rs117139969 (EGLN2): Lung Function in Smokers

Key takeaways

• In a meta-analysis of 13,532 current and former smokers, a chromosome 19 locus near CYP2A6/7 overlapping the RAB4B-EGLN2 and EGLN2 region reached genome-wide significance for FEV1, a standard airflow measure (p=3.49 x 10^-8).
• This variant increases CYP2A7 expression in skin and MIA expression in artery, pituitary, and tibial nerve tissue.
• All lung function evidence comes from smokers only; whether findings apply to non-smokers is not established by the available studies.
• GTEx data link this variant to five nearby genes across seven tissue types, including skin, artery, nerve, spleen, sigmoid colon, thyroid, and pituitary.

What the research says A genome-wide association study (GWAS, a method that scans hundreds of thousands of genetic variants simultaneously for associations with a measured trait) was conducted in 9,919 current and former smokers in the COPDGene cohort and extended in a three-cohort meta-analysis totalling 13,532 participants (COPDGene, ECLIPSE, GenKOLS); the meta-analysis identified a genome-wide significant association for post-bronchodilator FEV1 (forced expiratory volume in one second, the primary spirometric measure of airflow obstruction) at a chromosome 19 locus near CYP2A6/7 overlapping the RAB4B-EGLN2 and EGLN2 region (p=3.49 x 10^-8), though no per-allele effect size was reported for this locus in the available text. Separately, tissue-specific expression data from GTEx v11 (953 donors, FDR<0.05) show that rs117139969 acts as an eQTL (expression quantitative trait locus: a variant associated with changes in how much a nearby gene is produced in a specific tissue) for at least five genes across multiple body tissues GTEx Portal.

Reported associations

• FEV1 in current and former smokers: A three-cohort meta-analysis (COPDGene, ECLIPSE, GenKOLS; n=13,532) identified a genome-wide significant signal at a chromosome 19 locus near CYP2A6/7 overlapping the RAB4B-EGLN2, EGLN2 region (p=3.49 x 10^-8) for post-bronchodilator FEV1, the standard diagnostic measure of airflow whose decline characterizes obstructive lung diseases such as COPD.
• MIA expression in artery, pituitary, and nerve: The ALT allele is associated with increased expression of MIA (melanoma inhibitory activity gene) in aortic artery, pituitary gland, and tibial nerve GTEx Portal.
• CYP2A7 expression in skin: The ALT allele is associated with increased expression of CYP2A7 (cytochrome P450 2A7, a member of the enzyme family that processes drugs and foreign compounds in the body) in sun-exposed lower leg skin GTEx Portal.
• ENSG00000300700 expression in spleen and sigmoid colon: The ALT allele is associated with reduced expression of this gene (Ensembl ID ENSG00000300700) in spleen and sigmoid colon GTEx Portal.
• ENSG00000282951 expression in pituitary: The ALT allele is associated with increased expression of this gene (Ensembl ID ENSG00000282951) in pituitary gland GTEx Portal.
• CYP2G1P expression in thyroid: The ALT allele is associated with increased expression of CYP2G1P (a pseudogene, meaning a non-functional gene copy, in the cytochrome P450 CYP2 family) in thyroid tissue GTEx Portal.

Evidence quality The FEV1 association comes from a meta-analysis across three independent cohorts totalling 13,532 current and former smokers, reaching the conventional genome-wide significance threshold (p=3.49 x 10^-8 against a threshold of 5 x 10^-8). The primary COPDGene cohort included both non-Hispanic White (n=6,659) and African American (n=3,260) participants; ECLIPSE (n=1,942) and GenKOLS (n=1,671) added replication. The study was restricted to smokers, so findings cannot be generalized to non-smoking populations. The published study reports a region-level signal near CYP2A6/7 on chromosome 19 and does not name rs117139969 as the lead or causal variant; whether this specific variant drives the observed signal or is in linkage disequilibrium (statistical correlation with a nearby causal variant) has not been established from the available evidence. No per-allele effect size (beta coefficient or odds ratio) for this locus was reported in the available text. The GTEx eQTL associations are derived from a well-powered reference dataset (n=953 donors, FDR<0.05) but describe gene-regulatory mechanisms, not clinical outcomes. No conflicting findings were identified across the available evidence.

Tissue-specific expression effects

• MIA: Increased expression in aortic artery, pituitary gland, and tibial nerve; this gene is influenced across three distinct tissue types by the ALT allele GTEx Portal.
• ENSG00000300700: Reduced expression in spleen and sigmoid colon GTEx Portal.
• CYP2A7: Increased expression in sun-exposed lower leg skin GTEx Portal.
• ENSG00000282951: Increased expression in pituitary gland GTEx Portal.
• CYP2G1P: Increased expression in thyroid GTEx Portal.

Lifestyle considerations No lifestyle considerations on file for this variant.