rs11858836 (IREB2): Smoking and Lung Function Variant
Key takeaways
- rs11858836 sits at the 15q25 locus (CHRNA3/CHRNA5/AGPHD1/IREB2/CHRNB4), one of the most replicated genetic signals for smoking behavior and lung disease
- The locus reaches genome-wide significance for cigarettes smoked per day and for standard lung function measures (FEV1 and FEV1/FVC ratio) in smokers
- Effect sizes for daily cigarette quantity are modest (beta approximately 0.11-0.12 per allele copy) but compound into a meaningful tobacco burden over a lifetime of smoking
- The smoking quantity association is directionally consistent across COPD cases and healthy smokers, suggesting the locus shapes smoking behavior independently of disease status
- GTEx data show the alternate allele reduces CHRNA5 expression in brain, heart, muscle, and nerve tissues, pointing to a possible mechanism through nicotinic receptor activity
Key takeaways
- rs11858836 sits at the 15q25 locus (CHRNA3/CHRNA5/AGPHD1/IREB2/CHRNB4), one of the most replicated genetic signals for smoking behavior and lung disease
- The locus reaches genome-wide significance for cigarettes smoked per day and for standard lung function measures (FEV1 and FEV1/FVC ratio) in smokers
- Effect sizes for daily cigarette quantity are modest (beta approximately 0.11-0.12 per allele copy) but compound into a meaningful tobacco burden over a lifetime of smoking
- The smoking quantity association is directionally consistent across COPD cases and healthy smokers, suggesting the locus shapes smoking behavior independently of disease status
- GTEx data show the alternate allele reduces CHRNA5 expression in brain, heart, muscle, and nerve tissues, pointing to a possible mechanism through nicotinic receptor activity
What the research says
The 15q25 region (containing CHRNA3, CHRNA5, AGPHD1, IREB2, and CHRNB4 - genes encoding nicotinic acetylcholine receptor subunits and related proteins) shows genome-wide significant associations with average cigarettes smoked per day across multiple cohorts of heavy ever-smokers (combined n = 13,532; lowest p = 1.78 x 10^-15) PMID 31680179. The locus is also significantly associated with FEV1 (volume of air forcibly exhaled in one second) and the FEV1/FVC ratio (a measure of airflow obstruction) in non-Hispanic white smokers (n = 6,659; lowest p = 2.17 x 10^-11) PMID 26634245. Earlier genome-wide studies had already established this chromosomal region as a COPD susceptibility locus before the lung function and smoking analyses PMID 22080838.
Reported associations
- Cigarettes per day (non-Hispanic white smokers): Genome-wide significant across COPDGene, GenKOLS, and ECLIPSE cohorts (lowest p = 1.78 x 10^-15); stratified per-allele effects of beta = 0.11 in COPD cases (p = 5.58 x 10^-4) and beta = 0.12 in controls (p = 3.86 x 10^-5) PMID 31680179
- Cigarettes per day (African American smokers): Signal did not reach genome-wide significance in the COPDGene African American cohort alone (n = 3,260), though the direction of effect was consistent PMID 31680179
- FEV1 (forced expiratory volume): Genome-wide significant in COPDGene non-Hispanic white smokers (n = 6,659; lowest p = 2.17 x 10^-11) PMID 26634245
- FEV1/FVC ratio (airflow obstruction): Genome-wide significant in the same cohort at the same locus (p = 2.17 x 10^-11) PMID 26634245
- COPD susceptibility: Established risk locus acknowledged in a GWAS meta-analysis of 3,499 COPD cases and 1,922 controls across four cohorts PMID 22080838
Evidence quality
The smoking quantity signal was tested across four cohorts (COPDGene NHW n = 6,659; COPDGene AA n = 3,260; GenKOLS n = 1,671; ECLIPSE n = 1,942; combined n = 13,532) and reached genome-wide significance in the combined non-Hispanic white analysis but not in the African American cohort alone, a notable ancestry-related heterogeneity PMID 31680179. Lung function associations were confirmed in a three-cohort meta-analysis (n = 13,532 smokers) at p = 2.17 x 10^-11 PMID 26634245. COPD risk for this region has been replicated across multiple independent cohorts, though family-based replication in the ICGN study was supportive rather than statistically significant (rs7937: p = 0.28; rs2604894: p = 0.11) PMID 22080838. An exome array analysis found no exome-wide significant associations between rare coding variants at this locus and cigarettes per day, indicating the main signal is driven by common rather than rare coding variants PMID 31680179.
Tissue-specific expression effects
- CHRNA5: The alternate allele is linked to reduced expression in brain cortex, frontal cortex (BA9), tibial nerve, heart atrial appendage, heart left ventricle, skeletal muscle, and cultured fibroblasts GTEx Portal
- CHRNA3: The alternate allele is linked to reduced expression in skeletal muscle GTEx Portal
Lifestyle considerations
No lifestyle considerations on file for this variant.
Frequently asked questions
What is the IREB2 gene and what does it do?
IREB2 (Iron Responsive Element Binding Protein 2) is a gene on chromosome 15 involved in regulating iron metabolism in cells. It sits within the 15q25 region alongside nicotinic acetylcholine receptor genes CHRNA3 and CHRNA5, and variants across this cluster have been associated with smoking behavior and lung disease in large genetic studies.
Is rs11858836 linked to COPD?
The 15q25 locus containing IREB2 and CHRNA3/5 is an established COPD susceptibility region, confirmed across multiple genome-wide association studies combining thousands of cases and controls. Variants in this cluster have also been associated with lung function measures like FEV1 and FEV1/FVC in smokers.
Does this variant affect how much someone smokes?
Studies of heavy ever-smokers found genome-wide significant associations between the 15q25 locus and average cigarettes smoked per day. The per-allele effect size was modest (beta approximately 0.11-0.12), consistent across COPD cases and healthy smokers, and replicated across multiple independent cohorts of non-Hispanic white participants.
Does this variant only matter if you have COPD?
No. The association with cigarettes per day was directionally consistent and nominally significant in both COPD cases (beta = 0.11) and COPD-free smokers (beta = 0.12), suggesting the locus shapes smoking behavior regardless of disease status.
Does rs11858836 affect how genes are expressed in different tissues?
GTEx data show the alternate allele is linked to reduced CHRNA5 expression across brain, heart, muscle, and nerve tissues, and reduced CHRNA3 expression in skeletal muscle. These are expression-level effects that may point to a mechanism but do not directly indicate clinical outcomes.