Through an exploratory gene-based analysis, 22 genes were identified as significantly associated with COPD susceptibility, of which PTEN was the most significant gene after accounting for multiple comparisons. PTEN rs701848 and rs1903858, which were moderately correlated, were associated with a significantly decreased risk of COPD.
PTEN, or phosphatase and tensin homolog, is an important regulator of cell cycle progression and cellular survival via the AKT signaling pathway (12
). In fact, PTEN deletion is the most common mechanism of inappropriate AKT activation in human malignancy (14
). PTEN negatively regulates the AKT pathway and is essential to homeostatis (15
). As such, AKT and PTEN expression have been observed to be inversely correlated in lung cancer tissue samples (17
). While this is the first report, to the best of our knowledge, of specific PTEN
SNPs associated with COPD, we previously reported the association between PTEN
rs1903858 and lung cancer risk, in our parallel study in Xuanwei, which utilized the same controls (18
). The inverse relationship observed in our studies between COPD and lung cancer and PTEN
rs1903858 suggests that the variant may play an important role in respiratory diseases.
Smoke-induced mutations have been hypothesized to be associated with chronic inflammation of the airways and lung that accompanies COPD (19
is one such gene that is frequently mutated or deleted in the epithelium of smokers (20
). In mice, PTEN expression play a crucial role in mediating airway inflammation and responsiveness for asthma (21
). Further, PTEN overexpression also reduced airway hyperresponsiveness in mice (22
Although smoking is an established risk factor for COPD, it was only slightly associated with increased risk of COPD in our analyses. Our results are similar to a cohort study in Xuanwei, which also observed comparable smoking habits between cases and the general population (23
). Similarly, our lung cancer studies in Xuanwei find only a slight increased risk of lung cancer associated with smoking (24
). The relatively weak effect of smoking on respiratory diseases in Xuanwei may result from the indoor air pollution levels attributed to smoky coal combustion in overwhelming the effect of tobacco smoke. Given that smoking is an established risk factor for COPD, and that smoky coal use has been associated with COPD in the cohort study in Xuanwei, it was important to explore the interactions between the significant PTEN
SNPs and these important environmental risk factors, even though the statistical power was limited (<10%).
One of the major strengths of our population-based case-control study is the high participation rates. Further, our results are biologically plausible given that PTEN
could contribute to COPD. Since the small sample size may lead to false positive and false negative findings (25
), our findings should be viewed as hypothesis-generating. However, we adjusted the gene-based analyses for multiple comparisons to minimize the possibility of spurious findings. Due to our small sample size, we had limited power to detect modest risks at low minor allele frequencies (MAFs); however, we did have ample power (>80%) to detect risks of 2.0 and 2.5 for MAFs of ≥0.3 and ≥0.1, respectively. Specific SNP associations should be cautiously interpreted until these results are replicated, since SNP associations may be attributed to another SNP in linkage disequilibrium. Although the functionality of each SNP is not known, PTEN
rs701848 is likely to alter PTEN
expression and/or function provided that it is located in the 3′ translational termination codon. Further limitations of our study pertain to generalizability. As our analysis included only Asians, the generalizability of our findings to other ethnic groups is limited. The allelic frequency variation by ethnicity in HapMap found that the T allele at rs701848 is only 56% among individuals of Asian descent, compared to 81% for African descent. Similarly, the A allele at rs1903858 is only 44% among individuals of Asian descent, compared to 73% and 58% for European and African descent, respectively. Finally, our findings may not generalize to all COPD cases since disease degree of severity was not available for our analysis; however, it is likely that our study population consists of individuals with moderate to serve COPD as they sought treatment for symptoms in a hospital setting. While some controls may have had mild undiagnosed COPD, this would have underestimated our results.
In summary, our findings provide evidence of genetic variation that may be important to COPD susceptibility. Our results implicate the cell cycle and apoptosis regulatory AKT signaling pathway, particularly PTEN. Our results should be viewed as exploratory until they are replicated in larger studies.