Association Analysis Of The Cyclooxygenase-2Gene Single Nucleotide Polymorphism With Chronic Obstructive Pulmonary Disease

Background Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow obstruction that is largely irreversible[1]. Cigarette smoking is an environmental factor clearly associated with chronic bronchitis and obstructive pulmonary function impairment. Smokers with increased airway responsiveness had accelerated decline in lung function [2]. The rate of decline in FEV1in long term tobacco smokers who are susceptible to tobacco smoke is3-5fold that of the normal age related decline [3,4]. Only25%of chronic tobacco smokers develop COPD[5], which indicates that there are some genetic agents that would play a role in the development and severity of COPD besides smoking[6]. Cigarette-smoke perhaps stimulate airway epithelial and immune cells in respiratory diseases to release pro-inflammatory cytokines, which up-regulates various inflammation-related genes, like cyclooxygenase-2(COX-2)[7]. COX-2is induced by proinflammatory factors. COX-2is characteristic of cells involved in inflammatory processes and is an enzyme induced by proinflammatory cytokines, growth factors as well as bacterial lipopolysaccharides [8,9]. Its reaction products cause cytotoxicity, including neurotoxicity, and even cell death [10]. One of the cell damage mechanisms induced by COX-2involves generation of free radicals during the synthesis of PGE2and other mediators of inflammation in COPD [10,11].Gene expression levels in humans are highly heritable [12,13]. Single nucleotide polymorphisms (SNP) influence gene expression [14,15]. SNP are common in the human genetic pool, and it has been demonstrated that some SNP are strongly associated with pathophysiological properties of individuals such as responses to medications and mortalities of hereditary diseases [16,17]. Polymorphism-765G/C (rs20417) in COX-2-encoding gene promoter is associated with development of depression[18], breast cancer[19], gastric cancer[20], metastases in nasopharyngeal carcinoma [21]and other tumors [22]. Additionally, tobacco smoke has been demonstrated to induce COX-2in the smokers’ lungs, which is one of the numerous potential elements of the pathogenesis [23]. Polymorphism rs20147could change the transcription factors binding to this region. The-765C allele has been shown to be associated with30%reduction in promoter activity in vitro when compared to the wild-type-765G [24]. The products of cyclooxygenase enzymatic activity play an important, although not crucial, role in the pathogenesis of COPD [25]. In COPD, a recent report has shown that this allele is more common in resistant smokers, suggesting that a decreased activity of COX-2may protect smokers against the development of COPD [26]. Interestingly, another recent report has found that carriers of CC or GC genotypes were at a significantly lower risk for COPD compared to subjects carrying the homozygous GG. Genotyping these biallelic markers may convey great potential for the identification of disease-causing genes, definition of drug targets, and establishment of markers for individual medications [27]. A question arises, whether there is an association between the-765G/C polymorphism in COX-2-encoding gene promoter and the pathogenesis of COPD.Objective To investigate the relationship between cyclooxygenase-2single nucleotide polymorphisms-765G/C (rs20417) and the susceptibility of chronic obstructive pulmonary disease in Han population of Changzhou.Methods The anticoagulated whole blood samples of138patients of COPD and83healthy people were collected with a case-control study in Han population of Changzhou. Genomic DNA was extracted from whole blood by the3S DNA isolation kit. The COX-2gene was amplified by polymerase chain reaction (PCR) and products were sequenced using the sequencer. The sequenced results were compared to the normal sequence in Genbank.Results (1)There was a significant difference between the COPD group and the control group in the frequencies of rs20417locus genotypes and alleles (P<0.05).(2) Chi square test analysis showed that there was a statistically significant difference in the relative risk of COPD in rs20417locus genotype (P<0.05), and the individuals with the C allele had a decreased susceptibility to COPD (OR=0.351,95%CI:0.142-0.867, P=0.018)Conclusions In the Chinese Han population from Changzhou, the SNP in COX-2gene may have association with the susceptibility to COPD. The individuals with the G/C genotype may decrease the susceptibility to COPD and the C allele may be protective genes of COPD.