The genes that contribute to the genetic susceptibility to chronic obstructive pulmonary disease (COPD) remain largely unknown. We hypothesized that widely divergent rates of decline in lung function in smokers would be a robust phenotype for detection of genes that contribute to COPD severity. We selected 283 rapid decliners (deltaFEV1 = -154 +/- 3 ml/yr) and 308 nondecliners (deltaFEV1 = +15 +/- 2 ml/yr) from among smokers followed for 5 yr in the NHLBI Lung Health Study. Rapid decline of FEV1 was associated with the MZ genotype of the alpha1-antitrypsin gene (odds ratio [OR] = 2.8, p = 0.03). This association was stronger for a combination of a family history of COPD with MZ (OR = 9.7, p = 0.03). These data suggest that the MZ genotype results in an increased rate of decline in lung function and interacts with other familial factors. Haplotype frequencies of the microsomal epoxide hydrolase (mEH) gene were significantly different between rapid decliners and nondecliners (p = 0.03). A combination of a family history of COPD with homozygosity for the His113/His139 mEH haplotype was also associated with rapid decline of lung function (OR = 4.9, p = 0.04). The alpha1-antitrypsin S and 3' polymorphisms, vitamin D-binding protein isoforms, and tumor necrosis factor (TNF-alpha G-308A and TNF-beta A252G) polymorphisms were not associated with rate of decline of lung function.

We hypothesized that if airway remodeling is related to duration of asthma, that when matched for severity, the airways of older adults should show greater alterations than the airways of younger adults. Using standard morphometric techniques, we compared airways with basement membrane perimeters (Pbm) between 2 and 10 mm from young individuals who died of asthma (n = 14, range 17-23 yr), and older individuals with fatal asthma (n = 13, range 40-49 yr). Comparisons were also made with normal airways from age-matched adults. Wall area was increased in old individuals with fatal asthma compared with young individuals with fatal asthma, primarily due to greater adventitial area, whereas wall area in young individuals with fatal asthma was not different from control subjects. Within muscle bundles the connective tissue matrix was increased around individual cells in individuals with asthma, unrelated to age. After adjustment for this change, smooth muscle area in both asthma groups was still greater than in age-matched control subjects, in old individuals with fatal asthma 4-fold greater (p = 0.04), and in young individuals with fatal asthma 2-fold greater (p = 0.03). Airway narrowing was increased in old versus young individuals with fatal asthma, with both groups more narrowed than control subjects. Intralumenal obstruction and subepithelial collagen in the two asthma groups were significantly greater than in control subjects, but there was no age effect. These data provide support for the hypothesis that there is an increase in airway wall area, including smooth muscle, and airway narrowing with increasing duration of severe asthma or with older age. The observation that total wall thickness was not greater in young individuals with young fatal asthma than in control subjects suggests that factors other than airway wall geometry contribute to the pathogenesis of fatal attacks in this age group.