A genetic mutation present in approximately 90% of heavy smokers has been identified by researchers, offering a potential explanation for high relapse rates after quitting and paving the way for tailored smoking cessation treatments. The discovery, made by Franco-Italian teams in collaboration with researchers from the United States and Canada, centers on the CHRNA5 gene, which plays a critical role in the brain’s reward circuitry.
Worldwide, tobacco use kills an estimated eight million people annually. In France alone, it remains the leading cause of preventable death, responsible for 75,000 fatalities each year due to cancers, cardiovascular diseases, and chronic obstructive pulmonary diseases. Exposure to secondhand smoke as well poses significant health risks to non-smokers, increasing the risk of asthma in children and coronary heart disease in adults.
For decades, scientists have sought to understand why some individuals become dependent on nicotine quickly, while others can smoke without developing an addiction. The newly identified mutation in the CHRNA5 gene appears to disrupt the brain’s reward system. In individuals without the mutation, this system deactivates once a sufficient dose of nicotine is reached. However, in those carrying the mutation, the reward circuit remains open, compelling the brain to seek increasing doses of nicotine to achieve the same effect – requiring three times more nicotine to alleviate withdrawal symptoms.
“A drug capable of increasing the activity of receptors containing the α5 subunit could help reduce tobacco consumption and the risk of relapse after withdrawal,” stated Uwe Maskos, head of the Integrative Neurobiology of Cholinergic Systems unit at the Pasteur Institute, following the publication of the research in Current Biology. The study found that individuals with the mutation are significantly more likely to relapse after attempting to quit smoking, even when demographic factors are equal.
Researchers are also exploring therapeutic avenues targeting the CYP2A6 enzyme, which metabolizes nicotine. Inhibiting this enzyme can maintain stable nicotine levels in the bloodstream, reducing the urge to smoke, though these treatments remain experimental. Currently, no smoking cessation methods are specifically calibrated to an individual’s genetic profile, but a large-scale study published in Nature, involving over 3.4 million individuals, has identified 3,823 genetic variants associated with both tobacco and alcohol dependence, potentially paving the way for personalized approaches.
Genetic factors are estimated to influence addiction susceptibility by 40 to 50%, with cultural, socioeconomic, and public policy factors accounting for the remainder. A separate study, published in Nature Communications and involving nearly 38,000 active smokers in Mexico, identified a variant of the CHRNB3 gene linked to reduced daily cigarette consumption. Individuals with one copy of this mutation smoked approximately 21% fewer cigarettes, while those with two copies smoked up to 78% fewer. These findings have been validated in populations of Asian and European descent.
Researchers at the Regeneron Genetics Center, in collaboration with the National Autonomous University of Mexico and the University of Oxford, are working to replicate the results of the Nature study on a separate cohort to further validate the 99 genetic variants already linked to the initiation of tobacco use. Clinical trials evaluating CYP2A6 inhibitors are expected to yield initial results by 2027.
