Rare genetic variants in a little-studied nicotine receptor subunit are linked to markedly lower cigarette consumption, pointing to a potential new biological pathway for reducing smoking intensity across diverse populations.
Study: Rare coding variants in CHRNB3 associate with reduced daily cigarette smoking across ancestries. Image Credit: kungfu01 / Shutterstock
In a recent study published in the journal Nature Communications, researchers conducted an exome-wide association study (ExWAS) to identify rare genetic variants associated with fewer cigarettes smoked per day rather than directly diagnosing nicotine dependence. The study identified variants in the CHRNB3 gene that significantly reduced tobacco intake.
These variants, found in individuals of Indigenous Mexican and East Asian ancestry and supported by aggregate rare-variant analyses in European ancestry populations, suggest that inhibiting the β3 (beta-3) subunit of nicotinic receptors could serve as a potential future therapeutic intervention to reduce smoking intensity, pending further functional and clinical validation.
Tobacco Smoking Burden and Limits of Current Therapies
Tobacco smoking is recognized as one of the most physiologically detrimental modifiable behaviors worldwide. Studies have shown that smoking significantly increases the risk of mortality and comorbidities, including cardiovascular diseases (CVDs) and cancers.
While decades of government-backed anti-smoking campaigns have resulted in a gradual decline in global smoking rates, progress in the development of novel pharmaceuticals and interventions to treat nicotine addiction has been limited over the past 20 years.
Most current treatments, such as varenicline, target the α4β2 (alpha-4 beta-2) nicotinic acetylcholine receptors (nAChRs). These receptors mediate the rewarding effects of nicotine and are believed to contribute to its addictive potential.
Researchers have hypothesized that genetic mutations in α4β2 nAChRs may alter individual susceptibility to nicotine dependence and smoking behavior. However, because these receptors are complex ion channels composed of multiple subunits with differing functional contributions, investigating this hypothesis has proven challenging.
Exome-Wide Association Study of Rare Variants and Smoking Intensity
The study leveraged advances in next-generation sequencing methodologies, specifically ExWAS, to investigate whether rare genetic variants with a frequency below 1 percent in the population were associated with reduced cigarettes per day (CPD). CPD was used as a behavioral proxy for smoking intensity rather than a formal clinical diagnosis of nicotine dependence.
The discovery cohort was derived from the Mexico City Prospective Study (MCPS) and included 37,897 current smokers. Researchers performed exome sequencing to analyze protein-coding regions of DNA and conducted a GWAS to assess common genetic variants across the genome.
The primary endpoint was CPD, analyzed as a quantitative measure of smoking intensity. Statistical analyses were performed using REGENIE software to account for sample-relatedness and population structure, thereby increasing the robustness of genetic association results.
Cross-Ancestry Replication in UK Biobank and Japan Biobank
After identifying rare CPD-reducing variants, researchers evaluated their findings in additional datasets: the UK Biobank (UKB), which consists primarily of individuals of European ancestry, and publicly available Japan Biobank association data representing East Asian ancestry populations. An independent sample of former smokers within MCPS was also examined to assess the consistency of effects.
CHRNB3 Missense Variant and Smoking Reduction Effects
The most significant finding was the p.Glu284Gly missense variant in the CHRNB3 gene, identified exclusively in participants of Indigenous Mexican ancestry (p = 1.1 × 10-9).
Heterozygous carriers of p.Glu284Gly smoked approximately 21 percent fewer cigarettes per day than non-carriers (4.6 versus 5.6 cigarettes). Homozygous carriers, who were extremely rare and require cautious interpretation, smoked approximately 78 percent fewer cigarettes per day (1.25 cigarettes).
A separate loss-of-function variant in CHRNB3 was identified in East Asian participants in Japan Biobank data (p = 3.9 × 10-8). Although the specific mutations differed between populations, both rare variants were associated with substantial reductions in smoking intensity, underscoring the role of CHRNB3 in modulating tobacco consumption.
Differential Roles of CHRNB3 and CHRNB2 in Smoking Behavior
Comparative analyses suggested that CHRNB2 influences the likelihood of smoking initiation, or becoming an “ever smoker,” whereas CHRNB3 specifically affects smoking intensity among established smokers.
These findings support the hypothesis that the β3 subunit, expressed in the medial habenula of the brain, may regulate aversive or withdrawal-related effects of nicotine rather than its initial rewarding properties. This proposed mechanism is supported primarily by prior experimental and animal studies rather than direct human functional validation.
Therapeutic Implications and Study Limitations
This large-scale rare-variant analysis highlights population-specific coding variation associated with smoking intensity and suggests that the β3 subunit of nicotinic receptors may represent a potential therapeutic target for reducing tobacco consumption.
The authors hypothesize that pharmacologic inhibition of this subunit could potentially mimic the protective genetic effect observed in variant carriers, thereby reducing daily cigarette consumption. However, this implication remains speculative, and clinical nicotine dependence or tobacco use disorder was not comprehensively assessed in this analysis.
Limitations include the absence of replication in an independent Mexican cohort and the lack of direct functional laboratory experiments. Nevertheless, the convergence of findings across ancestries supports further investigation into the biological role of the β3 subunit to ensure that any future therapeutic strategies targeting this pathway are both safe and effective.
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