For decades, public health has been waging an all-out battle against . Smoking kills every year people in the world, its innumerable causes are well known, but the addiction is so powerful that, once you start, quitting can end up being an odyssey. There are treatments to combat smoking, but therapeutic options are limited and science continues to search for new strategies to help cut the dependency generated by smoking. In this sense, published this Tuesday in the magazine Nature Communications has opened a new path by discovering genetic variants that predispose one to smoke less. The authors suggest that this finding could serve as a starting point to design a new therapeutic target.
“We have found that people carrying rare natural 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 “We found this protective association independently in three different populations: indigenous Mexicans, East Asians and Europeans, which gives us great confidence that the finding has biological relevance,” emphasize these scientists from the Regeneron Genetic Center, a genomic research center of the pharmaceutical company Regeneron.
After analyzing a Mexican cohort of nearly 38,000 smokers, the authors found that people who had a specific variant in that gene smoked less than those who did not have that genetic alteration. Specifically, compared to people carrying the most common version of the gene, carriers of one copy of that variant in the CHRNB3 gene smoked 21% less, or in other words, one less 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% less,” the authors note. Rajagopa and Coppola assure that the effect of a single copy of this genetic variant has a magnitude comparable to that of other genetic alterations already known and closely related to smoking.
In the Mexican cohort, the authors saw that the genetic variant discovered slightly altered the structure of the β3 protein, but the mechanism that causes this change to affect tobacco consumption is still not clear, they admit. “Whether this occurs because it 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 assume.
Beyond the studies in the Mexican population, the research validated its findings in an Asian cohort and another European one. In all three cases he found mutations in the same DNA segment. The alterations were different, but they all involved the CHRNB3 gene and generated a similar effect in terms of the predisposition to smoke less. “This convergence between ancestry strongly implicates CHRNB3 as the causal gene,” the researchers say.
There are previous studies that have linked the CHRNB3 gene to smoking, but this study goes one 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 smoking,” the authors say.
The scientists propose that inhibiting the CHRNB3 gene “could help reduce or stop smoking.” But they then modulate short-term expectations and warn 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 possible therapy targeting β3-containing receptors could represent a complementary approach, particularly to reduce the intensity of smoking in habitual smokers. But several key questions remain, such as understanding the mechanism of the gene to influence smoking and its other functions in the brain.”
Caution in expectations
The authors raise the need for more comprehensive evaluations of localized variants. And they also see the 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), assures, in statements to the Science Media Center (SMC) portal, that the findings of this study are “promising”, but there are still gaps in knowledge. “The inactivation of the gene using drugs could have the same benefit. However, they do not study whether this same variant could be associated with other negative effects on health, which would be equivalent to possible side effects of a medication that inactivates the gene,” says the expert.
Costas assures that “additional evidence is needed, especially taking into account that the authors declare the existence of a conflict of interest, since many are shareholders or employees of a pharmaceutical company and owners of a patent on this gene.”
Miguel Barrueco, former head of the Pulmonology service at the Hospital of Salamanca, takes the same line of caution: he says that the article is “interesting”, but “it is advisable to be cautious in the interpretation of the results and not sow false therapeutic expectations, for example, about the short-term viability of a therapy for nicotine addiction such as the one proposed.”
“Similar studies carried out with other genes that also play a role in nicotine addiction have not ended with therapeutic applications of them. The spectrum of brain receptors and neurotransmitters (and the genes that encode them) involved is very broad and complex and to a large extent still unknown,” says Barrueco in statements to SMC.
