title: Association of Hck genetic polymorphisms with gene expression and COPD.
abstract: Polymorphonuclear leukocytes (PMNs) are major effector cells in the chronic airway inflammation in chronic obstructive pulmonary disease (COPD). PMN degranulation is associated with degradation of extracellular matrix and tissue damage. Hck is an essential molecule in the signaling pathway regulating PMN degranulation. We hypothesized that polymorphisms affect the expression level of Hck, which, in turn, modulates PMN mediator release and tissue damage and influences the development of COPD. Here we systematically investigated genetic tag polymorphisms of the Hck gene, Hck mRNA and protein expression pattern in PMNs, and PMN mediator release (myeloperoxidase) in 60 healthy white subjects, and assessed their association with the use of several genetic models. The association of genetic polymorphisms with COPD-related phenotypes was determined in the lung healthy study cohort (LHS). We identified a novel 15 bp insertion/deletion polymorphism (8,656 L/S) in intron 1 of the Hck gene, which was associated with differential expression of Hck protein and PMN myeloperoxidase release. In the LHS cohort, there was significant interaction between the 8,656 L/S polymorphism and smoking on baseline lung function and 8,656 L/S was associated with bronchodilator response. These data suggest that the insertion/deletion polymorphism could be a functional polymorphism of the Hck gene, may contribute to COPD pathogenesis and modify COPD-related phenotypes.
authors.affiliation: James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research , St. Paul's Hospital, University of British Columbia, 1081 Burrard Street, Room 166, Vancouver, BC, Canada.
authors.forename: Xiaozhu
authors.initials: X
authors.lastname: Zhang
authors.forename: Salahaddin
authors.initials: S
authors.lastname: Mahmudi-Azer
authors.forename: John E
authors.initials: JE
authors.lastname: Connett
authors.forename: Nicholas R
authors.initials: NR
authors.lastname: Anthonisen
authors.forename: Jian-Qing
authors.initials: JQ
authors.lastname: He
authors.forename: Peter D
authors.initials: PD
authors.lastname: Paré
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Sandford
mesh_terms: D000328:Adult; D004252:DNA Mutational Analysis; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D016254:Mutagenesis, Insertional; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D051572:Proto-Oncogene Proteins c-hck / Q000235:genetics* / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion
chemical_list: D012333:RNA, Messenger; C496631:HCK protein, human; D051572:Proto-Oncogene Proteins c-hck