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Genetic variants may predict smoking rates, lung cancer risk
The presence of two single-nucleotide polymorphisms was linked to an increase in both the number of cigarettes per day and serum cotinine levels among current smokers, according to study results.
Heavy smoking, lung cancer risk and other smoking-related health outcomes have been linked to two SNPs located within the nicotinic acetylcholine receptor gene cluster on chromosome 15q25 locus: rs1051730 and rs16969968.
Previous research has relied on self-report to determine the extent to which smokers have been exposed to tobacco. In the current study, researchers investigated possible associations between the two SNPs with self-reported daily cigarette consumption and with biochemically measured plasma or serum cotinine levels among smokers.
Data for 12,364 smokers were culled from six independent studies. The final analysis included 2,932 smokers. The researchers calculated per-allele associations of the two genotypes with consumption and cotinine levels among current smokers in each of the six studies. They also conducted a meta-analysis of per-allele associations.
Current smokers with one or two copies of the rs1051730-rs16969968 risk allele had a mean increase in unadjusted number of cigarettes per day of one cigarette (95% CI, 0.57-1.43). A mean increase in the unadjusted cotinine level per allele also was observed among current smokers with one or two copies of the risk allele, 138.72 nmol/L (95% CI, 97.91-179.53).
The increase in cotinine levels was linked to an increase in lung cancer risk with each additional copy of the risk allele, which was calculated as a per-allele OR of 1.31 (95% CI, 1.21-1.42).
“Our data show a stronger association of rs1051730-rs16969968 genotype with objective measures of tobacco exposure compared with self-reported cigarette consumption,” the researchers wrote. “The association of these variants with lung cancer risk is likely to be mediated largely, if not wholly, via tobacco exposure.”
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Nathan Pennell, MD, PhD
Tobacco smoke is far and away the leading risk factor associated with lung cancer (LC), with lifelong cigarette smokers having 20 times the risk of a nonsmoker of developing LC. It is also clear that inherited genetic risk plays both a role in LC oncogenesis and in tobacco addiction. Some of this risk may be explained by small, common genetic changes know as single nucleotide polymorphisms (SNPs), which differ from person to person and can be identified in a blood test. Genome wide association studies have identified a number of SNPs on chromosome 15, in the gene cluster coding for the nicotinic acetylcholine receptor, that are associated with an increased risk of developing LC. In particular, the SNPs rs16969968 and rs1051730 have been closely associated with both LC risk and with heavy tobacco smoking. What is not clear is whether these SNPs are associated with LC risk regardless of smoking, or if by altering the nicotine receptor they influence the amount of cigarette smoking which indirectly increases the risk of LC.
Munato and colleagues published a study pooling data from 6 studies comprising 12,364 subjects, and studied the association of these SNPs with both self-reported cigarette exposure, serum cotinine (an objective measurement of current tobacco exposure), and LC risk. They were able to show that these SNP genotypes were strongly associated with higher cigarette consumption, higher serum cotinine levels, and that increased risk of LC from these SNPs was comparable to the increased risk that would be expected from the increased cotinine level alone. They propose that the LC risk associated with the SNPs is directly related to increased tobacco exposure rather than the SNPs themselves. Although there are some weaknesses in the study, such as combining subjects from multiple different studies and the use of a measure of current rather than cumulative tobacco exposure (continine), this is an important step in elucidating the underlying elements of both nicotine addiction and LC risk. In addition to improving our understanding of the association between smoking and LC, these SNPs may represent potential biomarkers to identify people at high risk of tobacco addiction and smokers who might require more intensive smoking cessation efforts.
Nathan Pennell, MD, PhD
Medical Oncology, Internal Medicine
Taussig Cancer Center
Cleveland Clinic
Disclosures:
