Previously we found that variation in CYP2A6 and CHRNA5-CHRNA3-CHRNB4 combined to increase lung cancer risk in a case-control study in European American ever-smokers (n = 860).
In the present hospital-based, case-control study, we determined whether polymorphism in rs503464 of CHRNA5 is associated with lung cancer risk in Chinese individuals.
The potential association of three polymorphisms in the CHRNA3 (rs1051730(G > A)), CHRNA5 (rs16969968(G > A)), and AGPHD1 (rs8034191(A > G)) with the lung cancer risk has been widely investigated, but the results are inconsistent.
Nevertheless, no study has evaluated the association between CHRNA5-A3-B4 gene cluster variants (rs667282 and rs3743073, two variants modifying lung cancer risk) and risk of gastric cancer.
In addition, the A alleles in CHRNA3 rs1051730 and CHRNA5rs16969968 were associated with the risk for LC (OR = 1.66, P = 0.07 and OR = 1.57, P = 0.1, respectively) and for COPD (OR = 2.04, P = 0.01 and OR = 1.91, P = 0.02, respectively).
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).
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.
However, no studies have investigated the association between CHRNA5rs3841324, which has been proven to have the highest association with CHRNA5 mRNA expression, and the risk of other smoking-associated cancers, except lung cancer.
The transcription profile of CHRNA5 depleted MCF7 cells showed a significant positive correlation with that of A549 lung cancer cell line while exhibiting a negative association with the CHRNA5 co-expression profile obtained from Cancer Cell Line Encylopedia (CCLE).
Genetic variation in the cluster on chromosome 15, encoding the nicotinic acetylcholine receptor subunits (CHRNA5-CHRNA3-CHRNB4), has shown strong associations with tobacco consumption and an additional risk increase in smoking-related diseases such as chronic obstructive pulmonary disease (COPD), peripheral artery disease and 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.
CPD was found to be a nominally significant effect modifier between SNP and lung cancer for six SNPs, including CHRNA5 rs2036527[A](betaSNP*CPD = - 0.017, p = 0.0061, corrected p = 0.054), which was associated with CPD in a previous genome-wide meta-analysis of African-Americans.
Because the associations with lung disease remain after adjustment for self-reported smoking behaviors, it has been asserted that CHRNA5-CHRNA3-CHRNB4 variants increase COPD and lung cancer susceptibility independently of their effects on smoking.
In the chr15q25.1 region spanning the nicotinic receptors CHRNA3 and CHRNA5, we identified multiple SNPs associated with CPD (p<10(-3)), including rs1051730, which has been associated with nicotine dependence, smoking intensity and lung cancer risk.
Single-nucleotide polymorphisms (SNPs) in the cholinergic nicotinic receptor subunit genes on chromosome 15q25.1, including CHRNA3, CHRNB4 and CHRNA5, are well-established biomarkers of chronic obstructive pulmonary disease (COPD) and 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 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.
We conclude that there are at least two distinct mechanisms conferring risk for nicotine dependence and lung cancer: altered receptor function caused by a D398N amino acid variant in CHRNA5 (rs16969968) and variability in CHRNA5 mRNA expression.