Individuals carrying certain genetic variants involved in nicotine regulation are less likely to smoke intensively. These are the main findings of a study coordinated by the Regeneron Genetics Center in New York, United States, and the National Autonomous University of Mexico (UNAM), published in Nature Communications. Genome sequencing of around 38,000 smokers from this country has shown that it is a variant of the CHRNB3 gene, which encodes subunit 3, to which nicotine binds to exert its rewarding action in the brain.
The data, validated in populations with Asian and European ancestry, reveal that compared to individuals carrying the most common version of the gene, those carrying one or two copies of the identified variant smoked between 21% and 78% fewer cigarettes, depending on the version they carried, respectively.
The research explains that rare coding variants that alter protein function and confer beneficial health effects may suggest possible pharmacological targets. CHRNB3 encodes subunit 3 of the nicotinic acetylcholine receptors that bind to nicotine and mediate its action in the brain. In this study, involving centers from other countries, an exome-level association is reported on the number of cigarettes smoked per day in 37,897 current smokers from the Mexico City Prospective Study.
The authors identified a harmful missense variant in CHRNB3, p.Glu284Gly, which is associated with a significant reduction in daily cigarette consumption. "This missense variant is present in individuals of Mexican indigenous ancestry, but is rare in other ancestries. Additionally, we identified a predicted loss-of-function variant in CHRNB3 that is significantly associated with a reduction in the number of cigarettes smoked per day in participants from the Japan Biobank. This variant is enriched in individuals of East Asian ancestry but is infrequent in other ancestries."
Potential Therapeutic Strategies
Finally, rare harmful missense variants and predicted loss-of-function variants are collectively associated with a reduction in the number of cigarettes smoked per day in individuals of European ancestry from the UK Biobank. "Our results suggest that CHRNB3 loss of function is significantly associated with daily cigarette consumption, proposing inhibition of 3 as a possible therapeutic strategy for nicotine addiction," state Veera Rajagopal and Giovanni Coppola, both from the Regeneron Genetics Center.
Historical research suggests that variants in genes encoding nicotinic acetylcholine receptors, which mediate the 'rewarding' effects of nicotine in the brain, are related to changes in smoking behavior in individuals. For example, variants in a gene called CHRNB2, encoding a subunit (2) of these receptors (of which there are at least nine subunit types), have been associated with a lower likelihood of excessive smoking. However, further insights can be gained by studying the relationship between smoking frequency and variants in genes encoding other subunits of nicotinic acetylcholine receptors.
Overall, these data indicate that genetic variants affecting CHRNB3 activity can reduce the number of cigarettes smokers consume per day across various ancestries. However, researchers point out that "larger cohorts and more robust clinical measures research will be needed to fully evaluate the relationship between these variants and nicotine dependence."