Demeo, D. L. et al. The SERPINE2 gene is associated with chronic obstructive pulmonary disease. Am. J. Hum. Genet. 78, 253-264

Boston University, Boston, Massachusetts, United States
The American Journal of Human Genetics (Impact Factor: 10.93). 03/2006; 78(2):253-64. DOI: 10.1086/499828
Source: PubMed


Chronic obstructive pulmonary disease (COPD) is a complex human disease likely influenced by multiple genes, cigarette smoking, and gene-by-smoking interactions, but only severe alpha 1-antitrypsin deficiency is a proven genetic risk factor for COPD. Prior linkage analyses in the Boston Early-Onset COPD Study have demonstrated significant linkage to a key intermediate phenotype of COPD on chromosome 2q. We integrated results from murine lung development and human COPD gene-expression microarray studies with human COPD linkage results on chromosome 2q to prioritize candidate-gene selection, thus identifying SERPINE2 as a positional candidate susceptibility gene for COPD. Immunohistochemistry demonstrated expression of serpine2 protein in mouse and human adult lung tissue. In family-based association testing of 127 severe, early-onset COPD pedigrees from the Boston Early-Onset COPD Study, we observed significant association with COPD phenotypes and 18 single-nucleotide polymorphisms (SNPs) in the SERPINE2 gene. Association of five of these SNPs with COPD was replicated in a case-control analysis, with cases from the National Emphysema Treatment Trial and controls from the Normative Aging Study. Family-based and case-control haplotype analyses supported similar regions of association within the SERPINE2 gene. When significantly associated SNPs in these haplotypic regions were included as covariates in linkage models, LOD score attenuation was observed most markedly in a smokers-only linkage model (LOD 4.41, attenuated to 1.74). After the integration of murine and human microarray data to inform candidate-gene selection, we observed significant family-based association and independent replication of association in a case-control study, suggesting that SERPINE2 is a COPD-susceptibility gene and is likely influenced by gene-by-smoking interaction.

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    • "Yet, due to the low marker density, the identified loci are often large in size and can contain several hundreds of genes that need to be sorted through to find those that are associated with the disease. Fine-mapping procedures can eventually narrow the regions to more defined locations and potentially identify novel genes (DeMeo et al, 2006; Wilk et al, 2003). However, linkage studies lack the statistical power needed to identify genetic loci with small genetic effects that are commonly associated with complex diseases, such as COPD (Risch & Merikangas, 1996). "
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    ABSTRACT: Since the discovery of alpha-1 antitrypsin in the early 1960s, several new genes have been suggested to play a role in chronic obstructive pulmonary disease (COPD) pathogenesis. Yet, in spite of those advances, much about the genetic basis of COPD still remains to be discovered. Unbiased approaches, such as genome-wide association (GWA) studies, are critical to identify genes and pathways and to verify suggested genetic variants. Indeed, most of our current understanding about COPD candidate genes originates from GWA studies. Experiments in form of cross-study replications and advanced meta-analyses have propelled the field towards unravelling details about COPD's pathogenesis. Here, we review the discovery of genetic variants in association with COPD phenotypes by discussing the available approaches and current findings. Limitations of current studies are considered and future directions provided.
    Full-text · Article · Nov 2012 · EMBO Molecular Medicine
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    • "A genome-wide linkage analysis in the Boston Early-Onset COPD study suggested that SERPINE2 may be associated with the COPD-related phenotypes (Palmer et al., 2003; Silverman et al., 2002). Similarly, the association analysis of the family-based data showed significant association of multiple SERPINE2 single nucleotide polymorphisms (SNPs) with COPD related-phenotypes, which was confirmed by DeMeo et al. (2006) and Zhu et al. (2007) in two large European population-based association studies. Furthermore , it has been reported that polymorphisms in TGFB1 seem to be associated with COPD-related traits in European population (Hersh et al., 2006). "
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    ABSTRACT: Chronic Obstructive Pulmonary Disease (COPD) is a complex human disease which is driven not only by genetic factors, but also by various environmental variables, such as gender, age and smoking. Therefore, there is a demand for investigating the complexity among various risk factors involved in COPD. In this study, 44 tagging SNPs from EPHX1, GSTP1, SERPINE2 and TGFB1 were selected and genotyped in 310 COPD cases and 203 controls, all of which belong to the Han from North China. We integrated functional prediction algorithms of nonsynonymous SNPs (nsSNPs) into Bayesian network to explore the complex regulatory relationships among disease traits and various risk factors. The results showed that three basic variables (age, sex and smoking) were risk factors of COPD-related trait and phenotype. Besides these environmental risk factors, deleterious nsSNPs were found to perform better than those of significant synonymous SNPs when used as variables to make risk prediction of disease outcome. This study provides further evidences for detecting the complexity of COPD in Northern Chinese Han Population.
    Full-text · Article · Sep 2012 · Genes & Genetic Systems
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    • "DeMeo and associates observed that SERPINE2 was highly expressed in embryonic mouse lungs as well as in airway epithelial cells and vascular adventitia of adult human lungs. In addition, they suggest that the overexpression of SERPINE2 is associated with COPD.13 Other studies have confirmed the findings of DeMeo and colleagues. "
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    ABSTRACT: Polymorphisms of several candidate genes have been studied and associated with the development of chronic obstructive pulmonary disease (COPD). One such candidate is the SERPINE2 (Serpin peptidase inhibitor, clade E member 2) gene. To assess whether the SERPINE2 gene is associated with COPD in a Chinese Han population. Samples were collected from a Chinese Han population and analyzed for the association of single nucleotide polymor phisms (SNPs) or haplotypes of SERPINE2 gene with COPD in a case-control study. Three SNPs including rs840088 G/A in intron 1, rs1438831 A/G in 5' upstream sequence and rs3795879 G/A in intron 3 were detected using the polymerase chain reaction (PCR)-based restriction fragment length polymorphism technique in 409 COPD subjects and 411 controls. Genotyping of the SREPINE2 polymorphisms at positions rs840088, rs1438831and rs3795879 was performed. We found that none of the rs840088G/A, rs1438831G/A and rs3795879 G/A polymorphisms were associated with the disease. The p-values were 0.630, 0.208 and 0.398 respectively. Our data suggested that there was no significant association between SERPINE2 polymorphism and COPD susceptibility in the Chinese Han population.
    Full-text · Article · Nov 2011 · Yonsei medical journal
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