In conclusion, our results showed that several of the polymorphisms and their haplotypes in CHRNA5/CHRNA3 genes may have functional effects on (i) CHRNA5 mRNA levels, (ii) polycyclic aromatic hydrocarbon-DNA adduct levels, (iii) TP53 mutations and (iv) susceptibility to lung cancer.
CHRNA5-A3-B4, the gene cluster encoding nicotinic acetylcholine receptor subunits, is associated with lung cancer risk and smoking behaviors in people of European descent.
Indeed, genetic variation in the CHRNA5-CHRNA3-CHRNB4 gene cluster, encoding the α5, α3, and β4 nAChR subunits, respectively, has been shown to increase vulnerability to tobacco dependence and smoking-associated diseases including lung cancer.
Previous studies revealed association of lung cancer risk with single nucleotide polymorphisms (SNPs) in chromosome 15q25 region containing CHRNA5-CHRNA3-CHRNB4 nicotinic acetylcholine receptor (nAChR) subunit gene cluster.
Scope of Proposed Topic (50 words): Genome-wide association (GWA) studies both in lung cancer and COPD highlighted the same variants (SNPs) on the gene cluster CHRNA3-CHRNB4-CHRNA5.
Variation in the CHRNA5-A3-B4 gene cluster is a promising candidate region for smoking behavior and has been linked to multiple smoking-related phenotypes (e.g., nicotine dependence) and diseases (e.g., lung cancer).
Genetic variants located at 15q25, including those in the cholinergic receptor nicotinic cluster (CHRNA5) have been implicated in both lung cancer risk and nicotine dependence in recent genome-wide association studies.
In a nested case-control study comparing 746 lung cancer cases to 1,477 controls, all of whom were non-Hispanic white smokers in the β-Carotene and Retinol Efficacy Trial, we examined whether lung cancer risk is associated with single nucleotide polymorphisms (SNPs) tagging the AGPHD1, CHRNA5, CHRNA3, and CHRNB4 genes and whether such risk is modified by diet and other characteristics.
These results indicated a new associated risk pattern between CHRNA5 promoter activity and susceptibility to lung cancer that implies a complex role of the CHRNA5 gene in lung cancer.
Two variants in the nicotinic acetylcholine receptor subunit genes CHRNA5 and CHRNA3 on 15q25, rs16969968 and rs578776, were associated with cotinine (P = 0.001 and 0.03, respectively) in current smokers and with lung cancer risk (P < 0.001 and P = 0.001, respectively).
The authors applied a rigorous statistical approach, mediation analysis, to examine the mediating effect of smoking behavior and self-reported, physician-diagnosed emphysema (chronic obstructive pulmonary disease [COPD]) on the relation between the CHRNA5-A3 region genetic variant rs1051730 and the risk of lung cancer.