Association of dopamine-related gene alleles, smoking behavior and decline in FEV1 in subjects with COPD: Findings from the Lung Health Study

Cigarette smoking is the major risk factor for chronic obstructive pulmonary disease (COPD). Specific dopamine related gene alleles have previously been found to be associated with smoking initiation, maintenance and cessation. We investigated the association between specific dopamine related gene alleles and both change in smoking behavior and lung function change over time in individuals with mild-to-moderate COPD. Subjects included a subset of participants in the Lung Health Study (LHS), a smoking intervention study in smokers with mild to moderate COPD. Smoking status was determined and lung function performed at baseline and annually for 5 years. In post-hoc analyses, we assessed the association of the dopamine receptor (DRD2) TaqI A1⁺ allele (A1A1, A1A2 genotypes) and A1^- allele (A2A2 genotype), and the dopamine transporter (DAT) 9R⁺ allele (9R9R and 9R10R genotypes) and 9R^- allele (10R10R genotype) with both changes in smoking status and lung function in a subset of LHS subjects. No significant associations were noted between variants in these genes and success in smoking cessation. However, in exploratory analyses that did not adjust for multiple comparisons, sustained male (but not female) quitters with the DRD2 A1^- allele and/or the DAT 9R⁺ allele showed an accelerated decline in FEV1 similar to that of continuing smokers over 5 years after quitting smoking. These preliminary findings suggest that dopamine-related genes may play a role in the progression of COPD, at least in the subset of male ex-smokers whose disease continues to progress despite sustained quitting, and warrants additional confirmatory and mechanistic studies.