Male-biased association of endothelial nitric oxide synthase Asp298Glu substitution (NOS3-c.894G/T) with asthma risk and severity.

OBJECTIVE: The nitric-oxide pathway plays a crucial role in the pathogeneses of asthma and NOS3-encoded endothelial nitric oxide synthase is one of the main components of the pathway. Variants of NOS3 are known to contribute to asthma development and pathophysiology. METHODS: We investigated the association of NOS3-c.894G/T (rs1799983) with asthma risk and severity by studying frequencies of its genotypes and alleles in 555 asthmatics (93 intermittent, 240 mild, 158 moderate, and 64 severe asthma cases) and 351 control participants using the PCR-FRLP method, logistic regression analysis and generalized ordered logit estimates. RESULTS: GT genotype (ORadj: 1.39; CI: 1.04-1.85; p = 0.026), dominant model GT + TT (ORadj: 1.41; CI: 1.07-1.87; p = 0.015), and T allele (ORadj: 1.32; CI: 1.05-1.67; p = 0.018) was associated with increased ORs in asthmatics. Also, the frequency of GT + TT (ORadj: 1.55; CI: 1.01-2.38; p = 0.044) was significantly higher in males. Furthermore, GT genotype (ORadj: 1.39; CI: 1.04-1.85; p = 0.024), GT + TT (ORadj: 1.42; CI: 1.07-1.87; p = 0.014), and T allele (ORadj: 1.32; CI: 1.05-1.66; p = 0.018) in total population and GT + TT (ORadj: 1.56; CI: 1.02-2.37; p = 0.04) in males were significantly associated with increased risk of severe, moderate, mild, intermittent asthma vs. controls. Also, GT genotype (ORadj: 1.39; CI: 1.02-1.91; p = 0.039) was significantly more frequent in severe, moderate grades vs. lower severity grades in the total population. Frequencies of GT genotype (ORadj: 1.77; CI: 1.05-3.00; p = 0.032) and GT + TT (ORadj: 1.74; CI: 1.04-2.90; p = 0.036) in total population and GT genotype (ORadj: 2.40; CI: 1.16-4.97; p = 0.018) and GT + TT (ORadj: 2.30; CI: 1.12-4.74; p = 0.023) in male subpopulation were significantly higher in severe cases compared to lower grades. CONCLUSIONS: NOS3-c.894G/T may be associated with asthma risk and its severer grades, with greater effects in men.

Missense mutations involvement in COX-2 structure, and protein-substrate binding affinity: in-silico study.

Cyclooxygenase-2 (COX-2) is an inducible inflammatory enzyme, which produces prostanoids from arachidonic acid. COX-2 overexpression and over-activity can cause inflammation, tumorigenesis, and angiogenesis. Prostanoids are the main reason for the inflammation, and increase of mitogenesis by COX-2. So, any change such as mutations that can lead to COX-2 over-activity could ignite the tumor situations with increase of prostanoids production is one of its ways. The aim of this study was to check the effect of 166 missense mutations of COX-2 on protein features that can affect the COX-2 activity such as protein stability, fluctuation, 2D structure, and its binding affinity with the substrate by in silico methods, network modeling, and docking calculations, by which 44 of them shown to be deleterious. Among them, the S124I and S474F mutations can increase the stability of the protein. 11.36% of deleterious nsSNPs were part of the substrate-binding region among which the M508T, H337R, and V511G have the potential to affect the protein by 2D structure alteration. V511G can improve binding affinity and H337R showed a small decrease in the deformation overall energy that can represent a decrease in the stability of COX-2. Also, L517S showed a significant decrease in the binding power of COX-2/substrate but based on the anisotropic network modeling this mutation has a dual effect on COX-2 stability. These nsSNPs/mutations have the potential causing an increase or decrease of tumorigenesis because increasing of COX-2 stability and its binding affinity can lead to altering its activity.

PTGS2 Over-Expression: A Colorectal Carcinoma Initiator not an Invasive Factor.

BACKGROUND: Cyclooxygenase-2 (COX-2) main product is Prostaglandin E2 (PGE2) which cause mitogenesis and inflammation. COX-2 is the product of prostaglandin-endoperoxide synthase 2 (PTGS2) gene expression. COX-2 dysregulation can cause angiogenesis, differentiation, and promotion of cancer and its suppression related to control of the tumor's size, number, and cell shape. This study focused on the association of COX-2 expression with colorectal carcinoma (CRC) among Iranian patients on mRNA level and in the Cancer Genome Atlas Program (TCGA) colon and rectum RNAseq dataset, and its relation with pathological features. METHODS: PTGS2 expression was assayed by quantitative-PCR method from 90 tissue samples collected from 45 participants. The control samples come from the non-tumor area of the same patients. The data analyzed based on ΔΔCq. The PTGS2-RNAseq data extracted and analyzed by UCSC Xena browser, and its association assessed the occurrence of CRC and invasive-features. RESULTS: PTGS2 showed very significant over-expression in tumor tissues (p< 0.0001) with an N-fold expression of 2.25. But, there was not any significant association between PTGS2 and CRC invasive-pathological features such as Lymphatic, vascular and perineural invasion, the Grades of cancer, and Pathologic-M in both parts of this study. CONCLUSION: The increase in PTGS2 is related to the occurrence of CRC among patient samples. But in both part of this study, PTGS2 is not an invasive factor, and it does not affect the cell differentiation of tumors and metastasis. Based on the high N-fold for patient samples, it can be a strong candidate as a CRC initiator biomarker.

Prevalence of Null Genotypes of Glutathione S-Transferase T1 (GSTT1) and M1 (GSTM1) in Seven Iranian Populations.

BACKGROUND: Previous studies have revealed significant differences between populations for genotypic frequencies of glutathione S-transferase T1 (GSTT1) and M1 (GSTM1) polymorphisms. In order to find the frequency of the null genotypes of GSTM1 and GSTT1 in Iranian populations, the present study was carried out. METHODS: The total study subjects consisted of 1340 unrelated healthy Muslims/Iranian. From these 297, 200, 123, 168, 152, 200, and 200 individuals from Tabriz (East Azerbaijan Province; belong to Azaris), Yasuj (Kohgiluyeh-va-Boyerahmad Province; belong to Lurs), Abarku (Yazd Province; belong to Persians), Zahedan (Sistan-va-Balouchestan Province; belong to Balouchis), Zahedan (Sistan-va-Balouchestan Province; belong to Sistanis), Kermanshah (Kermanshah Province; belong to Kurds), and Gorgan (Golestan Province; belong to Turkmen) respectively. The genotypes were detected by multiplex PCR. RESULTS: The frequency of GSTM1 null genotype among Azaris, Lurs, Persians, Balouchis, Sistanis, Kurds, and Turkmen was 43.8, 50.0, 52.0, 50.0, 51.3, 56.0, and 53.0%, respectively. There was no significant difference between these populations for the genotypic distribution of the GSTM1 polymorphism (χ(2)=8.47, df=6, P=0.206). The frequency of GSTT1 null genotype among Azaris, Lurs, Persians, Balouchis, Sistanis, Kurds, and Turkmen was 18.2, 17.0, 29.3, 20.8, 17.8, 18.5, and 23.0%, respectively. There was very similarity between Azaris, Kurds and Lurs for the frequency of GSTT1 genotypes (χ(2)=0.17, df=2, P=0.916). CONCLUSION: By comparing the frequency of GSTT1 genotypes among Iranian populations, Caucasians and Asians, it is concluded that Azaris, Kurds and Lurs were similar to each other. Taken together, it is suggested that although Azaris are Turkish speaking belong to Caucasians.