Owing to the heterogeneous nature of COPD, multiple phenotypes could potentially be examined as outcomes in COPD pharmacogenetics studies. Candidate gene studies have found associations with several of these baseline COPD phenotypes, unrelated to drug treatments (). According to GOLD, COPD is defined by airflow obstruction (FEV1
/FVC < 0.7), determined by lung function testing [1
]. Lung function normally declines as part of the aging process, while accelerated lung function decline is a hallmark of COPD [32
]. Decline in lung function over time has been a common primary or secondary end point in clinical trials of COPD therapies [34
]. Lung function correlates with symptoms in COPD but not completely [1
]. Several studies have examined genetic associations with lung function decline in COPD. For example, He and colleagues performed a case–control comparison of subjects with the fastest and slowest rate of decline in FEV1
in smokers with COPD over 5 years of the Lung Health Study, finding association with SNPs in the IL-6
]. These investigators have identified other candidate genes using this approach [37
]. Other groups have found genetic associations with FEV1
decline in the general population [38
]. Although the association studies in the general population may be relevant in determining susceptibility to COPD, they may be less relevant to pharmacogenetics studies in subjects with established disease.
Genes associated with potential phenotypes for chronic obstructive pulmonary disease pharmacogenetics studies
These studies also demonstrate one of the drawbacks of using lung function decline as an outcome in COPD studies, namely the long timeframe needed to determine the rate of decline in an individual. Furthermore, lung function does not correlate perfectly with the symptoms that a COPD patient may experience, such as shortness of breath or exercise limitation [42
]. This has led to the use of other end points in COPD clinical trials [43
]. One such outcome is an acute exacerbation of COPD. Patients with COPD may experience acute exacerbations, consisting of increased symptoms of shortness of breath, cough and sputum production. These symptoms are troubling to patients, and often trigger a patient to seek medical attention. COPD exacerbations are a major cause of mortality and a major source of healthcare expenditure in patients with COPD [44
]. In research studies, COPD exacerbations can be determined by symptom-based or event-based definitions. Symptom-based definitions rely on patient report of symptoms such as shortness of breath, cough, sputum production and wheezing [48
]. Event-based definitions capture healthcare utilizations, such as prescriptions for antibiotics and/or systemic corticosteroids, urgent office or emergency room visits, and hospital admissions [49
Despite the clinical importance of COPD exacerbations, only a few studies have examined genetic effects on this outcome. Most of the studies have focused on genes involved in host defense, recognizing the importance of infections as a cause of COPD exacerbations [51
]. Yang et al.
found an association between polymorphisms in mannose binding lectin-2 and admissions for COPD exacerbations in 82 patients from the UK [52
]; the variants were not associated with COPD susceptibility. Takabatake and colleagues found a SNP in the chemokine (C-C motif) ligand 1 (CCL1
) gene to be associated with clinically determined exacerbations over a 2-year period in 276 male Japanese COPD patients [53
]. In 389 subjects from NETT, Foreman et al.
found association between multiple SNPs in surfactant protein B (SFTPB
) and COPD-related emergency room visits or hospital admissions [54
]. Other COPD genetics studies have examined exacerbations as a secondary outcome. SNPs in superoxide dismutase-3 (SOD3
) were associated with lower lung function and increased risks of COPD hospitalization and mortality in the population-based Copenhagen City Heart Study [55
]. In a Danish registry, heterozygous carriers of the AAT Z allele (PI MZ) were at increased risk for hospital admission for COPD, but the risk was confined to first-degree relatives of index cases with severe AAT deficiency [56
], indicating that other genetic or shared environmental factors may have contributed to increased exacerbation risk.
In addition to COPD exacerbations, other patient-centered COPD outcomes may have genetic contributions. Our group has identified variants in four genes – microsomal epoxide hydrolase (EPHX1
and latent TGF-β binding protein-4 (LTBP4
) – that were associated with exercise capacity, dyspnea symptoms and the multidimensional BMI, airflow obstruction, dyspnea and exercise capacity (BODE) score [57
] in 304 patients with severe COPD from NETT [58
]. The association between a promoter SNP in TGFB1
and dyspnea was replicated in the family-based Boston Early-Onset COPD Study.
Quantitative analysis of chest CT scans is useful for determining phenotypes in COPD patients, specifically emphysema and airway wall thickening [59
]. Although it may be clinically silent to patients, the change in the amount of emphysema over serial CT scans may be a marker of a drug's effect and is starting to be used as an outcome in COPD clinical trials [61
]. In a small randomized trial of AAT augmentation therapy, CT densitometry was a more sensitive measure of disease progression than traditional measures, such as decline in lung function [62
]. However, long timeframes and large sample sizes may still be required to detect differences in the rate of change of emphysema on chest CT scans. There is no single ideal phenotype for COPD pharmacogenetics studies; the choice of outcome may depend on the specific treatment considered. COPD exacerbations are a relevant clinical outcome, and studies using this end point may require shorter follow-up times than studies of lung function decline or progression of chest CT emphysema, although the latter may provide important anatomical insight into disease.