Polymorphisms In DDAH1, CYP2J2 And EPHX2 Genes And Genetic Susceptibility Of Lung Cancer

Backgrounds:Lung cancer is the leading cause of cancer death in the world. Nitric oxide synthase(NOS) and nitric oxide play important role in the development of lung cancer. Asymmetricdimethylarginine (ADMA) is competitive inhibitors of NO synthesis. ADMA is extensivelymetabolized by dimethylarginine dimethylaminohydrolase 1(DDAH1), which is the majordeterminant of ADMA level. A polymorphism in DDAH1 promoter -396 GCGTinsert/delete (-396 4N I/D) has been founded, which could associated to the lung cancer.Arachidonic acid is metabolized by cytochrome P450 epoxygenases to epoxyeicosatrienoicacids (EETs), which is another vasodilator. EETs could inhibit cell apoptosis,promote human cancer metastasis and angiogenesis. CYP2J2 is a human cytochrome P450epoxygenase. The G-50T promoter polymorphism in the CYP2J2 gene was found to beindependently associated with plasma concentrations of EETs. Soluble epoxide hydrolase,encoded by the EPHX2 gene, metabolizes EETs to dihydroxy- eicosatrienoic acids, G860Apolymorphism in EPHX2 gene results in decreased enzyme activity.Objective:To investigate the association of the -396 GCGT insert/delete (-396 4N I/D) promoterpolymorphism in DDAH1 gene, G-50T promoter polymorphism of CYP2J2 gene andG860A polymorphism of EPHX2 gene with lung cancer, respectively.Methods:Four hundred and fifty-seven patients with lung cancer and 300 healthy peoples as control were collected. All the patients and control subjects provided their medical history,including age, gender, ethnic background and history of smoking. Blood of study subjectswas drawn from an arm vein into a sterile tube containing Ethylenediamine tetraacetic acid.Genomic DNA was extracted using the QG-Mini80 workflow with DB-S kit as instructed.The -396 4N I/D promoter polymorphism in DDAH1, the G-50T promoter polymorphismin CYP2J2 gene and G860A polymorphism in EPHX2 gene were detected using theTaqMan SNP Genotyping Assay, and the association between those polymorphisms andlung cancer was analyzed.Results:The allele frequency of DDAH1 promoter -396 GCGT insert in patients with lungcancer was higher significantly than that in control group (15.1% vs 11.0%, P=0.022).Smoking peoples with genotype of DDAH1 promoter -396 4N D/I or I/I had higher risk forlung cancer, compared to no-smoking peoples with genotype of -396 4N D/D (adjusted OR:6.76, 95%CI: 3.018-15.139). The allele frequency of CYP2J2 gene -50T in patients withnon-small cell lung cancer was higher significantly than that in control group (5.8% vs3.5%, P=0.042). The allele frequency of EPHX2 gene 860A in patients with small cell lungcarcinoma was lower significantly than that in control group (12% vs 21.67%, P=0.026).Logistic regression analysis showed that EPHX2 gene G860A polymorphisms wasassociated to small cell lung cancer significantly (adjusted OR: 0.374, 95%CI 0.142-0.984,P=0.046) , but not to non-small cell long cancer. However, there was no significantlyassociation between CYP2J2 gene G-50T polymorphism and lung cancer.Conclusion:The-396 4N I/D promoter polymorphism in DDAH1 gene was associated with lungcancer in smoking peoples, which suggested that this polymorphism could become apredictor of lung cancer in smoking peoples. G860A polymorphism in EPHX2 gene wasassociated to small cell lung carcinoma, which could become a predictor of small cell lungcarcinoma in high risk population.