Susceptibility genes for rapid decline of lung function in the Lung HealthStudy

The genes that contribute to the genetic susceptibility to chronic obstruct ive pulmonary disease (COPD) remain largely unknown. We hypothesized that w idely divergent rates of decline in lung function in smokers would be a rob ust phenotype for detection of genes that contribute to COPD severity. We s elected 283 rapid decliners (Delta FEV1 = -154 +/- 3 ml/yr) and 308 nondecl iners (Delta FEV1 = + 15 +/- 2 ml/yr) from among smokers followed for 5 yr in the NHLBI Lung Health Study. Rapid decline of FEV1 was associated with t he MZ genotype of the alpha (1)-antitrypsin gene (odds ratio [OR] = 2.8, p = 0.03). This association was stronger for a combination of a family histor y of COPD with MZ (OR = 9.7, p = 0.03). These data suggest that the MZ geno type results in an increased rate of decline in lung function and interacts with other familial factors. Haplotype frequencies of the microsomal epoxi de hydrolase (mEH) gene were significantly different between rapid decliner s and nondecliners (p = 0.03). A combination of a family history of CORD wi th homozygosity for the His(113)/His(139)mEH haplotype was also associated with rapid decline of lung function (OR = 4.9, p = 0.04). The alpha (1)-ant itrypsin S and 3' polymorphisms, vitamin D-binding protein isoforms, and tu mor necrosis factor (TNF-alpha G-308A and TNF-beta A252G) polymorphisms wer e not associated with rate of decline of lung function.