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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.

Proteinase/antiproteinase imbalance is a widely accepted theory for the pathogenesis of COPD. Among various proteinases, matrix metalloproteinases (MMPs) digest extracellular matrix of the lung and play significant roles in the development of COPD. Polymorphisms of an MMP that upregulate its activity may result in the degradation of the lung matrix. A case-control study was performed to investigate the association of polymorphisms of the MMP14 gene with COPD. Japanese subjects (96 COPD patients and 61 controls) and Egyptian subjects (106 COPD patients and 72 controls) were recruited. Each subject was genotyped for seven single nucleotide polymorphisms (SNPs) of the MMP14 gene; -165 G/T and -72 G/A in the promoter region, +221 C/T in exon 1, +6727 C/G and +6767 G/A in exon 5, +7096 T/C in exon 6, and +8153 G/A in exon 8. The distributions of the genotype frequencies of these SNPs were not significantly different between the COPD patients and the controls in either ethnic group after correction of multiple comparisons. In the haplotype analysis, however, the haplotype -165 T : +221 T : +6727 C : +7096 C had a significantly higher frequency in the Egyptian COPD group than the control group (pcorr = 0.0063). The haplotype of the MMP14 gene, -165 T : +221 T : +6727 C : +7096 C, might be involved in the pathogenesis of COPD.

It is recognized that genetic factors play a role in the susceptibility to COPD. COPD is characterized by airflow limitation. Chronic inflammation causes small airway disease and parenchymal destruction, leading to the airflow limitation. Polymorphisms in pro-inflammatory cytokine genes may confer a risk for the development of COPD. A case-control association study was performed in Japanese population (88 COPD patients and 61 controls) and Egyptian population (106 patients and 72 controls). Genotype and allele frequencies of the TNFalpha -308 G/A and +489 G/A polymorphisms, the IL1beta -511 C/T, -31 T/C, and +3954 C/T polymorphisms, and a VNTR polymorphism in intron 2 of the IL1RN gene were investigated. In addition, pairwise haplotype frequencies were analyzed. When studied independently, none of the polymorphisms were associated with the development of COPD in both populations. However, in the Egyptian population, the distributions of the haplotype (IL1beta -31 T/C : IL1beta +3954 C/T) were significantly different between the COPD patients and the controls (p(corr)=0.0037). Our findings suggest that this haplotype within the IL1beta gene may be involved in the pathogenesis of COPD and that the genetic factors of COPD susceptibility might be different between different populations.

Proteinase/antiproteinase imbalance is recognized to play an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). A relative increase in the activities of matrix metalloproteinases might be caused by mutations of tissue inhibitor of metalloproteinase2 (TIMP2). Recently, two polymorphisms of the TIMP2 gene, +853 G/A and -418 G/C (+551 and -720 from the translation initiation site), have been shown to be associated with the development of COPD in the Japanese population. In this study, a case-control association analysis for these polymorphisms was conducted in the Egyptian population using 106 COPD patients and 72 healthy controls. The genotype frequency of +853 G/A was significantly different between the patient and the control groups (P = 0.029), although no significant difference was detected in the allele frequency between the two groups. These results suggest that the +853 G/A polymorphism of the TIMP2 gene might be associated with COPD across ethnicities. In contrast, neither the distributions of genotype nor allele frequencies of -418 G/C were significantly different between the two groups, raising the possibility that a combination of different genetic factors contributes to the development of COPD in different ethnic groups.

Study Objectives: Interleukin (IL)-4, IL-13, and beta(2)-adrenoceptor (ADRB2) are involved in airway hyperresponsiveness (AHR), and their coding genes are located on chromosome 5q31-q33. AHR is one of the risk factors for COPD. Investigating polymorphisms within these genes may help to pinpoint the genetic susceptibility to COPD., Subjects and Measurements: A case-control association study was conducted on two different ethnic groups: Japanese subjects (88 patients with COPD and 61 control subjects) and Egyptian subjects (106 patients with COPD and 72 control subjects). The following polymorphisms were genotyped: - 589 C/T, - 33 C/T, and variable number of tandem repeat (VNTR) in IL4, - 1111 C/T and + 2044 G/A in IL13, and + 46 A/G and + 79 C/G in ADRB2. Pairwise haplotype frequencies as well as genotype and allele frequencies were analyzed., Results: The distribution of the genotype frequencies of ADRB2 + 79 C/G was significantly different between the COPD and the control groups in the Egyptians (p = 0.002). The distributions of the haplotypes in the Japanese (IL4 - 589 C/T: IL4 VNTR; IL4 - 33 C/T: IL4 VNTR) [corrected p values < 0.001 and 0.022, respectively], and those in the Egyptians (IL4 - 589 C/T: ADRB2 + 79 C/G; IL4 VNTR: ADRB2 + 79 C/G) [corrected p values, 0.033 and 0.001, respectively] showed significant differences between the COPD and the control groups., Conclusions: The ADRB2 + 79 C/G polymorphism and the haplotypes shown in this study may be involved in the pathogenesis of COPD.