Association of genetic determinants of alpha one antitrypsin, neutrophil elastase, and matrix metalloproteinase one with the risk of COPD, lung cancer, and lung cancer survival

Background. Chronic obstructive pulmonary disease (COPD) is a recognized clinical risk indicator for lung cancer; however, because cigarette smoking is an overwhelmingly strong risk factor for both diseases it has been difficult to determine whether these two diseases also have a common pathological etiology. It was hypothesized that genetic variation in alpha-1 antitrypsin (AAT), a protein that protects against tissue degradation, and neutrophil elastase (NE) and matrix metalloproteinase-1 (MMP1), two proteins that degrade pulmonary tissue, play a role in the development of both diseases and in lung cancer progression. Methods. To determine if SNPs in and around genes that encode AAT (SERPINA1), NE ( ELA2) and MMP1 (MMP1) were associated with the risk of either disease we conducted two case-control studies. A prospective cohort study of 369 lung cancer cases was also conducted to determine if the MMP1 SNPs were associated with lung cancer survival. All studies were conducted within the same parent study and African Americans and Caucasians were analyzed separately. Results. Among African Americans, having the less efficient S or Z variants for SERPINA1 was associated with an increased risk of COPD both alone and in the presence of lung cancer. Among Caucasians these variants were associated with a decreased risk of lung cancer in the absence of COPD. Associations were observed for five ELA2 tagging SNPs, among African Americans, and six ELA2 tagging SNPs, among Caucasians, but the results were not consistent. The functional MMP1-10 polymorphism was not associated with COPD risk in either race but was associated with lung cancer risk in the presence of COPD among African Americans and with lung cancer survival among Caucasians. Inconsistent results were also observed for five other MMP1 polymorphisms. Conclusion. There was no compelling evidence that variation in the vicinity of SERPINA1, ELA2, or MMP1 is strongly associated with risk of COPD, lung cancer or lung cancer survival among African Americans or Caucasians. There was also no compelling evidence that any of these polymorphisms could help to explain the racial disparities observed for the incidence of COPD or lung cancer.