CHRNB3: People Carrying Rare Variants Of This Gene Are Far Less Likely To Be Heavy Smokers

Tobacco is implicated in more than 7 million deaths per year, according to the World Health Organization, and that includes around 1.6 million non-smokers who die from second-hand smoke exposure. It remains a huge public health challenge, yet there hasn’t been much progress in developing drugs that could help those experiencing nicotine addiction. 

"Smoking addiction is a complex behavioral trait influenced by many biological, psychological, and social factors, which makes it inherently difficult to target with a single drug," corresponding authors Drs Veera Rajagopal and Giovanni Coppola told IFLScience.

One thing that does set nicotine apart is the wealth of detailed research that exists looking at how it affects the human body at a molecular level. 

"One of the core challenges has been identifying new, strong biological targets with sufficient confidence to pursue drug discovery and development efforts. Human genetics may be able to change that – by finding people who are naturally protected from heavy smoking due to their genes, we can identify precise biological mechanisms that may be worth targeting, just as our study does," said Rajagopal and Coppola.

Back in the 1990s, the first genetic variants that could impact levels of tobacco use were identified. One example is a deletion in the CYP2A6 gene, which slows nicotine metabolism in the blood, leading those who carry this mutation to smoke fewer cigarettes per day on average. 

Variants in another gene called CHRNB2, which encodes a component of nicotinic acetylcholine receptors in the brain, have also been linked to differences in smoking behavior. A recent review explains that the binding of nicotine to these receptors plays an important role in the genesis of nicotine addiction by activating the brain’s reward system. The smoking cessation drug varenicline works by targeting these receptors.

It stands to reason that changes in the other genes encoding subunits of these receptors could also alter their function – and if smoking is less rewarding to the brain, addiction is less likely.

Some people are genuinely wired differently, and understanding that wiring is the first step toward developing better tools to help them.

Drs Veera Rajagopal and Giovanni Coppola

In their new study, Rajagopal, Coppola, and colleagues from the US, UK, and Mexico sequenced the genomes of 37,897 current smokers who had enrolled in a long-running population health study in Mexico City. 

They identified a variant in CHRNB3, which encodes another subunit of the nicotinic acetylcholine receptor. The variant was more prevalent in individuals with Indigenous Mexican ancestry than in other populations. 

"The key discovery – the p.Glu284Gly variant – exists almost exclusively in people of Indigenous Mexican ancestry," said Rajagopal and Coppola. "Had we only studied Europeans, as most genomic studies historically have, we would have missed it entirely. Representative research is not just an ethical imperative, it is a scientific one."

People carrying one or two copies of this variant, as opposed to the usual version of the gene, were found to be much less likely to smoke heavily: those with one copy smoked 21 percent fewer cigarettes on average, while for those with two copies the figure was 78 percent – "a remarkably large effect for a genetic variant on a complex behavioral trait," said Rajagopal and Coppola.

The fact that these variants affect how much people smoke, but not whether they start smoking in the first place, is different from what Rajagopal and Coppola have seen in their own work on CHRNB2, they told us: "This suggests different nicotinic receptor subunits play surprisingly specific roles in different aspects of addictive behavior."

In genetics, that kind of cross-ancestry convergence is relatively rare and particularly compelling.

Drs Veera Rajagopal and Giovanni Coppola

Comparing their data with European and Asian cohorts collected from the UK Biobank and Biobank Japan, they found similar effects associated with variants in CHRNB3. It suggests that these variants may be impacting smoking behavior across a diverse range of ancestries, though the authors stress that this will need to be confirmed in more wide-ranging studies.

Rajagopal and Coppola told IFLScience that "the sheer strength and consistency of the signal across three completely independent populations was striking. The Indigenous Mexican variant, the East Asian variant, and the European aggregate signal are all different mutations in the same gene, yet they produce almost identical effect sizes. In genetics, that kind of cross-ancestry convergence is relatively rare and particularly compelling."

Overall, the findings suggest that CHRNB3, along with other genes that have previously been identified, may be a good target for drugs that could help with nicotine addiction. The Food and Drug Administration has approved seven drugs to help people quit smoking, most of which are nicotine replacement therapies like patches and lozenges. Targeting these genetic variants could provide a new avenue to explore.

"The finding we are most excited to follow up on is the existence of natural human knockouts of CHRNB3 (people who carry two copies of the variant). Conducting detailed profiling of these individuals would help us understand: How do they feel? Are there any health differences we can detect? How does their brain respond to nicotine?" said Rajagopal and Coppola.

"[F]indings like ours are a reminder that for many people, struggling to control how much they smoke is not a failure of willpower, it is biology. Some people are genuinely wired differently, and understanding that wiring is the first step toward developing better tools to help them."

The study is published in the journal Nature Communications.