Susceptibility genes for rapid decline of lung function in the lung health study

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 (ΔFEV₁ = -154 ± 3 ml/yr) and 308 nondecliners (ΔFEV₁ = +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 α₁-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 α₁-antitrypsin S and 3′ polymorphisms, vitamin D-binding protein isoforms, and tumor necrosis factor (TNF-α G-308A and TNF-β A252G) polymorphisms were not associated with rate of decline of lung function.