Objective

Diabetes damages major organ systems through disrupted glycemic control and increased inflammation. The effects of diabetes on the lung have been of interest for decades, but the modest reduction in pulmonary function and its nonprogressive nature have limited its investigation. A recent systematic review found that diabetes was associated with reductions in forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and diffusing capacity for carbon monoxide of the lung and increased FEV1/FVC. They reported pooled results including few smokers. This study will examine measures of pulmonary function in participants with extensive smoking exposure.

Research design and methods

We examined pulmonary function in participants with a >10-pack-year history of smoking with and without diabetes with and without chronic obstructive pulmonary disease (COPD). We measured pulmonary function, exercise capacity, and pulmonary-related quality of life in 10,129 participants in the Genetic Epidemiology of Chronic Obstructive Pulmonary Disease (COPDGene) Study.

Results

Participants with diabetes were observed to have reduced pulmonary function after controlling for known risk factors and also significant reductions in exercise capacity and quality of life across functional stages of COPD.

Conclusions

Pulmonary function in patients with ≥10 pack-years of smoking and diabetes is reduced, and this decrease is associated with significant reductions in activity-related quality of life and exercise capacity.

Background

Pulmonary function decline is a major contributor to morbidity and mortality among smokers. Post bronchodilator FEV1 and FEV1/FVC ratio are considered the standard assessment of airflow obstruction. We performed a genome-wide association study (GWAS) in 9919 current and former smokers in the COPDGene study (6659 non-Hispanic Whites [NHW] and 3260 African Americans [AA]) to identify associations with spirometric measures (post-bronchodilator FEV1 and FEV1/FVC). We also conducted meta-analysis of FEV1 and FEV1/FVC GWAS in the COPDGene, ECLIPSE, and GenKOLS cohorts (total n = 13,532).

Results

Among NHW in the COPDGene cohort, both measures of pulmonary function were significantly associated with SNPs at the 15q25 locus [containing CHRNA3/5, AGPHD1, IREB2, CHRNB4] (lowest p-value = 2.17 × 10(-11)), and FEV1/FVC was associated with a genomic region on chromosome 4 [upstream of HHIP] (lowest p-value = 5.94 × 10(-10)); both regions have been previously associated with COPD. For the meta-analysis, in addition to confirming associations to the regions near CHRNA3/5 and HHIP, genome-wide significant associations were identified for FEV1 on chromosome 1 [TGFB2] (p-value = 8.99 × 10(-9)), 9 [DBH] (p-value = 9.69 × 10(-9)) and 19 [CYP2A6/7] (p-value = 3.49 × 10(-8)) and for FEV1/FVC on chromosome 1 [TGFB2] (p-value = 8.99 × 10(-9)), 4 [FAM13A] (p-value = 3.88 × 10(-12)), 11 [MMP3/12] (p-value = 3.29 × 10(-10)) and 14 [RIN3] (p-value = 5.64 × 10(-9)).

Conclusions

In a large genome-wide association study of lung function in smokers, we found genome-wide significant associations at several previously described loci with lung function or COPD. We additionally identified a novel genome-wide significant locus with FEV1 on chromosome 9 [DBH] in a meta-analysis of three study populations.