For decades, public health has been waging an all‑out battle against smoking. Tobacco kills seven million people worldwide every year, and its countless harmful effects are thoroughly documented, yet the addiction is so powerful that once someone starts smoking, quitting can become an ordeal. There are treatments to combat smoking, but therapeutic options remain limited, and science continues searching for new strategies to break the dependence created by the habit. In this context, a study published Tuesday in Nature Communications has opened a new path by identifying genetic variants that predispose people to smoke less. The authors suggest that this finding could serve as a starting point for designing a new therapeutic target.
“We have discovered that people carrying rare, naturally occurring mutations in a gene called CHRNB3 tend to smoke significantly fewer cigarettes per day,” explain the study’s lead authors, geneticists Veera Rajagopa and Giovanni Coppola, in an email response.
The CHRNB3 gene encodes a protein (the β3 subunit) that is part of the receptor through which nicotine acts in the brain. “We found this protective association independently in three different populations: Indigenous Mexicans, East Asians, and Europeans, which gives us strong confidence that the finding has biological relevance,” say the scientists from the Regeneron Genetic Center, a genomic research center belonging to the pharmaceutical company Regeneron.
After analyzing a Mexican cohort of nearly 38,000 smokers, the authors found that people with a specific variant in this gene smoked less than those without the genetic alteration. Specifically, compared to people carrying the most common version of the gene, those with one copy of this variant in the CHRNB3 gene smoked 21% less, or one fewer cigarette per day.
“And the small number of people who carried two copies of the variant — essentially a natural deletion of the gene — smoked approximately 78% fewer cigarettes per day,” the authors note. Rajagopa and Coppola argue that the effect of a single copy of this genetic variant is comparable in magnitude to that of other known genetic alterations closely linked to smoking.
In the Mexican cohort, the authors observed that the discovered genetic variant slightly altered the structure of the β3 protein, but the mechanism by which this change affects tobacco use remains unclear, they admit. “Whether this occurs because the brain’s response to nicotine is altered in terms of how rewarding or aversive it feels remains an open and interesting question that future research will need to address,” the authors note.
Beyond the studies in the Mexican population, the research validated its findings in an Asian cohort and a European one. In all three cases, it found mutations in the same segment of DNA. The alterations were different, but all involved the CHRNB3 gene and produced a similar effect in terms of predisposition to smoke less. “This convergence between ancestries strongly implicates CHRNB3 as the causal gene,” the researchers argue.
Previous studies have linked the CHRNB3 gene to smoking, but this study goes a step further and points directly to its therapeutic potential. “Our study provides the first direct human genetic evidence that loss of CHRNB3 function reduces cigarette consumption,” the authors state.
The scientists suggest that inhibiting the CHRNB3 gene “could help reduce or stop smoking.” However, they immediately temper short-term expectations, cautioning that “it is too early to confirm whether a treatment is possible and, if so, whether it would be effective or safe”: “Specifically, our genetic findings suggest that a potential therapy targeting receptors containing β3 could represent a complementary approach, particularly for reducing smoking intensity in regular smokers. But several key questions remain, such as understanding the gene’s mechanism for influencing smoking and its other functions in the brain.”
Managing expectations
The authors argue that more exhaustive evaluations of the identified variants are needed. They also see a need for “laboratory studies to understand exactly how the absence of this protein helps people smoke less.”
Javier Costas, lead researcher of the Psychiatric Genetics group at the Health Research Institute of Santiago de Compostela (IDIS) in Spain, told the Science Media Center (SMC) that the findings of this study were “promising,” but key questions remain. “Inactivating the gene with drugs could have the same benefit. However, they haven’t studied whether this same variant could be associated with other negative health effects, which would translate into potential side effects of the medication that inactivates the gene,” the expert explained.
Costas says that “additional evidence is needed, especially considering that the authors declare a conflict of interest, as many are shareholders or employees of a pharmaceutical company and owners of a patent on this gene.”
Miguel Barrueco, former head of the pulmonology department at the Hospital of Salamanca, takes the same cautious stance: he says the article is “interesting,” but “it is advisable to be prudent in interpreting the results and not sow false therapeutic expectations, for example, about the short-term viability of a therapy for nicotine addiction like the one proposed.”
“Similar studies conducted with other genes that also play a role in nicotine addiction have not resulted in their therapeutic applications. The spectrum of brain receptors and neurotransmitters (and the genes that encode them) involved in nicotine addiction is very broad and complex and largely still unknown,” Barrueco told SMC.
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