Association of phosphodiesterase 4D gene polymorphisms with chronic obstructive pulmonary disease: relationship to interleukin 13 gene polymorphism.

Activation of the cyclic AMP (cAMP) signaling pathway leads to the suppression of inflammation in the airways and relaxation of airway smooth muscle. Intracellular cAMP levels are determined by a balance between the activities of adenylate cyclase and phosphodiesterases. We hypothesized that polymorphisms of the phosphodiesterase 4D (PDE4D) gene activate its protein function which leads to the downregulation of cAMP, resulting in the development of chronic obstructive pulmonary disease (COPD). A case-control study was performed using Japanese (96 COPD patients and 61 controls) and Egyptians (106 COPD patients and 72 controls) to investigate the association between the polymorphisms of the PDE4D gene and the development of COPD. Genotyping of all subjects for SNP7 (dbSNP ID, rs10075508), SNP13 (rs829259) and SNP15 (rs702531) in exon 15 of the PDE4D gene was conducted. Furthermore, the distributions of haplotypes consisting of PDE4D polymorphisms and those of interleukin (IL) 4, IL13 and beta2 adrenoceptor were analyzed. The distribution of SNP13 allele frequencies of the PDE4D gene was significantly different between the COPD and control groups in the Japanese population (p = 0.041). In haplotype analysis, haplotypes composed of PDE4D SNP7 and IL13 +2044 G/A in the Japanese population showed significant difference between the patients and controls (pcorr = 0.00048). Thus, SNP13 and haplotypes, SNP7 G/A and IL13 +2044 G/A, may be useful for predicting COPD susceptibility.

[1]  L. Wollin,et al.  Roflumilast fully prevents emphysema in mice chronically exposed to cigarette smoke. , 2005, American journal of respiratory and critical care medicine.

[2]  M. Mata,et al.  Phosphodiesterase 4 inhibition decreases MUC5AC expression induced by epidermal growth factor in human airway epithelial cells , 2005, Thorax.

[3]  M. Pruniaux,et al.  Nonredundant Function of Phosphodiesterases 4D and 4B in Neutrophil Recruitment to the Site of Inflammation1 , 2004, The Journal of Immunology.

[4]  M. Kozak.  How strong is the case for regulation of the initiation step of translation by elements at the 3' end of eukaryotic mRNAs? , 2004, Gene.

[5]  K. Sekizawa,et al.  Polymorphisms of IL4, IL13, and ADRB2 genes in COPD. , 2004, Chest.

[6]  Mark Gurney,et al.  The gene encoding phosphodiesterase 4D confers risk of ischemic stroke , 2003, Nature Genetics.

[7]  D. Umetsu,et al.  PDE4D plays a critical role in the control of airway smooth muscle contraction , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[8]  R. Flavell,et al.  Interleukin-13 mediates a fundamental pathway for airway epithelial mucus induced by CD4 T cells and interleukin-9. , 2002, American journal of respiratory cell and molecular biology.

[9]  D. Corry,et al.  The Th2 lymphocyte products IL-4 and IL-13 rapidly induce airway hyperresponsiveness through direct effects on resident airway cells. , 2002, American journal of respiratory cell and molecular biology.

[10]  B. O'connor,et al.  Identification and quantification of phosphodiesterase 4 subtypes in CD4 and CD8 lymphocytes from healthy and asthmatic subjects , 2001, British journal of pharmacology.

[11]  H. Byrnes,et al.  Evaluation of Signal Transduction Pathways in Chemoattractant-Induced Human Monocyte Chemotaxis , 2001, Inflammation.

[12]  R. Pauwels,et al.  Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. , 2001, American journal of respiratory and critical care medicine.

[13]  Dirkje S Postma,et al.  Histamine airway hyper-responsiveness and mortality from chronic obstructive pulmonary disease: a cohort study , 2000, The Lancet.

[14]  D. Tilley,et al.  Expression of Phosphodiesterase 4D (PDE4D) Is Regulated by Both the Cyclic AMP-dependent Protein Kinase and Mitogen-activated Protein Kinase Signaling Pathways , 2000, The Journal of Biological Chemistry.

[15]  S. Jin,et al.  Absence of muscarinic cholinergic airway responses in mice deficient in the cyclic nucleotide phosphodiesterase PDE4D. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[16]  K. Dabbagh,et al.  IL-4 induces mucin gene expression and goblet cell metaplasia in vitro and in vivo. , 1999, Journal of immunology.

[17]  T. Torphy.  Phosphodiesterase isozymes: molecular targets for novel antiasthma agents. , 1998, American journal of respiratory and critical care medicine.

[18]  R. Bascom.  Differential susceptibility to tobacco smoke: possible mechanisms. , 1991, Pharmacogenetics.

[19]  A. Buist,et al.  Correlates of FEV1 and prevalence of pulmonary conditions in Japanese-American men. , 1988, The American review of respiratory disease.

[20]  R. Lewontin,et al.  On measures of gametic disequilibrium. , 1988, Genetics.

[21]  K. Offord,et al.  Familial prevalence of chronic obstructive pulmonary disease in a matched pair study. , 1977, The American journal of medicine.

[22]  L. Jorde,et al.  Nucleotide diversity and haplotype structure of the human angiotensinogen gene in two populations. , 2002, American journal of human genetics.

[23]  L R Cardon,et al.  Extent and distribution of linkage disequilibrium in three genomic regions. , 2001, American journal of human genetics.

[24]  M. Mäkelä,et al.  Inhibition of phosphodiesterase 4 attenuates airway hyperresponsiveness and airway inflammation in a model of secondary allergen challenge. , 2001, American journal of respiratory and critical care medicine.

[25]  P. Matricardi,et al.  Association of persistent bronchial hyperresponsiveness with beta2-adrenoceptor (ADRB2) haplotypes. A population study. , 1998, American journal of respiratory and critical care medicine.

[26]  G. Snider.  Chronic obstructive pulmonary disease: risk factors, pathophysiology and pathogenesis. , 1989, Annual review of medicine.