The role of lncRNAs in intermittent hypoxia and sleep Apnea: A review of experimental and clinical evidence.

In this narrative review, we present a comprehensive assessment on the putative roles of long non-coding RNAs (lncRNAs) in intermittent hypoxia (IH) and sleep apnea. Collectively, the evidence from cell culture, animal, and clinical research studies points to the functional involvement of lncRNAs in the pathogenesis, diagnosis, and potential treatment strategies for this highly prevalent disorder. Further research is clearly warranted to uncover the mechanistic pathways and to exploit the therapeutic potential of lncRNAs, thereby improving the management and outcomes of patients suffering from sleep apnea.

Circulating levels of miR125a, miR126, and miR146a-5p in patients with obstructive sleep apnea and their relation with markers of endothelial dysfunction.

BACKGROUND: obstructive sleep apnea (OSA) is a prevalent sleep disorder that is associated with increased risk factors for cardiovascular diseases (CVDs). Oxidative stress, insulin resistance, inflammation, and endothelial dysfunction are increased in OSA patients and microRNAs (miRs) are regulatory elements that influence these pathological mechanisms. miR125a, miR126, and miR146a-5p play a role in these pathological mechanisms and have not been evaluated in patients with OSA. METHOD: This case-control study was performed on 90 OSA patients and 34 controls. Circulating levels of miR125a, miR126, and miR146a-5 were determined using real-time PCR, and serum levels of hsCRP, ICAM-1, and VCAM-1 were evaluated using ELISA kits. RESULTS: miR125a and miR146a were elevated in patients with OSA compared to controls while miR126 decreased significantly. All three miRs indicated a remarkable difference between the mild-OSA group compared to the severe-OSA group. Furthermore, patients with OSA showed elevated levels of hsCRP, ICAM-1, and VCAM-1. Multiple linear regression indicated an independent association of miR125a with ICAM-1 and hsCRP, miR126 associated with VCAM-1 and total cholesterol, and miR146a-5p represented an association with apnea-hypopnea index and ICAM-1. Furthermore, miR146a-5p illustrated a good diagnostic ability to differentiate between OSA and controls. CONCLUSIONS: Circulating miR125a, miR126, and miR146a-5p fluctuations in patients with OSA and their relations with markers of endothelial dysfunction provide in vivo evidence and suggest a potential role for these miRs with endothelial dysfunction in patients with OSA.

The effect of continuous positive airway pressure on total antioxidant capacity in obstructive sleep apnea: a systematic review and meta-analysis.

BACKGROUND: Obstructive sleep apnea (OSA), a sleep-related disorder with high prevalence, is associated with an imbalance in oxidative stress and is linked to cardiovascular disease. There are conflicting reports regarding the effectiveness of continuous positive airway pressure (CPAP) therapy on oxidative stress/antioxidant markers in patients with OSA. This review was performed to evaluate the influence of therapy with CPAP on serum/plasma total antioxidant capacity (TAC) in patients with OSA. METHODS: The Cochrane Library, Web of Science, Scopus, Embase, and PubMed were searched through June 2022 to obtain studies evaluating CPAP treatment on TAC in patients with OSA. Overall results were tested using standardized mean difference (SMD) with a 95% confidence interval (CI). Comprehensive Meta-Analysis V2 software was employed to perform analyses. RESULTS: Ten studies with 12 effect sizes were eligible for inclusion in this analysis. The overall SMD revealed that CPAP therapy significantly increased TAC [SMD 0.497; 95% CI: 0.21 to 0.77; p: 0.00] in OSA. Analyses based on subgroups showed that the effect of CPAP therapy was significant in all subgroups according to therapy duration, age, BMI, and AHI. Whereas the meta-regression results indicated that the impact of therapy with CPAP on TAC is associated with AHI, BMI, and age in patients with OSA. CONCLUSIONS: The finding of this meta-analysis demonstrated a favorable impact of CPAP therapy on TAC levels in patients suffering from OSA.

Survival prognostic factors in patients with acute myeloid leukemia using machine learning techniques.

This paper identifies prognosis factors for survival in patients with acute myeloid leukemia (AML) using machine learning techniques. We have integrated machine learning with feature selection methods and have compared their performances to identify the most suitable factors in assessing the survival of AML patients. Here, six data mining algorithms including Decision Tree, Random Forrest, Logistic Regression, Naive Bayes, W-Bayes Net, and Gradient Boosted Tree (GBT) are employed for the detection model and implemented using the common data mining tool RapidMiner and open-source R package. To improve the predictive ability of our model, a set of features were selected by employing multiple feature selection methods. The accuracy of classification was obtained using 10-fold cross-validation for the various combinations of the feature selection methods and machine learning algorithms. The performance of the models was assessed by various measurement indexes including accuracy, kappa, sensitivity, specificity, positive predictive value, negative predictive value, and area under the ROC curve (AUC). Our results showed that GBT with an accuracy of 85.17%, AUC of 0.930, and the feature selection via the Relief algorithm has the best performance in predicting the survival rate of AML patients.

Variants of Genes Involved in Metabolism of Folate Among Patients with Breast Cancer: Association of TYMS 3R Allele with Susceptibility to Breast Cancer and Metastasis.

BACKGROUND & OBJECTIVE: Breast cancer (BC) is known to be the most prevalent cancer among women. One-carbon metabolism disturbance might play an important role in the etiology of BC. The present study aimed to investigate the thymidylate synthase (TYMS), 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR), and methionine synthase reductase (MTRR) variants as good candidates for studying the role of genetic variants of folate metabolizing enzymes in the risk of BC. METHODS: The present case-control study includes 100 BC patients and 141 healthy females. The TYMS 2R/3R (rs34743033), MTR c.2756A>G (rs1805087), and MTRR c.66A>G (rs1801394) variants were detected by polymerase chain reaction (PCR), PCR-restriction fragment length polymorphism (RFLP), and a designed amplification-refractory mutation system (ARMS) method, respectively. RESULTS: The 3R allele of TYMS enhanced the risk of BC by 2.84-fold (P<0.001). In the presence of TYMS 3R/3R, compared to TYMS 2R/3R, there was a trend toward enhancing the risk of metastasis by 4.15-fold (95% CI: 0.96-17.85, P=0.055). The frequencies of MTR c.2756A>G and MTRR c.66A>G variants were not significantly different among patients and controls. CONCLUSION: We observed that the TYMS 3R is a risk allele for susceptibility to BC and this allele may increase the risk of metastasis in BC patients. .

The clinical significance of circulating DSCAM-AS1 in patients with ER-positive breast cancer and construction of its competitive endogenous RNA network.

Long Non-Coding RNAs (lncRNAs), with diagnostic and therapeutic applications in malignancies, are newly described tumour-related molecules. Here, we reported the importance of circulating DSCAM-AS1 as the biomarker to detect Estrogen Receptor (ER)-positive breast cancer (BC) cases. Moreover, the expression of a BC-associated lncRNAs, namely DSCAM-AS1, was measured in tumoural and Paired Adjacent Non-Tumoral (PANT) tissue, as well as plasma, using Real-Time Polymerase Chain Reaction (RT-PCR). Besides, the correlations between gene expression and the clinicopathological features were analyzed. The diagnostic power of circulating DSCAM-AS1 in BC was estimated using the Area Under the Curve (AUC) value. Furthermore, we studied the DSCAM-AS1 associated with the network of competitive endogenous RNA (ceRNA) in BC using the literature review and in silico analysis. We found a significant increase in the expression levels of lncRNA in the tumour (P < 0.001) and in plasma (P < 0.001) of ER-positive BC patients. The sensitivity and specificity of DSCAM-AS1 in plasma for detection of BC from healthy controls were 100 and 97%, respectively (AUC = 0.98, P < 0.001). Accordingly, we suggest an elevated level of circulating DSCAM-AS1 as a candidate biomarker of ER-positive BC patients. Moreover, perturbation of DSCAM-AS1, as a ceRNA, acts in the tumor progression and drug resistance by affecting different cell signaling.

Circulating CYTOR as a Potential Biomarker in Breast Cancer.

Long non-coding RNAs (lncRNAs) are newly introduced as tumor-related molecules. They are being considered as potential diagnostic and therapeutic targets in cancer studies. Here, we have assessed the importance of CYTOR (linc00152) as a biomarker for the detection of breast cancer in both tumoral tissue and plasma. The relative expression of breast cancer-associated CYTOR was measured in 20 tumoral and paired margin tissues, and moreover, in 80 plasma samples by real-time-polymerase chain reaction. In addition, plasma levels of CA 15-3 were measured using the ELISA test. The receiver operating characteristic curve (ROC) was applied for assessing the sensitivity and specificity of tested biomarkers. The results of the present study disclosed significantly increases in the CYTOR expression levels in tumor tissue with relative quantitation (RQ) equals to 5.15 (P<0.001) and in plasma (RQ =3.03, P<0.01) of breast cancer patients. The area under the ROC curve (AUC) of circulating CYTOR was 0.907 (95% CI: 0.842-0.972, P<0.001), while it was 0.868 (95% CI: 0.783-0.952, P<0.001) for CA 15-3. Based on these findings, we suggest lncRNA CYTOR as a new potential biomarker for breast cancer detection in both solid tumor tissue and plasma.

NOTCH1, SF3B1, MDM2 and MYD88 mutations in patients with chronic lymphocytic leukemia.

Mutations in certain genes have been suggested to be associated with the pathogenesis of chronic lymphocytic leukemia (CLL), which is the most common leukemia in adults. In a case-control study, 100 patients with CLL and 105 healthy individuals were investigated for Notch homolog 1, translocation-associated (Drosophila) (NOTCH1) c.7544-7545delCT, recombinant splicing factor 3B subunit 1 (SF3B1) c.2098A>G, mouse double minute 2 homolog (MDM2) 40-bp insertion/deletion and myeloid differentiation primary response 88 (MYD88) L265P mutations by using allele specific-polymerase chain reaction (AS-PCR), a designed AS-PCR, PCR and PCR-restriction fragment length polymorphism methods, respectively. The presence of NOTCH1 and SF3B1 mutations were confirmed by genomic DNA sequencing. The NOTCH1 mutation was detected in 10% of patients and not detected in the control group. A higher frequency of NOTCH1 mutation was detected in patients with stage III CLL (62.5%) compared with stages 0-II CLL (37.5%) (odds ratio, 4.69-fold; 95% confidence interval, 1.0-21.9; P=0.049). The SF3B1 mutation was observed in 12% of the patients compared with 1.9% of the controls (P=0.012). The presence of MDM2 polymorphism was not associated with the risk or the stage of the disease. In addition, the MYD88 L265P mutation was not detected in the patients or the controls. The current study established the frequency of NOTCH1, SF3B1, MDM2 and MYD88 mutations in patients with CLL from the Kurdish population of Western Iran. In summary, a high frequency of NOTCH1 and SF3B1 mutations were identified in patients with CLL compared with healthy individuals, and the NOTCH1 mutation was associated with a high stage of the disease.

New insight into the role of long non-coding RNAs in the pathogenesis of preeclampsia.

OBJECTIVE: Dysregulation of lncRNAs and the absence of coordination between them could affect the normal placentation, uteroplacental circulation, and endothelial cell function. All these misfunctions can finally lead to preeclampsia. METHODS:  In the present review, we discuss current literature (till May 2018) about lncRNAs expression and function in the placenta, trophoblast cells, and decidua. RESULTS AND CONCLUSION: It is explained how altered expression of the lncRNAs and abnormal regulation of them affect the risk of preeclampsia. However, the interaction between various lncRNAs and coordinate regulation of them in health and failure of such coordinative mechanisms in diseases such as preeclampsia need to be elucidated.

Interaction of long noncoding RNA MEG3 with miRNAs: A reciprocal regulation.

The competitive endogenous RNA (ceRNA) hypothesis suggests that a long noncoding RNA (lncRNA) can function as sinks for pools of microRNAs (miRNAs); thereby, in the presence of ceRNA, messenger RNAs (mRNAs) targeted by specific miRNAs can liberate and translate to protein. Maternally expressed gene 3 (MEG3) is a lncRNA, which its expression has been detected in various normal tissues, while it is lost or downregulated in human tumors. The MEG3 is an imprinted gene which, is methylated and suppressed by DNA methyltransferases (DNMTs) family. Also, miRNAs are involved in the regulation of MEG3 gene expression. Interestingly, the lncRNA MEG3 (lnc-MEG3), as a ceRNA affects various cell processes such as proliferation, apoptosis, and angiogenesis by sponging miRNAs. These miRNAs, in turn, regulate different mRNAs in different pathways. This review focuses on the interaction between lnc-MEG3 and experimentally validated miRNAs. In addition, the discussion supplemented by some data obtained from mirPath (v.3) and TarBase (v.8) databanks to provide more details about the pathways affected by this ceRNA.

Synergistic effect of temozolomide and thymoquinone on human glioblastoma multiforme cell line (U87MG).

AIMS: Temozolomide (TMZ) is an alkylating agent used for glioblastoma multiforme (GBM) treatment. Nevertheless, resistance to TMZ is a major obstacle to successful treatment of this cancer. The aim of the present study was to investigate the effects of TMZ and thymoquinone (TQ) on U87MG cell line. MATERIALS AND METHODS: The effect of TMZ and/or TQ on viability and invasion potential of U87MG cells was evaluated using various techniques including 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, lactate dehydrogenase activity, cell invasion, migration, and adhesion assays. Enzyme-linked immunosorbent assay and polymerase chain reaction were used to study the expression and secretion of matrix metalloproteinases (MMPs). RESULTS: Combination of TMZ and TQ had a synergistic cytotoxic effect on U87MG cells. TMZ and/or TQ significantly reduced the potential of U87MG cells invasion. In addition, after treating with TMZ and/or TQ, there was a decrease in the levels of matrix matrix metalloproteinase 2 nad 9 (MMP 2 and 9) expression and secretion in U87MG cells. CONCLUSIONS: The combination of TMZ and TQ may emerge as a promising strategy for the successful treatment of GBM.

Apoptosis induction in human breast cancer cell lines by synergic effect of raloxifene and resveratrol through increasing proapoptotic genes.

AIMS: Breast cancer is the most common cancer of women. The aim of this study was to investigate the synergic effect of raloxifene (Ral) and resveratrol (Res) on apoptosis of breast cancer cell lines (MCF7 and MDA-MB-231). MAIN METHODS: Cells were treated with Ral and Res alone and in combination. Cell viability (MTT assay), apoptosis (TUNEL assay) and nitric oxide (NO) production (Griess method) were investigated. Expression of proapoptotic gene (Bax and p53), anti-apoptotic gene (Bcl2) and caspases-3, caspase -8 were evaluated. One-way ANOVA test was used for data analysis. KEY FINDINGS: The viabilities of MCF7 and MDA-MB-231 cells treated by Ral (1 µM) and Res (20 µM) decreased significantly (p = 0.000) and their synergic use showed more reduction. Nitric oxide production by MCF7 and MDA-MB-231 cells exposed upon each drug alone and in combination showing a significant reduction (p = 0.000). There was also an increase in apoptosis in the cells treated with combination use of Ral and Res in both cell lines. Moreover, reduced expression of Bcl2 and increased expression of Bax and p53 genes were observed. SIGNIFICANCE: The synergic effects of Ral and Res through increased ratio of Bcl2/Bax and expressions of p53, caspase-3 and caspase-8 genes indicating a better therapeutic effect on breast cancer cells relative to each drug alone. Combination of Res and Ral via increased expression of apoptotic genes including Bax, p53 and caspase-3 and caspase-8 is able to promote apoptosis as a mitochondrial dependent pathway in MCF7 and MDA-MB-231. The synergic effect was more potent in MCF7 estrogen receptor positive cell line.

The effect of catalase C262T gene polymorphism in susceptibility to ovarian cancer in Kermanshah province, Western Iran.

Ovarian cancer has a heterogeneous biology and behaviour. Oxidative stress can initiate chronic inflammation, which can sequentially facilitate chronic diseases, including cancer. Oxidative stress may arise when there is extra reactive oxygen species (ROS) production and/or inadequate defence mechanisms. There are some antioxidant defences that can fight against oxidative damage, including catalase (CAT) enzyme. We sought to evaluate the association of CAT C262T gene polymorphism with increased risk of ovarian cancer. A total of 74 paraffin-embedded ovarian cancer blocks were taken from the archive of Imam-Reza Hospital, Kermanshah University of Medical Sciences, between 2010 and 2014. Also, 153 blood samples were harvested from healthy volunteers. For genotyping of CAT C262T, we designed allele-specific polymerase chain reaction (AS-PCR). 'T' allele of CAT C262T showed a protective effect against the risk of ovarian cancer [OR = 0.4 (95% CI 0.25-0.6), p value <.001]. Calculating adjusted odds ratio showed the distribution of alleles and genotypes was not affected by age. The present study reported a significant association between the distribution of CAT C262T gene polymorphism and ovarian cancer for the first time in a sample of the Iranian population. Impact Statement What is already known on this subject: Ovarian cancer has a heterogeneous biology and behaviour at the clinical, cellular and molecular aspects. Ovulation releases follicular fluid containing reactive oxygen species which is related to changes in the microenvironment, such as inflammation, that could be a factor in early ovarian carcinogenesis. There are some antioxidant defences that can protect cells against oxidative damage, including catalase (CAT). Different studies investigated the relationships between CAT C262T polymorphism and several diseases. Belotte et al. ( 2015 ), for the first time, indicated no significant association between CAT C262T and the risk of ovarian cancer, while they showed this SNP is associated with poor survival and therefore may serve as a prognostic factor for ovarian cancer. What the results of this study add: In the present study, 'T' allele of CAT C262T showed a protective effect against the risk of ovarian cancer. Calculating adjusted odds ratio showed that the distribution of alleles and genotypes is not affected by age. What the implications are of these findings for clinical practice and/or further research: Pair-wise genetic analyses using SNPSTATS software showed that this genotyping was more compatible with recessive models, i.e. two copies of the associated variant are required to increase the risk of ovarian cancer. Further research about other antioxidant genes in a larger population is needed to predict the risk of ovarian cancer and survival rate of patients.

Expression Changes of Apoptotic Genes in Tissues from Mice Exposed to Nicotine

Objective: Smoking is the leading preventable cause of various diseases such as lung cancer, chronic obstructive pulmonary disease and cardiovascular disease. Nicotine, one of the major toxic components of tobacco, contributes to the pathogenesis of different diseases. Methods: Given the controversy about nicotine toxicity, the present study was conducted to determine apoptotic effects of nicotine on the heart, kidney, lung and liver of male mice. Real-time PCR was performed to identify mRNA expression changes in apoptotic-related genes between nicotine treated and control mice. Result: In the heart and lung, nicotine caused significant decrease in P53, Bax and Caspase-3 mRNA expression levels compared to the control group. However, in the kidney and liver, the result was significant increase in Bax, Caspase-2, Caspase-3 and a significant decrease in P53 mRNA expression (p<0.01). DNA fragmentation assays indicated no fragmentation in the heart and lung, but in the kidney and liver of nicotine treated mice, isolated DNA was fragmented. Conclusion: Our study provided insight into the molecular mechanisms of nicotine anti-apoptotic effects on the heart and lung as well as pro-apoptotic effects on kidney and liver via a P53-independent pathway.

Functional Promoter Polymorphisms of MMP-2 C-735T and MMP-9 C-1562T and Their Synergism with MMP-7 A-181G in Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system. Matrix metalloproteinases (MMPs) play an important role in breakdown of blood-brain barrier, transmigration, and invasion of immune cells and formation of MS lesions. The aim of present study was to investigate the influence of MMP-2 C-735T and MMP-9 C-1562T variants and their synergism with MMP-7 A-181G on susceptibility to MS. In a case-control study 125 MS patients and 235 healthy individuals from Western Iran were investigated. The various genotypes of MMP-2, MMP-9, and MMP-7 were detected using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). In females the presence of MMP-2 C allele was associated with an increased risk of MS (OR = 1.69, p = 0.041). No significant difference was detected between the frequency of MMP-9 T allele in MS patients (8.2%) and controls (12.8%, p = 0.068). The concomitant presence of both MMP-2 C and MMP-7 G alleles was associated with 1.82-fold increased risk of MS (p = 0.002). Also, a synergism was detected between MMP-9 C and MMP-7 G alleles that elevated the risk of MS by 1.5-times (p = 0.035). The presence of haplotype MMP-9 T, MMP-7 G, and MMP-2 C (TGC) compared to haplotype CAG increased the risk of MS by 3.13-fold (p = 0.16). The present study suggests that gene-gene interactions and variants of more genes instead of single gene might play a role in susceptibility to MS. We indicated that synergism between variants of MMP-2, MMP-7, and MMP-9 genes might increase the risk of MS.

Manganese superoxide dismutase (MnSOD Val-9Ala) gene polymorphism and susceptibility to gastric cancer.

BACKGROUND: Oxidative stress caused by the generation of reactive oxygen species plays an important role in human carcinogenesis. Manganese superoxide dismutase (MnSOD) Val-9Ala in the mitochondrial target sequence is the best known polymorphism of this enzyme. The purpose of the current research was to assess the association of MnSOD Val-9Ala genotypes with the risk of gastric cancer. MATERIALS AND METHODS: This case- control study covered 54 gastric cancer patients compared to 100 cancer free subjects as controls. Extraction of DNA was performed on bioptic samples and genotypes were identified with a polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: The frequencies of MnSOD Ala/Ala, Ala/Val and Val/Val genotypes in healthy individuals were 24.3, 66.7 and 9%, respectively. However, in gastric cancer patients, Ala/Ala, Ala/Val and Val/Val were observed in 24.0, 48.0 and 28.0% (p=0.01). In patients the frequency of MnSOD Val allele was higher (52%) compared to that in controls (42%). CONCLUSIONS: The results of this study show a positive association between MnSOD Val-9Ala gene polymorphism and risk of gastric cancer disease in Iranian population.

IL-1B (C+3954T) gene polymorphism and susceptibility to gastric cancer in the Iranian population.

BACKGROUND: Gastric cancer as one of the most important diseases affecting health in all worldwide. Current studies have confirmed associations of cytokine gene polymorphisms with the risk of gastric cancer development. The current research aimed to assess the association of IL-1B+3954 genotypes with the risk of gastric cancer in the Iranian population. MATERIALS AND METHODS: This case-control study covered 49 gastric cancer patients compared to 53 cancer free individuals as a control group. Genomic-DNA extraction was carried out from bioptic samples of patients and peripheral blood of healthy volunteers. Polymorphism of IL-1B +3954 genotypes were analysed with a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: The frequencies of IL-1B +3954 A1A1, A1A2 and A2A2 genotypes in healthy individuals were 26.4, 66 and 7.6 %, respectively. However, in gastric cancer patients, A1A1, A1A2 and A2A2 with 4.1, 51 and 44.9% were observed (p<0.05). CONCLUSIONS: The findings of our results show a positive association between the IL-1B+3954 genotype distribution and the risk of gastric cancer disease in the Iranian population.

Effects of p53 codon 72 and MDM2 SNP309 polymorphisms on gastric cancer risk among the Iranian population.

BACKGROUND: Development of gastric cancer (GC) is a multistep process that requires alterations in the expression of oncogenes and tumor suppressor genes, occurring over several decades. The p53 tumor suppressor protein is involved in cell-cycle control, apoptosis and DNA repair. One of the most important regulators of p53 is MDM2, which acts as a negative regulator in the p53 pathway. Based on the key role of p53 and MDM2 in tumor suppression, polymorphisms that cause change in their function might affect cancer risk. We therefore elevated associations of the polymorphisms of p53 (R72P) and MDM2 (SNP309) with GC in Iran. MATERIALS AND METHODS: A total of 104 patients with gastric cancer and 100 controls were recruited. Genomic DNA was extracted from fresh gastric samples. Genotyping of the p53 and MDM2 genes was performed using allele specific PCR (AS-PCR). RESULTS: There was no significant difference between the p53 codon 72 polymorphism distribution in control and patient groups (p=0.54), but the G allele of MDM2 was found to be over-represented in patients (p=0. 01, Odds Ratio=2. 08, 95% Confidence Interval= 1.37-4.34). CONCLUSIONS: The p53 R72P seems not to be a potential risk factor for development of GC among Iranian patients, but our data suggest that MDM2 SNP309 might modify the risk related to GC.

Helicobacter pylori infection and MDM2 SNP309 association with gastric cancer susceptibility.

AIMS: MDM2 is a negative regulator of p53, and has also been implicated in carcinogenesis. The aim of this study was to define the causal association of Helicobacter pylori infection and the MDM2 SNP309 among northern Iranian patients with gastric cancer (GC). Two hundred and eight patients with GC and 200 cancer-free controls were genotyped for MDM2 SNP309 using the polymerase chain reaction-restriction fragment length polymorphism method. The ureC (glmM) gene was used for detection of H. pylori in this study. RESULTS: The G allele was found more frequently among patients with GC (55%) than among controls (37%). The risk of GC for MDM2 309G/G genotypes was considerably increased when compared with TT genotypes (odds ratio [OR]=15.93, 95% confidence interval [CI]=4.17-60.84). Among H. pylori-infected subjects, a significantly increased risk of GC associated with the GG genotype was quite clear (OR=14.66, 95% CI=3.54-60). CONCLUSIONS: The GG genotype was associated with an increased risk of gastric carcinoma. We also found that there is a joint effect of MDM2 SNP309G/G genotype and H. pylori infection for the development of gastric carcinoma. However, the findings need to be verified in large population-based prospective studies for more rigorous analyses of subgroups and gene-environment and gene-gene interactions.