Rare Gene Variant Slashes Cigarette Use by Up to 78%

A fascinating new paper may point the way towards drugs that could help reduce smoking prevalence.

I came across an engrossing X thread by US-based scientist Veera Rajagopal. The thread, which is a must-read, refers to a paper published this month in Nature titled "Rare coding variants in CHRNB3 associated with reduced daily cigarette smoking across ancestries."

Rajagopal is a good communicator, but this branch of science is complicated. I’ll admit that I needed to jump on a call with a smart friend to help me break down exactly what is going on here. I suspect some of you won’t have that issue, while others will feel a bit lost, like I was.

So, in plain English, the main thrust of the paper asks a question like, “Are some people born with brains that make cigarettes less ‘rewarding’, which results in them smoking less?”

To answer this question, the researchers looked at genetic variants in the CHRNB3 nicotinic receptor subunit. The CHRNB3 gene provides instructions for making the β3 subunit of nicotinic acetylcholine receptors in the brain. These receptors are the protein sockets that normally respond to acetylcholine. However, they can also bind nicotine, which is how the brain feels a reward from using nicotine.

What did the paper find?

Among ~38,000 current smokers from the Mexico City Prospective Study (MCPS), the researchers found that some people had rare mutations in CHRNB3 that make the socket work less well or not at all. The interesting thing is that while these people still smoke, they smoke fewer cigarettes per day than people without the change.

For example:

• In one Mexican group, people with a particular change (p.Glu284Gly) smoked noticeably fewer cigarettes; a few people with two copies of the change smoked very few.
• In a Japanese group, people with a different “broken” version of the same gene also smoked fewer cigarettes.

What can this tell us?

The interesting thing about these differences is that they suggest that nicotine needs these CHRNB3-containing receptors to deliver its “hit” or reward fully. In other words, nicotine is less satisfying and therefore less habit-forming if the receptor is weakened or missing. The finding could go a long way to shine a light on why some smokers are happy with one cigarette a day, while others burn through a pack or more.

What might this study say about the future of quitting smoking?

The exciting thing here is the suggestion that reducing CHRNB3 could make cigarettes unappealing. While the data found that Indigenous Mexican, East Asian, and European groups were most likely to carry this damaged or loss-of-function variant, it opens up the possibility for future impactful drug research.

A medicine designed to block or weaken β3‑containing nicotinic receptors could mimic these protective variants. In short, it could make nicotine less effective in the specific circuits that control how much you smoke. The upsides might include:

• Reducing the number of smoked cigarettes per day.
• Reduce the likelihood of progressing to heavier smoking.
• Help people who want to quit gradually reduce their daily smoking.

Indeed, if a drug can reproduce the degree of inhibition seen in variant carriers, developers can be cautiously optimistic that it will shift smoking behaviour in the same direction.