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The characterization of variation in the human genome has begun to pay dividends.
These are mainly being delivered through genome wide association studies (GWAS). Since early 2001, variation at nearly 100 regions of the genome have been associated with an increased risk for diseases with a complex genetic background.Such as diabetes, inflammatory bower disease, cancer and heart disease.
The latest installment in the GWAS story deals with lung cancer. It identified variation in the same region of the long arm of chromosome15 (15q24/15q25.1) as the top hit for genomic association with lung cancer. Among the genes in this region are those that encode subunits of nicotinic acetylcholine receptors which have an affinity for nicotine. The genetic variation analyzed was in the form of single nucleotide polymorphisms (SNP’s).
These studies provide strong evidence for an association between SNP variation at 15q24/15q25.1 and lung cancer. But differ on whether the connection is direct or mediated via smoking behavior. Precious studies had identified the genes encoding sub units of nicotinic acetylcholine receptors as strongly associated with smoking behavior.
Thorgeirsson et al report an association of SNP variation at 15q24/15q25.1 with the number of cigarettes smoked per day and a nicotine- dependence scale. They suggest that the link with lung cancer is primarily mediated through nicotine dependence and thus provides a case study of a gene- environment correlation in the pathogenesis of disease. Hungetal and Amos et al examined SNP variation in patients with lung cancer and control subjects and reach the conclusion that the association is primarily with lung cancer and not with smoking. In these kinds of studies researchers distinguish between ‘eversmokers’ and never smoker. Amos and colleagues describe the evidence for the association of their ‘lead’ SNP’s with smoking behavior (among ever smokers) as weak. Hung et al examined the relation between the lead SNP’s and smoking behavior and thus suggest that the genetic association in their study is unlikely to be due to confounding effects of smoking behavior.
The two studies that also examined never smokers reached different conclusions, Hung et al conclude that there is an association with the risk SNP’s while Amos et al. conclude that there is no such association.
These are the first GWAS to attempt to identify the genetic component of a disease that has such an overwhelming strong environmental cause. They signal the need for greater methodological rigour in attempt to account for both the genetic and the environmental cause that we think underlie most diseases. As GWAS have become available, the importance of large sample sizes to detect modest effects has become apparent. Much GWAS research has tended to be retrospective and thus this information could be biased; the requirements for public access to individuals data maybe suppressing the availability of potentially high quality data sets because of limitation in obtaining informed consent. These studies demonstrate importance of balancing the undeniable need for quantity in GWAS with the need for quality of ancillary data.
The next round of research will involve re-sequencing 15q24/15q25.1 and incorporating any additional SNP variants into future epidemiological work. Further genome-wide scans are needed in studies that can look to patients with lung cancer for when detailed data on smoking exposure, nicotine dependence and duration intensity of smoking are available. It is also essential to examine larger samples of non smoking lung cancer patients and perform analysis according to the specific type of cancer. Pooling of GWAS data will help, as will full disclosure of SNP rankings for the major smoking behavior to permit a better understanding of the genetic associations with these behaviors.
The rationale claimed for determining risk in individual is that it will encourage them to change their lifestyle and /or undergo screening so that disease can be detected earlier. On the other hand we may be able to evaluate smoking cessation treatments informed by knowledge of a person genetic predisposition to start smoking or to nicotine addiction and thus add new weapons to the anti-smoking arsenal. Follow-up studies should clear the differing conclusions of these papers and establish the biological rationale for the robust association of 15q24/15q25.1 with lung cancer. For most diseases more loci will surely be discovered adding to the first wave of results that have been primarily related to disease causation. On the horizon we can see the crest of studies reporting on disease outcomes but progress both in understanding the basic causes and in estimating personal risks will require environmental and lifestyle factors to be taken into account.
Work Cited Source
Stephen, J. and David, J. When The Smoke Clears, Vol. 452/3 2008.
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