Association of Hck genetic polymorphisms with gene expression and COPD |
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Authors: | Xiaozhu Zhang Salahaddin Mahmudi-Azer John E Connett Nicholas R Anthonisen Jian-Qing He Peter D Paré Andrew J Sandford |
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Institution: | (1) 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, V6Z 1Y6;(2) Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, USA;(3) Faculty of Medicine, University of Manitoba, Winnipeg, MB, Canada |
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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. |
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Keywords: | Hck Genetic polymorphism Gene expression COPD |
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