rs114205691 (CHRNA3): Lung Function and Emphysema

Key takeaways

• rs114205691 sits within the 15q25 locus (CHRNA3, CHRNA5, AGPHD1, IREB2, CHRNB4), which shows one of the strongest genetic signals for lung function decline in smokers.
• A GWAS of 9,919 current and former smokers found this region associated with airflow obstruction at a p-value as low as 2.17 x 10^-11, confirmed in a meta-analysis of 13,532 participants across three cohorts.
• The same CHRNA3-containing locus is also linked to distinct emphysema patterns visible on CT scans, extending beyond general airflow decline.
• 15q25 is described as the primary genomic region for nicotine dependence and smoking-related traits.
• All available evidence is restricted to current and former smokers; applicability to non-smokers is not established by the provided studies.

What the research says rs114205691 is a variant at the 15q25 locus (CHRNA3, CHRNA5, AGPHD1, IREB2, CHRNB4). A GWAS of 9,919 current and former smokers in the COPDGene cohort (6,659 non-Hispanic White and 3,260 African American participants) found genome-wide significant associations between this locus and both post-bronchodilator FEV1 (the volume of air expelled in the first second of a forced exhalation) and FEV1/FVC ratio (the fraction expelled in the first second, a standard index of airflow obstruction), with a minimum p-value of 2.17 x 10^-11; a meta-analysis across COPDGene, ECLIPSE, and GenKOLS (total n = 13,532) confirmed these findings. A separate GWAS of 9,614 smokers using quantitative CT scan-derived emphysema pattern scores identified the IREB2/CHRNA3 portion of this locus as one of seven genome-wide significant hits for distinct emphysema subtypes, with top variants overlapping enhancer and DNase I hypersensitivity regions active in lung fibroblasts and small airway epithelial cells.

Reported associations

• Post-bronchodilator FEV1 (lung volume): The 15q25 region was genome-wide significantly associated with FEV1 in non-Hispanic White smokers in COPDGene (minimum p-value = 2.17 x 10^-11, n = 6,659 discovery; n = 13,532 meta-analysis confirmation across three cohorts).
• FEV1/FVC ratio (airflow obstruction): The same locus was genome-wide significantly associated with FEV1/FVC in the non-Hispanic White COPDGene sample (minimum p-value = 2.17 x 10^-11), replicated in the three-cohort meta-analysis.
• CT-measured emphysema patterns: The IREB2/CHRNA3 locus reached genome-wide significance for association with distinct quantitative emphysema subtypes derived from CT scans in a GWAS of 9,614 COPDGene smokers; this locus was one of five known COPD-susceptibility regions among seven total significant hits.
• COPD susceptibility: Both studies describe the 15q25 locus as one of the most consistently replicated genetic regions for COPD risk in smokers.
• Nicotine dependence and smoking exposure: The 15q25 region is characterized in the source studies as the primary genomic locus for nicotine dependence and smoking exposure traits.

Evidence quality The lung function associations are supported by a discovery GWAS of 9,919 smokers and confirmed in a meta-analysis of three independent cohorts totalling 13,532 participants, with a minimum p-value of 2.17 x 10^-11, well below the conventional genome-wide significance threshold of 5 x 10^-8. The emphysema pattern findings come from a separate GWAS of 9,614 smokers using quantitative CT-derived phenotypes, with the CHRNA3 region among five of seven significant loci that coincided with previously known COPD-susceptibility regions. Both studies were limited to current and former smokers, meaning no evidence is available from these studies for never-smokers. The studies report locus-level results for the 15q25 region as a whole; the specific causal variant within this region is not identified in the provided data. No per-allele effect sizes (odds ratios or beta coefficients) for rs114205691 individually are reported in the provided study text.

Lifestyle considerations No lifestyle considerations on file for this variant.