = 1.01–3.41 respectively). However, No significant associations were found between lung cancer risk and both rs6495308 and rs11072768 genotypes among non-smokers and smokers after adjusting for age, occupation, and education.ConclusionThis study confirmed both rs6495308 and rs11072768 gene polymorphisms association with smoking behaviors and had an indirect link between gene polymorphisms and lung cancer risk.

CHRNA5 rs16969968 and CHRNA3 rs578776 polymorphisms are associated with multiple nicotine dependence phenotypes in Bangladeshi smokers

“…Our study also investigated the mRNA expression pattern of CHRNA5-A3-B4 gene cluster in normal and lung cancer patients using an in-silico approach. We reported overexpression of CHRNA5 and CHRNB4 in lung cancer patients compared to normal volunteers which is consistent with several previously published results [ 33 , 34 , 45 , 69 ]. However, CHRNB4 expression was found to be nonsignificant in case of Asian ethnicity which in a way corroborates our findings regarding rs11072768 and ND.…”

“…Moreover, Hong and colleagues identified rs578776 at-risk G-allele mediated overactivation of a specific brain circuit in dorsal anterior cingulate cortex and left anterior thalamus regions using fMRI technology [ 66 ], which might be sensitive to nicotine exposure suggesting a plausible link between rs578776 at-risk G-allele and ND. Being an intron variant, CHRNB4 rs11072768 polymorphism has been found to be associated with smoking cessation, CPD [ 12 , 43 ] as well as lung cancer [ 45 ]. Molecular study performed on B4 subunit null mice reported an increased tolerance development after chronically treated with nicotine [ 67 ], which might lead to neuroadaptation and subsequently to ND.…”

“…The most well-known hereditary influence related to ND is a missense mutation at rs16969968 (G>A) on the nAChRs CHRNA5 , resulting in an amino acid alteration from aspartate to asparagine at the 398th position [ 36 , 37 , 38 , 39 ]. CHRNA3 rs578776 (G>A) is a 3'-UTR variant and the minor allele genotype (AA) was found to be a protective factor against heaviness of smoking as well as ND [ 15 , 27 , 36 , 38 , 39 , 40 , 41 , 42 ] and CHRNB4 rs11072768 (T>G) is an intron variant significantly associated with cigarette per day (CPD) in Chinese males and lung cancer indirectly through smoking behavior [ 12 , 43 , 44 , 45 ].…”

Familial Lung Cancer: A Brief History from the Earliest Work to the Most Recent Studies

“…Kondo et al have shown a significant ( p < 0.001) dose-response relationship between the number of cigarettes smoked and TP53 mutation frequency in lung cancer patients [ 36 ]. Mutations in KRAS and several genes on 15q.25 have also been found to be significantly associated with smoking in multiple populations [ 37 , 38 , 39 , 40 , 41 , 42 , 43 ]. These results suggest that somatic mutations in these genes may be due to carcinogens or mutagens found in tobacco smoke.…”

Association of Polymorphism CHRNA5 and CHRNA3 Gene in People Addicted to Nicotine

“…The GG/AA genotype combination for the rs16969968/rs578776 variants provided the greatest “protection” against smoking, while AA/GG was associated with the highest risk of smoking [ 47 , 48 , 49 ]. On the other hand, rs11072768 is a variant of the intron, which turned out to be significantly related to the number of cigarettes smoked during the day, and smoking more for a long time in Chinese men [ 53 , 54 , 55 , 56 ]. In Korean men, the G allele in rs11072768 CHRNB4 was associated with the onset of smoking, the amount of smoking, and cessation of smoking [ 44 , 57 ].…”