title: The SERPINE2 gene is associated with chronic obstructive pulmonary disease.
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 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.
authors.affiliation: Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA. dawn.demeo@channing.harvard.edu
authors.forename: Dawn L
authors.initials: DL
authors.lastname: Demeo
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Mariani
authors.forename: Christoph
authors.initials: C
authors.lastname: Lange
authors.forename: Sorachai
authors.initials: S
authors.lastname: Srisuma
authors.forename: Augusto A
authors.initials: AA
authors.lastname: Litonjua
authors.forename: Juan C
authors.initials: JC
authors.lastname: Celedon
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Lake
authors.forename: John J
authors.initials: JJ
authors.lastname: Reilly
authors.forename: Harold A
authors.initials: HA
authors.lastname: Chapman
authors.forename: Brigham H
authors.initials: BH
authors.lastname: Mecham
authors.forename: Kathleen J
authors.initials: KJ
authors.lastname: Haley
authors.forename: Jody S
authors.initials: JS
authors.lastname: Sylvia
authors.forename: David
authors.initials: D
authors.lastname: Sparrow
authors.forename: Avrum E
authors.initials: AE
authors.lastname: Spira
authors.forename: Jennifer
authors.initials: J
authors.lastname: Beane
authors.forename: Victor
authors.initials: V
authors.lastname: Pinto-Plata
authors.forename: Frank E
authors.initials: FE
authors.lastname: Speizer
authors.forename: Steven D
authors.initials: SD
authors.lastname: Shapiro
authors.forename: Scott T
authors.initials: ST
authors.lastname: Weiss
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Silverman
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D008040:Genetic Linkage; D006239:Haplotypes; D006801:Humans; D007150:Immunohistochemistry; D008126:Lod Score; D008168:Lung / Q000737:chemistry / Q000473:pathology; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D058255:Protease Nexins; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics* / Q000473:pathology; D011956:Receptors, Cell Surface / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D058258:Serpin E2; D012907:Smoking
chemical_list: D016564:Amyloid beta-Protein Precursor; D058255:Protease Nexins; D011956:Receptors, Cell Surface; C545486:SERPINE2 protein, human; D058258:Serpin E2