In a multivariable analysis Tockman and colleagues

In a multivariable analysis, Tockman and colleagues found that airflow limitation (termed lung impairment) conferred a greater risk of lung cancer (5 fold) relative to age and pack years (1.5–2.0 fold) (). We suggest that there is much more to be done to elucidate the relationship between smoking exposure, lung function and immune modulation leading to pulmonary inflammatory response to smoking. In this regard it is interesting that the chr15q25 locus association with lung cancer exists in non-smokers (). This certainly raises the possibility that factors attributable to the chr15q locus, independent of smoking consumption (and nicotine addiction), are relevant to lung cancer susceptibility which brings us back to COPD. It has been shown that CHRNA3/5 ghrelin receptor are expressed on lung epithelium and mediate the lung\'s inflammatory response to smoking (). The ethnicity aspect is also relevant here, as the chr15q25 locus is highly conserved and may have important functions relevant to mediating lung inflammation (), where variation in immune response to pathogens is likely to result from greater evolutionary selective pressures than to variation affecting nicotine addiction (). Given COPD is thought to result in part from an exaggerated innate immune response, as does lung cancer, it is very hard to see how susceptibility to airflow limitation can continue to be overlooked in lung cancer studies (). The take home message from the study by David and colleagues is that the chr15q25 locus, previously linked to higher cigarettes consumption and greater nicotine addiction, is similarly relevant in smokers with African American ancestry (). However, while their findings support the hypothesis that the chr15q25 locus is independently related to cigarette consumption and lung cancer in African Americans, the exact contribution of genetic variation in this chromosomal region to lung cancer susceptibility remains far from clear. Disclosure
We appreciate Drs. Hopkins\' and Young\'s commentary () on some of the conclusions and limitations to our investigation () of gene by environment interactions for lung cancer in African–Americans. The investigation was not designed to examine underlying biological mechanisms of gene by environment interactions for lung cancer risk, but was instead intended to characterize the nature and directionality of such interactions in a sufficiently powered case–control study of African–Americans. Potential mediating processes, such as can be captured by measurements of airflow limitation resulting from chronic obstructive pulmonary disease and the inflammatory and oxidative stress processes – resulting from altered levels of inhaled, combusted tobacco smoke – are examples of precursor phenotypes, which could shed additional light on genetically-moderated mediation of lung cancer. The present study did not compare genetic interaction effects between different ethnic groups. Therefore, we cannot directly contrast our results with those of Asian-, American–Indian- or European-ancestry studies. Although it may appear that the dose–response of cigarettes smoked per day is lost in smokers with 2 risk alleles, this may not necessarily be the case. It may be more accurate to conclude that the genetic association with lung cancer is most prominent in light smokers. Nonetheless, our results, including the predeceasing genome-wide association studies of smoking quantity and fine mapping studies of lung cancer confirm the importance of the chromosome 15q25.1 region (CHRNA3, CHRNA5, IREB2 and PSMA4) in lung cancer risk in African–Americans. Differences in genetic architecture of this region between African-ancestry and those of non-African ancestry, such as varying prevalence of polymorphisms linked to smoking exposure and lung cancer and lower levels of linkage disequilibrium, necessitate careful evaluation within African-ancestry study populations in order to demonstrate the clinical validity of lung cancer susceptibility variants that have been more widely studied in European-ancestry populations. Overall, these results point to a complex web of causation whereby the chromosome 15q25.1 region represents a lung cancer susceptibility locus in African–Americans vis-a-vis increased smoking exposure and intrinsic lung cancer risk.