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Title: The SERPINE2 gene is associated with chronic obstructive pulmonary disease
Authors: Dawn L. DeMeo
Thomas J. Mariani
Christoph Lange
Sorachai Srisuma
Augusto A. Litonjua
Juan C. Celedón
Stephen L. Lake
John J. Reilly
Harold A. Chapman
Brigham H. Mecham
Kathleen J. Haley
Jody S. Sylvia
David Sparrow
Avrum E. Spira
Jennifer Beane
Victor Pinto-Plata
Frank E. Speizer
Steven D. Shapiro
Scott T. Weiss
Edwin K. Silverman
Brigham and Women's Hospital
Beth Israel Deaconess Medical Center
Boston Medical Center
Caritas St. Elizabeth's Medical Center
Mahidol University
University of California, San Francisco
Channing Laboratory
Keywords: Biochemistry, Genetics and Molecular Biology;Medicine
Issue Date: 1-Jan-2006
Citation: American Journal of Human Genetics. Vol.78, No.2 (2006), 253-264
Abstract: 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 serpinel 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 SEEPINE2 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. © 2005 by The American Society of Human Genetics. All rights reserved.
ISSN: 00029297
Appears in Collections:Scopus 2006-2010

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