Two naturally occurring variants in the area of the genome that initiates expression of genes linked to nicotine use have been identified. A new study, published by researchers at Penn State and University of Colorado, has identified how small differences in a particular region of the mouse genome can alter nicotine consumption.
“We know that genes influence nicotine behaviors, but trying to figure out what specific genetic variants do requires different types of tools,” said Helen Kamens, assistant professor of bio behavioral health, Penn State. “This work was based on associations that were found in human genetic studies. Genetic variants were shown to affect certain nicotine behaviors, but the question was why? Here we focused on trying to figure out what these genetic variants actually do.”
The naturally occurring variant of the beta-3 subunit of nicotinic acetylcholine receptors — the major allele — are more likely to cause problems with nicotine use. People who have the minor allele, the less common version, are protected against nicotine dependence and the expression of the minor allele results in less beta-3 protein being produced. There are three differences in the DNA sequence in the area involved in turning on nicotine-related genes
“All three of these single nucleotide changes are inherited together, so in a human population, you get a sequence where all three nucleotides are either major or minor,” said Kamens. “Using a cell culture system, we were able to disentangle which of the nucleotide changes actually has an effect on protein amounts, which is something we could never see in a human population.”
Mice, genetically engineered, who were lacking one or both copies of the gene encoding the beta-3 subunit consumed less nicotine than normal mice suggesting that other genetic factors also play a role in nicotine cravings. By individually reversing each of the three genetic differences in the minor allele in mouse cells in culture, the researchers found that only one of the three differences reduced the amount of beta-3 protein the cells produced.
”The β3 subunit of the nicotinic acetylcholine receptor: Modulation of gene expression and nicotine consumption” Helen M. Kamens, Jill Miyamoto, Matthew S. Powers, Kasey Ro, Marissa Soto, Ryan Cox, Jerry A. Stitzel, Marissa A. Ehringer. Neuropharmacology, doi:10.1016/j.neuropharm.2015.08.035. Available online 25 August 2015