We investigated the association between SNPs in the SERPINE2 gene, which is a positional candidate gene for COPD susceptibility, and the risk of COPD in a Korean population. In the present study, the SNP rs16865421 and haplotypes composed of the four SNPs rs16865421, rs7583463, rs729631, and rs6734100, were significantly associated with the risk of COPD, particularly in younger individuals. This study is an important addition to previous studies that have shown an association between SERPINE2 SNPs and COPD-related phenotypes. In addition, this is the first case-control study investigating an association of SERPINE2 SNPs with the risk of COPD in an Asian population.
In the present study, the polymorphic allele frequencies of the SERPINE2
SNPs rs16865421A>G, rs7583463A>C, rs729631C>G, and rs6734100C>G among healthy Koreans were 0.15, 0.24, 0.45, and 0.21, respectively, which were similar to those of Asians quoted in the NCBI database. However, the frequencies were significantly different from those of Norwegians (0.08, 0.82, 0.84, and 0.13 respectively) (12
), Europeans (0.04, 0.83, 0.16, and 0.13, respectively) and Africans (0.17, 0.59, 0.32, and 0.03, respectively) reported in the NCBI database.
To date, three studies investigating the association of SERPINE2
SNPs and COPD-related phenotypes have been reported; however, the results have been inconsistent. DeMeo et al. (10
) evaluated the associations of 48 SERPINE2
SNPs with COPD phenotypes in both family and case-control cohorts, and found that 18 SNPs were significantly associated with quantitative and/or qualitative spirometric phenotypes in the family study of severe early-onset COPD pedigrees, and that eight SNPs (rs1438831, rs7579646, rs840088, rs7562213, rs920251, rs3795877, rs6747096, and rs3795879), including 5 SNPs (underlined), that were significant in the family-based study demonstrated a significant association with severe COPD (FEV1
of ≤45% predicted) in a case-control study of American Caucasians. In contrast, Chappell et al. (11
) reported that five SNPs (rs1438831, rs920251, rs6747096, rs3795879, ss49785625) that were significantly associated with COPD phenotypes in the family-based or case-control study conducted by DeMeo et al. (10
) were not significantly associated with the risk of COPD in a European case-control study. Furthermore, Zhu et al. (12
) investigated the association of 25 SERPINE2
SNPs with COPD phenotypes in a family-based study and a case-control study in a Norwegian population. They reported that five SNPs (rs6748795, rs7583463, rs975278, rs729631, and rs6734100) were significantly associated with the risk of COPD in the family-based study. However, in the case-control study, only the SNP rs16865421 was associated with a significantly increased risk of COPD, while the five SNPs (rs6748795, rs7583463, rs975278, rs729631, and rs6734100) were only associated with a reduction of FEV1
/VC in the COPD patients. In the current study, we examined the six SERPINE2
SNPs that were significantly associated with COPD-related phenotypes in the study conducted by Zhu et al. (12
). In concordance with their study, we found that the SNP rs16865421 was significantly associated with the risk of COPD in the present case-control study performed in a Korean population; however, the other five SNPs were not associated with the quantitative spirometric phenotypes. In addition, in contrast to the Norwegian study (12
), the SNP rs16865421 was found to be associated with a significantly decreased risk of COPD in this study.
Although it is hard to decipher the reasons for the different results across studies, particularly the conflicting association of the SNP rs16865421 with COPD, the different genetic backgrounds and environmental factors in the study populations may have been responsible for these differences. The allele and genotype frequencies of the SERPINE2
SNPs, as well as the status of LD between the SNPs, vary greatly between ethnic groups (10
). Therefore, the genetic effects of the SERPINE2
SNPs and haplotypes on the susceptibility to COPD may differ by ethnicity. In a complex polygenic disease such as COPD, it is likely that multiple genes are involved in its pathogenesis, which would result in the genetic susceptibility being dependent on the coincidence of several polymorphisms acting together. Therefore, a protective genotype in one population may increase the risk of COPD in another population due to other linked polymorphisms that exhibit stronger effects on the susceptibility to COPD. These discrepancies may be related to differences in the distribution of COPD phenotypes across studies. COPD is a heterogeneous disorder that includes obstructive bronchiolitis and emphysema. These COPD phenotypes share some similar pathophysiology, and likely share some similar genetic determinants; however, there may also be divergent underlying pathways involved in their development (20
). Therefore, it is possible that the effects of the SERPINE2
SNPs on the risk of COPD will differ according to the phenotype of COPD (19
). In addition, differences in the severity of the disease in COPD cases across different studies should be also considered. Furthermore, the SERPINE2
SNPs and haplotypes were only associated with the risk of COPD in younger individuals in the present study. This may indicate that the negative association observed in the study conducted by Chappell et al. (11
) occurred due to their study primarily consisting of older-aged patients. The inadequacies in the study design, such as nonrandom sampling, limited sample sizes and the pitfalls arising from unknown confounders, also need be considered.
The physiologic function of SERPINE2 and its role in the pathogenesis of COPD remains to be elucidated. One of the most prevailing hypotheses for the pathogenesis of COPD is the inflammatory theory, which suggests that cigarette smoke and other inhaled irritants stimulates inflammatory cells such as neutrophils, macrophages and CD8+ T cells to release a variety of mediators, oxidants and proteases. These inflammatory events then induce airways remodeling and parenchymal destruction. Based on this theory, disturbance of the balance between proteases and their inhibitors by an excess of protease or lack of inhibitor is believed to allow structural damage to the lung to occur (22
). SERPINE2 is a 43-kDa member of the serine protease inhibitor (SERPIN) superfamily that has been shown to inhibit several serine proteases, including thrombin, urokinase, and plasmin, which play important roles in inflammation and wound repair following tissue injury (24
). In addition, it has been shown that SERPINE2
gene expression is up-regulated by cytokines such as interleukin-1, tumor necrosis factor-α, and transforming growth factor-β, which play important roles in the development of COPD (26
). Taken together, these findings suggest that SERPINE2 may play a role in the pathogenesis of COPD by mediating the maintenance of the protease-antiprotease balance (10
). However, further studies must be conducted to confirm this.
In disease-gene association studies, analysis of haplotypes composed of multiple SNPs can increase the power to detect disease associations when compared with single SNP analysis due to the higher heterozygosity and tighter LD with the disease-causative variants. In addition, these analyses allow for the possibility of an ungenotyped functional variant to be in LD with the genotyped SNPs (28
). Because none of the SERPINE2
SNPs examined in the present study were located in potentially functional regions of the gene, it is likely that the association between the SNPs and COPD susceptibility may be due to LD with other functional SERPINE2
variant(s) rather than to direct functional effects of the SNPs examined. Therefore, our investigation was extended to an analysis of the SERPINE2
haplotypes composed of the four SNPs. In the haplotype analysis, ht5 was associated with a significantly decreased risk of COPD when compared to ht1 among the four haplotypes carrying the rs16865421A allele.
It is important to note that this study had several limitations. Because this study was designed to evaluate the effects of SERPINE2 SNPs on the risk of overall COPD, the stratification analyses according to age, smoking status and spirometric phenotypes might have a type I error (due to multiple comparisons) and/or a type II error (due to the small number of subjects in the subgroups). Therefore, additional studies with a larger sample sizes should be conducted to confirm our findings. Second, among several candidate SNPs in the SERPINE2 gene, only 6 intronic SNPs were examined, which obviously limit the ability to elucidate the entire effect of the SERPINE2 gene on the susceptibility to COPD. Therefore, a comprehensive evaluation of SERPINE2 SNPs and identification of functional variants are needed to better understand the role of SERPINE2 in the development of COPD.
In conclusion, this case-control study demonstrates a significant association of SERPINE2 SNPs and haplotypes with decreased risk of COPD, particularly among younger individuals. However, because this is the first case-control study investigating the associations of SERPINE2 SNPs with the risk of COPD in an Asian population, additional studies are required to confirm our findings. Moreover, further study is needed to identify functional variants of the SERPINE2 gene.