Publications by authors named "Abdolreza Daraei"

27 Publications

  • Page 1 of 1

Perturbation of miR-146b and relevant inflammatory elements in esophageal carcinoma patients supports an immune downregulatory mechanism.

Pathol Res Pract 2021 Sep 20;225:153560. Epub 2021 Jul 20.

Women's Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address:

Background: Esophageal Cancer is known as one of the deadliest cancers worldwide with the squamous cell carcinoma (ESCC) being the predominant subtype. There is a growing body of evidence linking the dysregulated microRNA (miRNA) pathway of immune cells to the progression of several tumors. In a previous study, we investigated molecular alterations pertaining to miR-146a and some components of NF-kB signaling pathway and proposed a possible immune downregulatory mechanism in peripheral blood mononuclear cells (PBMCs) of ESCC patients. Here, we further scrutinized other components of this pathway by evaluating PBMC levels of miR-146b, TLR4, IL10, and TNFA.

Methods: Gene expressions were quantified using RT-qPCR assays. To prevent the vulnerability of results to the expression instability of reference genes, nine additional transcripts were quantified, and stable reference genes for normalizing qPCR data were identified using the NormFinder and the geNorm algorithms. The efficiency-corrected normalized relative quantity values were used to compare gene expressions among study groups.

Results: The PBMC expression of miR-146b and TNFA was downregulated in ESCC patients as compared to healthy subjects. While the level of TLR4 was not different among the study groups, the PBMC level of IL10 was upregulated in ESCC patients. Logistic regression analyses coupled with the ROC curve and cross-validation analysis suggested that PBMC expression may serve as potential candidate biomarker for discriminating ESCC patients from healthy subjects.

Conclusion: The present findings, in line with our previous report, propose a particular gene expression pattern in PBMCs of ESCC patients, providing evidence in support of an immune downregulatory mechanism.
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http://dx.doi.org/10.1016/j.prp.2021.153560DOI Listing
September 2021

Critical roles of microRNA-196 in normal physiology and non-malignant diseases: Diagnostic and therapeutic implications.

Exp Mol Pathol 2021 Jun 21;122:104664. Epub 2021 Jun 21.

Women's Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address:

MicroRNAs (miRNAs) have emerged as a critical component of regulatory networks that modulate and fine-tune gene expression in a post-transcriptional manner. The microRNA-196 family is encoded by three loci in the human genome, namely hsa-mir-196a-1, hsa-mir-196a-2, and hsa-mir-196b. Increasing evidence supports the roles of different components of this miRNA family in regulating key cellular processes during differentiation and development, ranging from inflammation and differentiation of stem cells to limb development and remodeling and structure of adipose tissue. This review first discusses about the genomic context and regulation of this miRNA family and then take a bird's eye view on the updated list of its target genes and their biological processes to obtain insights about various functions played by members of the microRNA-196 family. We then describe evidence supporting the involvement of the human microRNA-196 family in regulating critical cellular processes both in physiological and non-malignant inflammatory conditions, highlighting recent seminal findings that carry implications for developing novel therapeutic or diagnostic strategies.
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http://dx.doi.org/10.1016/j.yexmp.2021.104664DOI Listing
June 2021

Novel SCN5A variants identified in a group of Iranian Brugada syndrome patients.

Funct Integr Genomics 2021 Jul 27;21(3-4):331-340. Epub 2021 Feb 27.

Department of Cancer Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Isar 11 St, Babol, 47138-18983, Iran.

Brugada syndrome (BrS) is a rare hereditary arrhythmia syndrome that increases an individual's risk for sudden cardiac death (SCD) due to ventricular fibrillation. This disorder is regarded as a notable cause of death in individuals aged less than 40 years, responsible for up to 40% of sudden deaths in cases without structural heart disease, and is reported to be an endemic in Asian countries. Mutations in SCN5A are found in approximately 30% of patients with Brugada syndrome. This study aimed to investigate mutations in the SCN5A gene in a group of Iranian Brugada syndrome patients. Nine probands (n = 9, male, mean age = 39) diagnosed with Brugada syndrome were enrolled in this study. Exon 2 to 29 were amplified by PCR and subjected to direct sequencing. Eight in silico prediction tools were used to anticipate the effects of non-synonymous variants. Seven known polymorphisms and 2 previously reported disease-causing mutations, including H558R and G1406R, were found in the studied cases. Twenty novel variants were identified: 15 missense, 2 frameshift, 2 synonymous, and one nonsense variants. In silico tools predicted 11 non-synonymous variants to have damaging effects, whereas frameshift and nonsense variants were considered inherently pathogenic. The novel variants identified in this study, alongside previously reported mutations, are highly likely to be the cause of the Brugada syndrome phenotype observed in the patient group. Further analysis is required to understand the physiological effects caused by these variants.
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http://dx.doi.org/10.1007/s10142-021-00778-9DOI Listing
July 2021

A methylation signature at the CpG island promoter of estrogen receptor beta (ER-β) in breasts of women may be an early footmark of lack of breastfeeding and nulliparity.

Pathol Res Pract 2021 Feb 28;218:153328. Epub 2020 Dec 28.

Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

Although little is known regarding the mechanisms behind the onset of breast cancer (BC) through reproductive risk factors, new researches have highlighted some early tumor-related methylation footmarks in the breast tissue of apparently clinically healthy women as their potential epigenetic mechanism. Previous evidence supports that the estrogen receptor beta (ER-β), whose anti-cancer roles had already been revealed in BC, is downregulated in the breasts of healthy nulliparous women. Nevertheless, data on such a link about its methylation alterations have not been reported. The goal of current study was to determine possible methylation alterations at CpG island promoter of the ER-β gene, including promoter 0 N and exon 0 N, in relation to aspects of reproductive history in the healthy breasts. The DNA was extracted from the breasts of 120 subjects undergoing cosmetic mammoplasty. Thereafter, the methylation levels of targeted regions in ER-β gene were determined by using MeDIP-qPCR assay. The results revealed that ER-β exon 0 N had no methylation in 84.2 % of the women, whereas the rest, comprising 2.5 % and 13.3 % of the samples, showed a lower and higher of its methylation, respectively. Interestingly, nulliparous women were found to have an elevated methylation level of the ER-β exon 0 N than parous women (P = 0.036). Moreover, we observed a high methylation of the ER-β exon 0 N in the breasts of non-breastfeeding women compared to breastfeeding subgroup (P = 0.048). Likewise, the non-breastfeeding subgroup showed exon 0N high methylation in comparison to women with breastfeeding >24 months (P = 0.023). Finally, although we found that 6.67 % of the samples had a high methylation level at the promoter 0N, no any relationship was found between its methylation and reproductive history. These results may provide key clues to revealing the epigenetic mechanism through which the nulliparity and lack of breastfeeding influencing the risk factor of BC as well as introducing the potential new early prediction and prevention strategies. Although further investigations need to be done in order to gain a better understanding the roles of these epigenetic signatures.
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http://dx.doi.org/10.1016/j.prp.2020.153328DOI Listing
February 2021

Toll-Like Receptor (TLR)-9 rs352140 Polymorphism is an Immunopathology Protective Factor in Parkinson's Disease in the Northern Iranian Population.

Iran J Immunol 2020 12;17(4):313-323

Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran.

Background: Neuroinflammation and immunopathology in Parkinson's disease (PD) are believed to be associated with genetic and environmental factors.

Objective: We conducted the current study to evaluate the Toll-like receptors (TLR4 and TLR9) genes polymorphism in patients with Parkinson's disease in northern Iran.

Methods: We extracted DNA from peripheral blood samples of 100 sporadic cases of Parkinson's disease and 100 healthy-matched controls with the mean age of 69.98 and 71.94 years, respectively. Subsequently, single-nucleotide polymorphisms (SNPs) of TLR4 and TLR9 were genotyped using restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR). Results were confirmed employing Sanger sequencing. For the analysis of our data, we used SNPStats and SPSS 22 software.

Results: Our findings indicated that the allele distribution for rs352140 of TLR9 gene was significantly different in the PD group compared with the healthy controls (p=0.02). Moreover, rs352140 T allele was observed to be correlated with PD reduced risk (TT + TC vs. CC). The dominant rs352140 model was approved as the most acceptable inheritance model for fitting the data (OR 0.41, 95% CI 0.23-0.75, p=0.0031). Additionally, haplotype analysis revealed a significant correlation between TLR9 polymorphisms and Parkinson's disease.

Conclusion: The results of this study indicated that rs352140T of TLR9 gene was a protective factor in Parkinson's disease. Furthermore, this SNP could be regarded as a prognostic factor. However, this conclusion should be confirmed by further investigations.
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http://dx.doi.org/10.22034/iji.2020.87454.1803DOI Listing
December 2020

Dysregulated Expression of miR-146a and Its Associated Immune Effectors in Peripheral Blood Mononuclear Cells of Esophageal Carcinoma Patients.

Immunol Invest 2020 Oct 2:1-11. Epub 2020 Oct 2.

Women's Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

Esophageal cancer is one of the least studied aggressive tumors, with the squamous cell carcinoma (ESCC) being the most frequent histological type around the world. Growing evidence has shown that the abnormal expression of microRNAs (miRNAs) in peripheral blood mononuclear cells (PBMCs) is closely related to the pathogenesis of cancers. MiR-146a is a crucial regulator of inflammatory cascades. There is currently no data available regarding the possible role of miR-146a in PBMCs of ESCC patients. We evaluated the expression of miR-146a, as well as its target genes (IRAK1 and TRAF6) and its associated immune effectors (NF-κB1, IL1B, and IL6) in PBMCs of 40 ESCC patients and 50 control subjects. The geometric mean expression of five transcripts was used for normalizing expressions. The PBMC level of miR-146a, as measured by RT-qPCR, was upregulated, whereas levels of its target genes, IRAK1 and TRAF6, were downregulated in ESCC patients. NF-κB1 and IL6 was downregulated in PBMCs of ESCC patients. There was no difference in terms of the IL1B level between patients and the control group. Logistic regression and receiver operating characteristic curve analysis suggested that a model with PBMC levels of either NF-κB1+ IL6 or NF-κB1+ miR-146a as predictors may discriminate ESCC patients from subjects of the control group. Our findings, in the context of the current literature, may suggest a possible downregulatory mechanism of immune responses in PBMCs of ESCC patients.
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http://dx.doi.org/10.1080/08820139.2020.1828454DOI Listing
October 2020

Peripheral Blood Mononuclear Cells Expression Levels of miR-196a and miR-100 in Coronary Artery Disease Patients.

Immunol Invest 2020 Sep 15:1-11. Epub 2020 Sep 15.

Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

As a chronic inflammatory disease, coronary artery disease (CAD) is a common cause of death worldwide. Dysregulation of microRNA expression levels in peripheral blood mononuclear cells (PBMCs) may contribute to CAD and serve as a potential diagnostic biomarker. Here, we evaluated PBMC expression of two CAD-related inflammatory miRNAs, miR-196a and miR-100, in PBMCs of CAD patients with significant stenosis (CAD, n: 72), patients with insignificant coronary stenosis (ICAD, n: 30), and controls (n: 74) and checked whether they can segregate study groups. MiRNA expression was evaluated using the standard stem-loop RT-qPCR method. MiR-196a expression was downregulated in ICAD compared to CADs and healthy groups. MiR100 expression levels were not different between groups. The receiver operating characteristic (ROC) curve analysis acquainted that miR-196a expression levels in PBMC could segregate CAD individuals or any of its clinical manifestations (i.e. unstable angina, stable angina, acute myocardial infarction) from ICADs. In conclusion, this study reported a distinct miR-196a expression pattern in PBMCs of all patient groups and recommended a biomarker potential for miR-196a in discriminating ICADs from CADs or healthy controls.
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http://dx.doi.org/10.1080/08820139.2020.1791177DOI Listing
September 2020

Expression and clinicopathological significance of AOC4P, PRNCR1, and PCAT1 lncRNAs in breast cancer.

Pathol Res Pract 2020 Oct 21;216(10):153131. Epub 2020 Jul 21.

Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

Long none coding RNAs (lncRNAs) AOC4P, PRNCR1, and PCAT-1 are dysregulated in various types of malignancies. However, their expression and clinicopathological significances are uncertain in breast cancer (BC). Quantitative real-time polymerase chain reaction (RT- qPCR) was used to measure the expression levels of the selected lncRNAs in tumor tissues obtained from 50 BC patients compared to the normal adjacent tissues (NATs) and 50 clinically healthy normal tissues. Our results revealed a significant downregulation of AOC4P, however, upregulated PRNCR1 and PCAT1 were found in tumor tissues compared to NATs and clinically healthy normal tissues (P < 0.05). Interestingly, remarkable decreased expression of AOC4P was observed in NATs than clinically healthy normal tissues. Dysregulation of the lncRNAs was correlated with worse outcomes of patients. Furthermore, our data showed that the altered expression levels of lncRNAs AOC4P, PRNCR1, and PCAT1 might be occurred through the function of demographic and reproductive variables. Taken together, the altered regulation of AOC4P, PRNCR1, and PCAT1 may highlight their crucial roles in BC development and pathogenesis. Our findings also proposed demographic and reproductive variables as risk factors in BC through the possible influence on the expression of the studied lncRNAs. Nevertheless, further explorations are required to elucidate the more detailed functions of these lncRNAs in BC.
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http://dx.doi.org/10.1016/j.prp.2020.153131DOI Listing
October 2020

Evidences from a Systematic Review and Meta-Analysis Unveil the Role of MiRNA Polymorphisms in the Predisposition to Female Neoplasms.

Int J Mol Sci 2019 Oct 14;20(20). Epub 2019 Oct 14.

Women's Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz 5138663134, Iran.

Breast (BCa) and gynecological (GCa) cancers constitute a group of female neoplasms that has a worldwide significant contribution to cancer morbidity and mortality. Evidence suggests that polymorphisms influencing miRNA function can provide useful information towards predicting the risk of female neoplasms. Inconsistent findings in the literature should be detected and resolved to facilitate the genetic screening of miRNA polymorphisms, even during childhood or adolescence, and their use as predictors of future malignancies. This study represents a comprehensive systematic review and meta-analysis of the association between miRNA polymorphisms and the risk of female neoplasms. Meta-analysis was performed by pooling odds-ratios (ORs) and generalized ORs while using a random-effects model for 15 miRNA polymorphisms. The results suggest that miR-146a rs2910164 is implicated in the susceptibility to GCa. Moreover, miR-196a2 rs11614913-T had a moderate protective effect against female neoplasms, especially GCa, in Asians but not in Caucasians. MiR-27a rs895819-G might pose a protective effect against BCa among Caucasians. MiR-499 rs3746444-C may slightly increase the risk of female neoplasms, especially BCa. MiR-124 rs531564-G may be associated with a lower risk of female neoplasms. The current evidences do not support the association of the remaining polymorphisms and the risk of female neoplasms.
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http://dx.doi.org/10.3390/ijms20205088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834313PMC
October 2019

Dysregulated expression of STAT1, miR-150, and miR-223 in peripheral blood mononuclear cells of coronary artery disease patients with significant or insignificant stenosis.

J Cell Biochem 2019 12 18;120(12):19810-19824. Epub 2019 Jul 18.

Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Coronary artery disease (CAD) is a multicellular disease characterized by chronic inflammation. Peripheral blood-mononuclear cells (PBMCs), as a critical component of immune system, actively cross-talk with pathophysiological conditions induced by endothelial cell injury, reflecting in perturbed PBMC expression. STAT1 is believed to be relevant to CAD pathogenesis through regulating key inflammatory processes and modulating STAT1 expression play key roles in fine-tuning CAD-related inflammatory processes. This study evaluated PBMC expressions of STAT1, and its regulators (miR-150 and miR-223) in a cohort including 72 patients with CAD with significant ( ≥ 50%) stenosis, 30 patients with insignificant ( < 50%) coronary stenosis (ICAD), and 74 healthy controls, and assessed potential of PBMC expressions to discriminate between patients and controls. We designed quantitative real-time polymerase chain reaction (RT-qPCR) assays and identified stable reference genes for normalizing PBMC quantities of miR-150, miR-223, and STAT1 applying geNorm algorithm to six small RNAs and five mRNAs. There was no significant difference between CAD and ICAD patients regarding STAT1 expression. However, both groups of patients had higher levels of STAT1 than healthy controls. miR-150 and miR-223 were differently expressed across three groups of subjects and were downregulated in patients compared with healthy controls, with the lowest expression levels being observed in patients with ICAD. ROC curves suggested that PBMC expressions may separate between different groups of study subjects. PBMC expressions also discriminated different clinical manifestations of CAD from ICADs or healthy controls. In conclusion, the present study reported PBMC dysregulations of STAT1, miR-150, and miR-223, in patients with significant or insignificant coronary stenosis and suggested that these changes may have diagnostic implications.
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http://dx.doi.org/10.1002/jcb.29286DOI Listing
December 2019

Expression pattern of miR-21, miR-25 and PTEN in peripheral blood mononuclear cells of patients with significant or insignificant coronary stenosis.

Gene 2019 May 6;698:170-178. Epub 2019 Mar 6.

Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran. Electronic address:

Coronary artery disease (CAD) is primarily caused by atherosclerosis, which is a series of chronic inflammatory processes leading to the initiation and progression of vascular endothelial cell injury enhancing plaque formation. As critical components of the immune system, peripheral blood mononuclear cells (PBMCs) actively cross-talk with pathophysiological conditions induced by endothelial cell injury, reflecting in altered PBMC expression pattern. This study explored PBMC expression levels of miR-21, miR-25 and PTEN in patients with angiographically proven significant coronary stenosis (the CAD group), patients with insignificant coronary stenosis (the ICAD group) and healthy subjects, and assessed potentials of PBMC expressions in discriminating groups of study subjects. In-silico analysis was also performed to obtain insights into CAD-related pathways and biological processes that may be influenced by altered miRNA expressions. A reduced level of PBMC miR-21 was observed in the ICAD group compared to the CAD group (P: 0.004) or healthy controls (P: 0.0001). PBMC miR-21 level was negatively correlated with the PTEN expression (Spearman r: -0.43, P: 3.9e-09). The PTEN expression was increased in the CAD or ICAD group compared to the control group (CAD vs. controls P: 0.0003, ICAD vs. controls P: 0.03). A stepwise increase in PBMC miR-25 levels was observed from healthy controls to ICADs and CAD patients (Kruskal-Wallis P: 7.68e-12). PBMC gene expressions had reasonable power to discriminate between pairs of study groups. PBMC miR-21 levels were able to discriminate ICADs from both CADs and controls and miR-25 levels had potentials to differentiate among all pairs of study groups (i.e. CADs-ICADs, CADs-controls, CADs-all other subjects, ICADs-controls). PBMC PTEN expression was able to discriminate patients with CAD or ICAD from control subjects. Overrepresentation enrichment analysis of experimentally validated targets of miR-21 and miR-25 highlighted key biological processes and pathways, such as "angiogenesis" and "leukocyte cell-cell adhesion", that may be influenced by dysregulation of PBMC miR-21 and miR-25. In conclusion, these findings suggest that patients with insignificant coronary stenosis may have a distinct PBMC miRNA expression profile than those with significant stenosis or healthy controls.
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http://dx.doi.org/10.1016/j.gene.2019.02.074DOI Listing
May 2019

Methylation of progesterone receptor isoform A promoter in normal breast tissue: An epigenetic link between early age at menarche and risk of breast cancer?

J Cell Biochem 2019 08 28;120(8):12393-12401. Epub 2019 Feb 28.

Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Emerging evidence indicates that some altered patterns of methylation that occur in breast tumors may also be found in breast tissue of healthy women in relation to the breast cancer (BC) risk factors. Progesterone receptor (PR) isoform α is a crucial regulator of breast hormone responsiveness and its hypermethylation plays an important role in the initiation and development of breast tumors. However, such a methylation change in healthy women and its link with the different risk factors has not yet been investigated. In the present study, we aimed to examine the relationship of possible methylation changes within a critical region in the promoter CpG island of PGR-α (progesterone receptor α) gene in the healthy women with a set of reproductive and nonreproductive BC risk factors. The breast tissues were collected from 120 cancer-free women who had undergone cosmetic mammoplasty. The genomic DNA was extracted from the breast tissues and the methylation level of PGR-α promoter CpG island was determined by using MeDIP-qPCR assay. Using regression analysis, we found that increasing menarche age is inversely associated with the high methylation of PGR-α promoter ( β = -0.790, SE = 0.362; P = 0.031). Although lactating women had more methylation than nonlactating women (P = 0.026, the t test), this result was not confirmed by regression models. Such an observation may be helpful in better understanding of the underlying mechanisms by which early age at menarche increases the risk of BC. However, this perspective requires further validations in larger studies of more subjects as well as the inclusion of other related genes.
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http://dx.doi.org/10.1002/jcb.28505DOI Listing
August 2019

The intricate role of miR-155 in carcinogenesis: potential implications for esophageal cancer research.

Biomark Med 2019 02 23;13(2):147-159. Epub 2019 Jan 23.

Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

MiRNAs have immerged as essential modulators of key cellular procuresses involved in post-transcriptional regulation of the human transcriptome. They are essential components of complex regulatory networks that modulate most important physiological functions of cells. MicroRNA-155 (miR-155) is a multifaceted regulator of cell proliferation, cell cycle, development, immunity and inflammation that plays pivotal, and sometimes contradictory, roles in numerous cancers including esophageal cancer. Here, we review the intricate role of miR-155 in cancer by exemplifying carcinogenesis of various tumors, focusing on recent findings that may provide a link between miR-155 and esophageal cancer-related pathways.
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http://dx.doi.org/10.2217/bmm-2018-0127DOI Listing
February 2019

miRNA Polymorphisms and Risk of Cardio-Cerebrovascular Diseases: A Systematic Review and Meta-Analysis.

Int J Mol Sci 2019 Jan 12;20(2). Epub 2019 Jan 12.

Women's Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz 5138663134, Iran.

Recently extensive focus has been concentrated on the role of miRNAs in the initiation and progression of cardio-cerebrovascular diseases (CCDs) which constitute a range of conditions including cardiovascular diseases (CVDs, especially coronary artery disease (CAD)), congenital heart disease (CHD) and cerebrovascular diseases (CBVDs, especially the ischemic stroke (IS)). An increasing number of studies are evaluating the association between different miRNA polymorphisms and risk of CCDs, but results have been inconclusive. This study represents a comprehensive systematic review and meta-analysis of the association between miRNA polymorphisms and risk of CCDs. PubMed, Embase, Scopus, and Web of Science were queried to identify eligible articles. Odds ratios and 95% confidence intervals were used to assess the association of miRNA polymorphisms with CCD susceptibility. A total of 51 eligible articles evaluating the association of 31 miRNA polymorphisms were identified. Meta-analysis was performed for six miRNA polymorphisms. miR-146a rs2910164 (30 studies: 13,186 cases/14,497 controls), miR-149 rs2292832 (Nine studies: 4116 cases/3511 controls), miR-149 rs71428439 (Three studies: 1556 cases/1567 controls), miR-196a2 rs11614913 (20 studies: 10,144 cases/10,433 controls), miR-218 rs11134527 (Three studies: 2,322 cases/2,754 controls) were not associated with overall CCD. miR-499 rs3746444 was associated with CCD (20 studies: 9564 cases/8876 controls). In the subgroups, rs2910164 and rs3746444 were only associated with CVDs, especially CAD. In conclusion, the results support the existence of a role for miR-146a rs2910164 and miR-499 rs3746444 in determining susceptibility to CCDs, especially CAD.
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http://dx.doi.org/10.3390/ijms20020293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6359604PMC
January 2019

Breast cancer-linked lncRNA u-Eleanor is upregulated in breast of healthy women with lack or short duration of breastfeeding.

J Cell Biochem 2019 06 11;120(6):9869-9876. Epub 2018 Dec 11.

Department of Genetics, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran.

Recently, it has been revealed that estrogen-related reproductive factors are linked with some early gene expression lesions associated with malignancy in clinically healthy breasts. Accordingly, the aim of the current study was to evaluate the association of expression levels of estrogen-related long noncoding RNAs (lncRNAs) upstream Eleanor (u-Eleanor) and HOX antisense intergenic RNA (HOTAIR) with the different patterns of reproductive factors in breast tissue of healthy women. The subjects of this study were 98 cancer-free women who had undergone cosmetic mammoplasty. The expression levels of u-Eleanor and HOTAIR were measured using quantitative real-time polymerase chain reaction. The results of the current study showed that the women without a history of breastfeeding had a high-level expression of u-Eleanor compared with the women with a breastfeeding duration greater than 6 to 24 months (P = 0.03) as well as the women with a breastfeeding duration of more than 24 months (P = 0.005). Furthermore, a higher expression of u-Eleanor was found in the women with a short breastfeeding duration for 1 to 6 months than that in the women with a breastfeeding duration of greater than 24 months (P = 0.02). In the same way, the results of correlation test (r = -0.258; P = 0.036) and multivariate regression model (β = -0.321; P = 0.023) are indicative of a significant relationship of elevated expression of u-Eleanor with decreasing breastfeeding duration in the women. These findings could be important to identify the molecular mechanisms behind the relationship between a lack or short duration of the breastfeeding and the risk of breast cancer, which has previously been reported by epidemiological studies.
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http://dx.doi.org/10.1002/jcb.28269DOI Listing
June 2019

Competing endogenous RNA (ceRNA) cross talk and language in ceRNA regulatory networks: A new look at hallmarks of breast cancer.

J Cell Physiol 2019 07 10;234(7):10080-10100. Epub 2018 Dec 10.

Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Breast cancer (BC) is the most frequently occurring malignancy in women worldwide. Despite the substantial advancement in understanding the molecular mechanisms and management of BC, it remains the leading cause of cancer death in women. One of the main reasons for this obstacle is that we have not been able to find the Achilles heel for the BC as a highly heterogeneous disease. Accumulating evidence has revealed that noncoding RNAs (ncRNAs), play key roles in the development of BC; however, the involving of complex regulatory interactions between the different varieties of ncRNAs in the development of this cancer has been poorly understood. In the recent years, the newly discovered mechanism in the RNA world is "competing endogenous RNA (ceRNA)" which proposes regulatory dialogues between different RNAs, including long ncRNAs (lncRNAs), microRNAs (miRNAs), transcribed pseudogenes, and circular RNAs (circRNAs). In the latest BC research, various studies have revealed that dysregulation of several ceRNA networks (ceRNETs) between these ncRNAs has fundamental roles in establishing the hallmarks of BC development. And it is thought that such a discovery could open a new window for a better understanding of the hidden aspects of breast tumors. Besides, it probably can provide new biomarkers and potential efficient therapeutic targets for BC. This review will discuss the existing body of knowledge regarding the key functions of ceRNETs and then highlights the emerging roles of some recently discovered ceRNETs in several hallmarks of BC. Moreover, we propose for the first time the "ceRnome" as a new term in the present article for RNA research.
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http://dx.doi.org/10.1002/jcp.27941DOI Listing
July 2019

Early Parity Epigenetic Footprint of FOXA1 Gene Body in Normal Breast Tissue of Iranian Women

Iran Biomed J 2019 03 28;23(2):99-106. Epub 2018 Jul 28.

Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Background: Young age at first full-term pregnancy (FFTP) is an important factor in breast cancer risk reduction. It is postulated that this protective effect is the result of stable molecular signatures imprinted by physiological process of pregnancy, but the molecular mechanism of this protective role is unclear. The aim of the current study was to identify the effect of early FFTP on methylation status of FOXA1 gene body. FOXA1 is an essential transcription factor for mammary gland development and estrogen responsiveness of breast tissue.

Methods: Fresh frozen normal breast tissues (n = 51) were collected from Iranian women who underwent cosmetic mammoplasty (27 nulliparous women and 24 parous women who have experienced first pregnancy before the age of 25). DNA was extracted and then methylated DNA immunoprecipitation (MeDIP) real-time PCR was used to assess FOXA1 gene body methylation.

Results: Our results revealed that FOXA1 methylation level is significantly higher in early parous compared with nulliparous group (p = 0.041).

Conclusion: Our study provides new hint about the association between early FFTP and epigenetic modifications within gene body of FOXA1 in normal breast tissue. More investigation is required for clarifying molecular mechanisms underlying this association in order to develop breast cancer prevention strategies.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707108PMC
March 2019

Expression levels of breast cancer-related GAS5 and LSINCT5 lncRNAs in cancer-free breast tissue: Molecular associations with age at menarche and obesity.

Breast J 2018 11 21;24(6):876-882. Epub 2018 May 21.

Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Long noncoding RNAs (lncRNAs) constitute a major class of the human transcriptome which play crucial roles in the key biological processes of both normal and malignant breast cells. Although the aberrant expression of lncRNAs has been well-documented in breast cancer (BC), little is currently known about the association between their expression levels in the breast tissue of healthy women and BC risk factors, especially the reproductive or demographic characteristics that are among the most well-known BC risk modifiers. This study was an attempt to investigate the correlation between the expression levels of 2 breast cancer-related lncRNAs, including GAS5 and LSINCT5, and reproductive and demographic characteristics in 145 normal breast tissues that were obtained from women without breast cancer undergoing cosmetic surgery. Total RNA was extracted from fresh normal breast tissues, and the expression level of target lncRNAs was quantified using real-time qPCR. Differences in the mean normalized gene expression among the subgroups of different variables were analyzed. The expression levels of both genes was lower in the overweight-obese (BMI ≥ 25) subgroup than that in the normal BMI (BMI < 25) subgroup (GAS5 P = .019, LSINCT5 P = .036). Moreover, the expression level of GAS5 was negatively correlated with BMI (r: -.170, P: .041). The expression level of GAS5 was higher in women with late menarche (>13 years) than that with early menarche (≤13 years; P = .017). These findings may assist to obtain insights into the molecular mechanisms through which the reproductive or obesity-related estrogen changes contribute to the breast carcinogenesis. In conclusion, this study presents the first evidence for the presence of a link between the lncRNA expression and the reproductive or obesity related factors in the breast tissue of healthy women.
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http://dx.doi.org/10.1111/tbj.13067DOI Listing
November 2018

A link between expression level of long-non-coding RNA in breast tissue of healthy women and obesity.

Int J Biol Markers 2018 Nov 24;33(4):500-506. Epub 2018 Apr 24.

Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Background: Epidemiological and experimental literature indicates that the risk of breast cancer incidence is strongly linked to hormone-dependent factors, including reproductive history and obesity. However, the molecular mechanisms underlying the association between these factors and breast cancer risk are poorly understood. The aim of this study, therefore, was to determine whether obesity and reproductive history are associated with expression levels of two breast cancer-related long non-coding RNAs (lncRNAs), namely and in cancer-free breast tissues of women.

Methods: In the current research, 145 healthy women were recruited, and the quantitative expression levels of the two lncRNAs were determined through qPCR assay after gathering the mammoplasty breast tissue samples.

Results: It was found that women with body mass index (BMI)≥30 kg/m and BMI 25-29 kg/m show a low expression of compared to the BMI<25 kg/m (=0.031 and =0.027, respectively). Then, the correlation analysis disclosed a negative correlation of low expression with increasing BMI (r=-0.194, =0.019). Interestingly, this analysis demonstrated a negative correlation between low expression of the and high BMI in women with menarche age below 14 (r=-221; =0.028). Lastly, it was also revealed that there was a negative association of the low expression level of with increasing BMI in women through regression models (B=-0.048, =0.019).

Conclusions: These findings suggest interesting clues about the links between high BMI and the expression levels of in non-diseased breasts that may help us better understand the underlying mechanisms through which obesity contributes to breast carcinogenesis. However, such results need more validations in future research.
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http://dx.doi.org/10.1177/1724600818762258DOI Listing
November 2018

Duchenne muscular dystrophy: an updated review of common available therapies.

Int J Neurosci 2018 Sep 5;128(9):854-864. Epub 2018 Feb 5.

b Student Research Committee, Department of Medical Genetics, Faculty of Medicine , Mashhad University of Medical Sciences , Mashhad , Iran.

Background And Purpose: Duchenne muscular dystrophy (DMD) is a lethal progressive pediatric muscle disorder and genetically inherited as an X-linked disease that caused by mutations in the dystrophin gene. DMD leads to progressive muscle weakness, degeneration, and wasting; finally, follows with the premature demise in affected individuals due to respiratory and/or cardiac failure typically by age of 30. For decades, scientists tried massively to find an effective therapy method, but there is no absolute cure currently for patients with DMD, nevertheless, recent advanced progressions on the treatment of DMD will be hopeful in the future. Several promising gene therapies are currently under investigation. These include gene replacement, exon skipping, suppression of stop codons. More recently, a promising gene editing tool referred to as CRISPR/Cas9 offers exciting perspectives for restoring dystrophin expression in patients with DMD. This review intents to briefly describe these methods and comment on their advances. Since DMD is a genetic disorder, it should be treated by replacing the deficient DMD copy with a functional one. However, there are different types of mutations in this gene, so such therapeutic approaches are highly mutation specific and thus are personalized. Therefore, DMD has arisen as a model of genetic disorder for understanding and overcoming of the challenges of developing personalized genetic medicines, consequently, the lessons learned from these approaches will be applicable to many other disorders.

Conclusions: This review provides an update on the recent gene therapies for DMD that aim to compensate for dystrophin deficiency and the related clinical trials.
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http://dx.doi.org/10.1080/00207454.2018.1430694DOI Listing
September 2018

Epigenetic Changes of the ESR1 Gene in Breast Tissue of Healthy Women: A Missing Link with Breast Cancer Risk Factors?

Genet Test Mol Biomarkers 2017 Aug 14;21(8):464-470. Epub 2017 Jul 14.

1 Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences , Tehran, Iran .

Background: Reproductive history and obesity are among the well-recognized risk factors in the development of breast cancer, which are partially mediated by the increased exposure of breast tissues to estrogens. However, only a few studies have investigated the link between these risk factors and the pattern of methylation signatures in the breast tissue of healthy women. The role of the estrogen receptor 1 (ESR1) gene hypermethylation is reportedly important in the development of breast cancer. Thus, it is speculated that such ESR1 epigenetic changes may be influenced or shaped by obesity and reproductive history-related factors before and during breast carcinogenesis.

Materials And Methods: Breast samples were collected from 120 cancer-free women who had undergone cosmetic mammoplasty. DNA was extracted from the breast tissues and, then, the methylation levels at the promoter and exon 1 regions of the ESR1 gene CpG island were determined by using the methylated DNA immunoprecipitation-quantitative PCR assay.

Results: The methylation level of the ESR1 promoter observed in women with a body mass index (BMI) ≥30 kg/m (p ≤ 0.001) was higher than in the subgroups of women of BMI <25 kg/m (p < 0.001) and BMI 25-29 kg/m (p < 0.001) and was also higher in postmenopausal women compared with that in premenopausal women (p = 0.046). Pearson correlation coefficient analyses also showed that the high methylation of the ESR1 promoter was correlated with increasing age (r = -0.246, p = 0.007) and BMI (r = -0.331, p ≤ 0.001). Finally, linear multivariate regression revealed a significant association between high methylation rates in the ESR1 gene promoter and increased BMI (β = -0.285, 95% CI = -0.457 to -0.113, p = 0.001). Furthermore, a higher methylation level at the ESR1 gene exon 1 was found in the BMI ≥ 30 kg/m subgroup compared to the BMI 25-29 kg/m subgroup (p = 0.023).

Conclusion: These findings provide new hints about the relationship between epigenetic changes within the ESR1 gene CpG island and postmenopausal obesity and aging in cancer-free women. In terms of lifestyle intervention opportunities, this study also highlights the significance and feasibility of such interventions for BMI as a modifiable risk factor.
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http://dx.doi.org/10.1089/gtmb.2017.0028DOI Listing
August 2017

The SDF1 A/G Gene Variant: A Susceptibility Variant for Myocardial Infarction.

Genet Test Mol Biomarkers 2017 Aug 26;21(8):506-511. Epub 2017 Jun 26.

2 Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences , Tehran, Iran .

Background: Although environmental factors play an important role in susceptibility to myocardial infarction (MI), genetic determinants also provide a significant contribution. This study aimed to determine whether or not MI susceptibility is influenced by the SDF1-rs1801157A/G and HHEX-rs1111875 A/G polymorphisms in an Iranian population.

Methods: A total of 120 patients with MI and 120 healthy controls were enrolled. Blood samples were collected from all the participants for genomic DNA extraction and testing. Polymorphism genotyping was determined by the polymerase chain reaction-restriction fragment length polymorphism technique.

Results: Multiple logistic regression analysis revealed that the A allele and AA genotype of the SDF1-rs1111875 polymorphism produce a significant risk of MI both before (crude odds ratio [OR] = 8.83, 95% confidence interval [95% CI] = 1.05-73.76, p = 0.025) and after adjustment (adjusted OR = 8.12, 95% CI = 5.02-19.42, p = 0.04). In contrast, the GG genotype of the SDF1-rs1111875 polymorphism provides a protective effect on MI in a recessive model (GG vs. AA+AG) before (crude OR = 0.57, 95% CI = 0.34-0.97, p = 0.037) and after adjustment (adjusted OR = 0.53, 95% CI = 0.3-0.82, p = 0.021). No association was found between the HHEX-rs1111875 A/G polymorphism alleles and the susceptibility to MI.

Conclusion: Taken together, the current findings suggest that the SDF1-rs1801157A/G gene variant may play an important role in relation to MI in this Iranian population. Nevertheless, more replication studies and meta-analyses should be carried out in this area.
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http://dx.doi.org/10.1089/gtmb.2017.0023DOI Listing
August 2017

miRNA-Related Polymorphisms in miR-423 (rs6505162) and PEX6 (rs1129186) and Risk of Esophageal Squamous Cell Carcinoma in an Iranian Cohort.

Genet Test Mol Biomarkers 2017 Jun 21;21(6):382-390. Epub 2017 Apr 21.

1 Medical Genetics Department, School of Medicine, Tehran University of Medical Sciences , Tehran, Iran .

Aims: Iran is located in the Asian esophageal cancer belt. It is a high-risk region for esophageal squamous cell carcinoma (ESCC). The extent to which genetic components, especially variants within miRNAs or their binding sites, contribute to risk of ESCC in the region is not yet fully understood. Herein, tests were done on an Iranian cohort to evaluate the association of miRNA-related polymorphisms in miR-423 (rs6505162) and peroxisomal biogenesis factor 6 (PEX6) (rs1129186 within a miR-149-5p-binding site) with the risk of ESCC risk.

Methods: This study recruited 200 ESCC patients and 300 healthy individuals. Genotyping was performed using the polymerase chain reaction-restriction fragment length polymorphism method. Target genes and biological processes that are regulated by miR-423 and may be affected by a change in miR-423 expression were identified by in silico analysis.

Results: Logistic regression analyses revealed an association between rs6505162 and ESCC, assuming codominant (AA vs. CC, odds ratios, OR [95% confidence interval, CI]: 0.32 [0.15-0.69], p-value: 0.0076), recessive (AA vs. CC+CA, OR [95% CI]: 0.35 [0.16-0.73], p-value: 0.0027), and log-additive models (OR [95% CI]: 0.69 [0.52-0.91], p-value: 0.0084). No significant association was observed for PEX6 rs1129186. In silico analyses revealed several genes and biological processes that are regulated by miR-423 in ESCC.

Conclusion: This study identified the first evidence of an association of a miRNA-related variant with risk of ESCC in an Iranian cohort. PEX6 rs1129186 may not modulate the risk of ESCC in the cohort.
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http://dx.doi.org/10.1089/gtmb.2016.0346DOI Listing
June 2017

Influences of IL-1b-3953 C>T and MMP-9-1562C >T Gene Variants on Myocardial Infarction Susceptibility in a Subset of the Iranian Population.

Genet Test Mol Biomarkers 2017 Jan 8;21(1):33-38. Epub 2016 Nov 8.

2 Noncommunicable Diseases Research Center, Fasa University of Medical Sciences , Fasa, Iran .

Aims: IL-1b-3953 C>T and MMP-9-1562C>T variants have been shown to be linked to the development of myocardial infarction (MI), although previous studies have reported inconsistent results. The aim of the present study was to determine whether these genetic variations are associated with MI susceptibility in an Iranian population.

Methods: In the current study, 117 patients with MI and 120 control group members were selected as participants. Peripheral blood samples were taken from all the subjects for genomic DNA extraction. Single nucleotide polymorphism (SNP) genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays.

Results: Multiple logistic regression analysis revealed that the TT genotype of the IL-1b-3953 C>T polymorphism is associated with a significant MI protective effect in: the homozygote model after adjustment for MI risk factors (odds ratio [OR]: 0.18, confidence interval [95% CI] = 0.04-0.72; p = 0.01); and also in the recessive genetic model both before (OR: 0.39, 95% CI: 0.15-0.96, p = 0.04) and after (OR: 0.15, 95% CI: 0.04-0.58, p = 0.006) adjustment for MI risk factors. Furthermore, multiple logistic regression analysis indicated that the individuals with the TT genotype of the MMP-9-1562C>T polymorphism were significantly protected against MI in comparison with the CC genotype (OR: 0.01, 95% CI: 0.002-0.68, p = 0.03).

Conclusion: The findings suggest that the minor alleles of the two polymorphisms under study both have protective effects with respect to MI susceptibility in the Iranian population.
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http://dx.doi.org/10.1089/gtmb.2016.0240DOI Listing
January 2017

Significance of a common variant in the CDKAL1 gene with susceptibility to type 2 diabetes mellitus in Iranian population.

Adv Biomed Res 2015 11;4:45. Epub 2015 Feb 11.

Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.

Background: Type 2 diabetes mellitus (T2DM) is a worldwide problem that threatens the public health and economies of all countries. A multifactorial etiology and interaction between environmental factors and genetic components are responsible for triggering and progression of T2DM. Recently, rs7754840 single nucleotide polymorphism (SNP) in the CDKAL1 gene was reported to be associated with T2DM in various populations. However, due to inconsistent results in various populations about the association of rs7754840 with T2DM, and lack of information in the Iranian population, we have evaluated its association with T2DM in a subset of the Iranian population from Isfahan province, central part of Iran.

Materials And Methods: The study included 140 patients and 140 controls selected based on the World Health Organization guidelines. Genomic DNA was extracted from blood samples and the rs7754840 SNP was genotyped using a polymerase chain reaction-restriction fragment length polymorphism assay with specific primers and restriction enzyme (Ac1I).

Results: The frequency of the C allele in the cases was higher than that in the controls (72.9% vs. 65%; P = 0.045). Using logistic regression analysis, we found a significant risk association of CC genotype with T2DM susceptibility (OR = 2.319, 95% CI = 1.436-3.744, P = 0.001). Furthermore, compared with the CC genotype, individuals with the GC genotype had a lower risk (protective association) of developing T2DM (OR = 0.332, 95% CI = 0.202-0.547, P < 0.001).

Conclusions: We confirmed that there is a significant risk association between rs7754840 polymorphism and development of T2DM in a subset of the Iranian population from Isfahan province.
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http://dx.doi.org/10.4103/2277-9175.151256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4358034PMC
March 2015

PTGS2 (COX2) -765G>C gene polymorphism and risk of sporadic colorectal cancer in Iranian population.

Mol Biol Rep 2012 May 16;39(5):5219-24. Epub 2011 Dec 16.

Division of Genetics, Department of Biomedical Sciences, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.

Colorectal cancer (CRC) is one of the leading cancers worldwide. Through genome wide association studies, several single nucleotide polymorphisms scattered in the genome emerged to be influential in the development of sporadic CRC in some populations. However, replicative studies failed to prove a particular SNP-CRC association in populations and ethnic groups. Cyclooxygenase-2 (PTGS2) is a crucial enzyme involved in the metabolism of prostaglandins. The aim of this replicative study is to investigate the possible association between PTGS2 -765G>C polymorphism and sporadic CRC risk in a subset of Iranian population. A total of 110 patients with sporadic CRC, and 120 controls were genotyped for PTGS2 -765G>C polymorphism by using polymerase chain reaction-based restriction fragment length polymorphism. There were no significant differences in the genotype and allele frequencies of PTGS2 -765G>C between two groups except in irregular aspirin or non-steroidal anti-inflammatory drugs (NSAID) consumers. Frequencies of genotypes and alleles were as follows: GG = 44.2, GC = 48.3, CC = 7.5%, in controls and GG = 34.55, GC = 60.9, CC = 4.55% in cases. Regarding the allele frequency, the following values were found: G = 65, C = 35% in cases and 68.3, 31.7% in the controls, respectively. In irregular aspirin or NSAID consumers combined GC+CC genotype was found to be a risk genotype (OR = 1.933, 95% CI: 1.067-3.501, P = 0.036). Overall, no significant relation was found between this polymorphism and sporadic CRC in Iranians. However, in irregular aspirin or NSAID consumers the combined GC+CC genotype proved to be a risk genotype.
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http://dx.doi.org/10.1007/s11033-011-1319-8DOI Listing
May 2012

DNA-methyltransferase 3B 39179 G > T polymorphism and risk of sporadic colorectal cancer in a subset of Iranian population.

J Res Med Sci 2011 Jun;16(6):807-13

Department of Genetics and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.

Background: Epigenetic event is a biological regulation that influences the expression of various genes involved in cancer. DNA methylation is established by DNA methyltransferases, particularly DNAmethyltransferase 3B (DNMT3B). It seems to play an oncogenic role in the creation of abnormal methylation during tumorigenesis. The polymorphisms of the DNMT3B gene may influence DNMT3B activity in DNA methylation and increase the susceptibility to several cancers. These genetic polymorphisms have been studied in several cancers in different populations.

Methods: In this study, we performed a case-control study with 125 colorectal cancer patients and 135 cancer-free controls to evaluate the association between DNMT3B G39179T polymorphism (rs1569686) in the promoter region and the risk of sporadic colorectal cancer. Up to now, few studies have investigated the role of this gene variant in sporadic colorectal cancer with no familial history. The genotypes of DNMT3B G39179T polymorphism was analyzed by PCR-RFLP.

Results: We found that compared with G allele carriers, statistically the DNMT3B TT genotype (%34) was significantly associated with increased risk of colorectal cancer (adjusted OR, 3.993, 95% CI, 1.726-9.238, P = 0.001). Compared with DNMT3B TT genotype, the GT and GG genotypes had lower risk of developing sporadic colorectal cancer (OR = 0.848, 95% CI = 0.436-1.650).

Conclusions: Our findings were consistent with that of previously reported case-control studies with colorectal cancer. These results suggest that the DNMT3B G39179T polymorphism influences DNMT3B expression, thus contributing to the genetic susceptibility to colorectal cancer. Further mechanistic studies are needed to unravel the causal molecular mechanisms.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3214400PMC
June 2011
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