Animal studies can directly examine the effects of genetic variants given a constant carcinogenic exposure. For example, the variant rs16969968, which causes the amino acid change in the α5 nicotinic receptor, can be inserted into a mouse model (a “knock in” mouse) so that the only difference between the two groups of mice is this one nucleotide change. Animals with and without this human variant can be exposed to a carcinogenic agent, and the frequency of subsequent lung cancer can be measured. If there is a difference in incidence of lung cancer development between mice with the variant and those without, the polymorphism likely has a direct role in the etiology of lung cancer. If no difference is seen, it is more likely that this variant alters smoking behavior in subtle ways that are not captured in smoking measures such as cigarettes per day, which subsequently changes the risk for lung cancer. In other words, the genetic risk is indirect and mediated through smoking. Mouse models are now being developed.
