CHRNB4 – Lung Cancer

Genome-wide association studies (GWAS) have robustly implicated the 15q25 locus, which includes CHRNB4, in lung cancer susceptibility. A landmark GWAS analysing 1,989 lung cancer cases and 2,625 controls identified a significant association at 15q25 (P = 9 × 10⁻¹⁰), with replication in an additional 2,513 cases and 4,752 controls (P = 5 × 10⁻²⁰) (PMID:18385738). The attributable risk for lung cancer from this locus was estimated at 14%.

Subsequent meta-analyses confirmed the independent contribution of CHRNB4 variants to lung cancer risk. In a meta-analysis of 7,700 lung cancer cases and 5,914 smoking controls, the CHRNB4-associated SNPs retained genome-wide significance for lung cancer risk after adjustment for cigarettes per day (P < 10⁻²⁰) (PMID:20700436). In African American populations (467 cases, 388 controls), CHRNB4 SNPs demonstrated strong associations with lung adenocarcinoma (e.g., rs684513 OR = 0.47, P = .0003) independent of smoking phenotypes (PMID:20554942).

The genetic architecture at 15q25 is complex and polygenic, with multiple statistically distinct signals in CHRNB4 contributing to lung cancer risk. No Mendelian segregation data are available for CHRNB4; rather, risk is conferred by common and rare alleles acting additively across populations.

Functional studies of CHRNB4 have demonstrated that rare missense variants alter receptor function and nicotine processing. In pooled sequencing of nicotine-dependent and non-dependent smokers, conserved CHRNB4 missense variants (e.g., p.Thr91Ile) were associated with reduced smoking behavior (OR = 0.31 African Americans, P = 0.0025) and decreased lung cancer risk, and in vitro assays showed increased nicotine-evoked currents for these alleles (PMID:22042774). Expression of CHRNB4 in lung epithelial and neuroendocrine cells further supports a direct role in carcinogen response (PMID:18385738).

No significant conflicting evidence disputes the association of CHRNB4 with lung cancer risk. The collective genetic and functional findings consistently implicate CHRNB4 in lung carcinogenesis across ancestries, smoking statuses, and histological subtypes.

Key Take-home: CHRNB4 variants at 15q25 confer a robust, reproducible increase in lung cancer susceptibility via altered nicotinic receptor function, supporting clinical risk stratification and potential chemopreventative targeting.

References

• Nature • 2008 • A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25. PMID:18385738
• PLoS Genetics • 2010 • Multiple independent loci at chromosome 15q25.1 affect smoking quantity: a meta-analysis and comparison with lung cancer and COPD. PMID:20700436
• Journal of the National Cancer Institute • 2010 • Nicotinic acetylcholine receptor region on chromosome 15q25 and lung cancer risk among African Americans: a case-control study. PMID:20554942
• Human Molecular Genetics • 2012 • Rare missense variants in CHRNB4 are associated with reduced risk of nicotine dependence. PMID:22042774

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