Background
Smoking is a notorious risk factor for chronic mucus hypersecretion (CMH). CMH frequently occurs in Chronic Obstructive Pulmonary Disease (COPD). The question arises whether the same single nucleotide polymorphisms (SNPs) are related to CMH in smokers with and without COPD.
Methods
We performed two genome wide association studies on CMH under an additive genetic model in male heavy smokers (≥20 pack-years) with COPD (n=849, 39.9% CMH) and without COPD (n=1,348, 25.4% CMH), followed by replication and meta-analysis in comparable populations, and assessment of the functional relevance of significantly associated SNPs.
Results
GWA analysis on CMH in COPD and non-COPD yielded no genome wide significance after replication. In COPD, our top SNP (rs10461985, p=5.43×10−5) was located in the GDNF-antisense gene that is functionally associated with the GDNF gene. Expression of GDNF in bronchial biopsies of COPD patients was significantly associated with CMH (p=0.007). In non-COPD, 4 SNPs had a p-value <10−5 in the meta-analysis, including a SNP (rs4863687) in the MAML3 gene, the T-allele showing modest association with CMH (p=7.57×10−6, OR=1.48) and with significantly increased MAML3 expression in lung tissue (p=2.59×10−12).
Conclusions
Our data suggest the potential for differential genetic backgrounds of CMH in individuals with and without COPD.