Publications by authors named "Jalal Gharesouran"

35 Publications

STRs: Ancient Architectures of the Genome beyond the Sequence.

J Mol Neurosci 2021 May 30. Epub 2021 May 30.

Division of Medical Genetics, Tabriz Childrens Hospital, Tabriz University of Medical Sciences, Tabriz, Iran.

Short tandem repeats (STRs) are commonly defined as short runs of repetitive nucleotides, consisting of tandemly repeating 2-6- bp motif units, which are ubiquitously distributed throughout genomes. Functional STRs are polymorphic in the population, and their variations influence gene expression, which subsequently may result in pathogenic phenotypes. To understand STR phenotypic effects and their functional roles, we describe four different mutational mechanisms including the unequal crossing-over model, gene conversion, retrotransposition mechanism and replication slippage. Due to the multi-allelic nature, small length, abundance, high variability, codominant inheritance, nearly neutral evolution, extensive genome coverage and simple assaying of STRs, these markers are widely used in various types of biological research, including population genetics studies, genome mapping, molecular epidemiology, paternity analysis and gene flow studies. In this review, we focus on the current knowledge regarding STR genomic distribution, function, mutation and applications.
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http://dx.doi.org/10.1007/s12031-021-01850-6DOI Listing
May 2021

DOCK8-related Immunodeficiency Syndrome (DIDS): Report of Novel Mutations in Iranian Patients.

J Mol Neurosci 2021 May 4. Epub 2021 May 4.

Division of Medical Genetics, Tabriz Children's Hospital, Tabriz University of Medical Sciences, Tabriz, Iran.

DOCK8 immunodeficiency syndrome (DIDS) is a rare autosomal recessive (AR) disorder characterized by elevated serum IgE levels, eosinophilia, recurrent cutaneous infections, severe eczema, and sinopulmonary and gastrointestinal infections. This syndrome is a multisystem disease that is associated with both immune deficiency and neurological complications. In this study, we describe the clinical characteristics of two Iranian patients with DOCK8 deficiency and propose possible mechanisms for this condition. By using whole exome sequencing (WES), we identified two novel mutations, namely c.3233_3234del AG (p.Q1078fs) in exon 6 and a large deletion with 94 kb (c.405-3231 deletion, p.K135fs), in these two patients. These variations are confirmed with Sanger sequencing and CGH array. Subsequent co-segregation analysis is performed to identify inheritance patterns. Both patients were homozygote and their parents were heterozygote for the variations. For further investigation, prediction tools were applied to identify the pathogenicity of the variations and also for modeling the truncated proteins. The patients did not show neurological abnormalities associated with a deficiency of the N terminal region of DOCK8. The absence of neurological complications in the first patient is justifiable due to the maintenance of the proline-rich region in DOCK8, but for the second patient with expanded deletion which is almost like null DOCK8 protein, it is not presumable, pointing to the fact that the C terminal region of the protein might have functions in the proliferation and migration neurons in the peripheral nervous system. Alternatively, it is possible that neurological abnormalities follow an age-dependent pattern, leading to the appearance of related symptoms later in life. Further multiple functional studies are needed to model different identified variants in animal models to confirm our results and suggest possible mechanisms associated with DOCK8 deficiency in this study.
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http://dx.doi.org/10.1007/s12031-021-01843-5DOI Listing
May 2021

New insight into clinical heterogeneity and inheritance diversity of FBLN5-related cutis laxa.

Orphanet J Rare Dis 2021 01 28;16(1):51. Epub 2021 Jan 28.

Department of Medical Genetics, Tabriz University of Medical Sciences, Tabriz, Iran.

Background: FBLN5-related cutis laxa (CL) is a rare disorder that involves elastic fiber-enriched tissues and is characterized by lax skin and variable systemic involvement such as pulmonary emphysema, arterial involvement, inguinal hernias, hollow viscus diverticula and pyloric stenosis. This type of CL follows mostly autosomal recessive (AR) and less commonly autosomal dominant patterns of inheritance.

Results: In this study, we detected a novel homozygous missense variant in exon 6 of FBLN5 gene (c.G544C, p.A182P) by using whole exome sequencing in a consanguineous Iranian family with two affected members. Our twin patients showed some of the clinical manifestation of FBLN5-related CL but they did not present pulmonary complications, gastrointestinal and genitourinary abnormalities. The notable thing about this monozygotic twin sisters is that only one of them showed ventricular septal defect, suggesting that this type of CL has intrafamilial variability. Co-segregation analysis showed the patients' parents and relatives were heterozygous for detected variation suggesting AR form of the CL. In silico prediction tools showed that this mutation is pathogenic and 3D modeling of the normal and mutant protein revealed relative structural alteration of fibulin-5 suggesting that the A182P can contribute to the CL phenotype via the combined effect of lack of protein function and partly misfolding-associated toxicity.

Conclusion: We underlined the probable roles and functions of the involved domain of fibulin-5 and proposed some possible mechanisms involved in AR form of FBLN5-related CL. However, further functional studies and subsequent clinical and molecular investigations are needed to confirm our findings.
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http://dx.doi.org/10.1186/s13023-021-01696-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845118PMC
January 2021

GAA gene mutation detection following clinical evaluation and enzyme activity analysis in Azeri Turkish patients with Pompe disease.

Metab Brain Dis 2020 10 5;35(7):1127-1134. Epub 2020 Jun 5.

Division of Medical Genetics, Tabriz Children's Hospital, Tabriz University of Medical Sciences, Tabriz, Iran.

Pompe disease (PD) is a rare autosomal recessive multi-systemic lysosomal storage disorder, caused by mutations in the acid alpha-glucosidase (GAA) gene located on 17q25.2-q25.3. It is one of about 50 rare genetic diseases categorized as lysosomal storage disorders. This disease is characterized by a range of different symptoms related to acid alpha-glucosidase deficiency. Mutation recognition in the GAA gene can be very significant for purposes such as therapeutic interference, early diagnosis and genotype-phenotype relationship. In the current study, peripheral blood samples were gathered from patients with PD and healthy members of three families. Enzymatic activity of GAA was checked. Then, mutation detection was performed by polymerase chain reaction followed by direct sequencing of all exons in samples with decreased enzyme activity. The identified mutations were investigated using bioinformatics tools to predict possible effects on the protein product and also to compare the mutated sequence with near species. Three novel mutations (c.1966-1968delGAG, c.2011-2012delAT and c.1475-1481dupACCCCAC) were identified in the GAA gene. Assessment of the effects of these mutations on protein structure and function showed the possibility of harmful effects and their significant alterations in the protein structure. The three novel GAA gene mutations detected in this study expand the information about the molecular genetics of PD and can be used to helpdiagnosis and genetic counseling of affected families.
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http://dx.doi.org/10.1007/s11011-020-00586-3DOI Listing
October 2020

RUNX1 variant as a genetic predisposition factor for acute myeloid leukemia.

Exp Mol Pathol 2020 08 12;115:104440. Epub 2020 Apr 12.

Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address:

Acute myeloid leukemia (AML) is the most common hematological malignancy among adults and is characterized by accumulation of immature myeloid cells. Different genetic factors have role in the occurrence of AML. Among different proteins, RUNX1 and BAALC are involved in the development AML. It has been shown that BAALC overexpression is a factor that indicate shorter disease free survival in a subset of AML patients. RUNX1 has been implicated in the development of breast, prostate, lung, and skin cancers. The aim of this study is determination of the prevalence of common polymorphisms in BAALC (rs6999622 and rs62527607) and RUNX1 (rs13051066 and rs61750222) in AML patients compared with healthy subjects. A total of 100 AML patients and 100 healthy control subjects were included in our study. Genomic DNA was isolated from peripheral blood and the polymorphisms were genotyped by applying ARMS and PCR-RFLP methods. Finally, data was analyzed using SPPSS software. Our results demonstrate a significant association between the RUNX1 rs13051066 and AML in the co-dominant (odd ratio = 6.66, 95% Cl = 1.85-25, p = .006) and dominant (GT + TT versus GG: odd ratio = 6.15, 95% CI = 1.73-21.87, p = .002) models. The RUNX1 rs13051066 polymorphism is associated with risk of AML in Iranian population. Future studies should consider larger sample size for assessment of RUNX1 gene polymorphisms, and employ cytogenetic and molecular analyses in AML patients from different ethnic origins.
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http://dx.doi.org/10.1016/j.yexmp.2020.104440DOI Listing
August 2020

Dual biomarkers long non-coding RNA GAS5 and its target, NR3C1, contribute to acute myeloid leukemia.

Exp Mol Pathol 2020 06 4;114:104399. Epub 2020 Feb 4.

Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address:

Acute myeloid leukemia (AML) is a complex hematological neoplasm with poor prognosis. At present, overwhelming evidence indicates that different genetic abnormalities are relevant to the pathogenesis of AML. Nevertheless, its exact molecular mechanism is still unknown. Recently, it was reported that lncRNAs play crucial roles in tumorigenesis. But, their role in the molecular pathogenesis of AML has not been extensively explored. GAS5, one of the earliest known lncRNAs, has an essential role in the formation and progression of multiple human cancers. It was recently demonstrated that GAS5 acts as a riborepressor of the Glucocorticoid receptor) GR) and abnormal levels of GAS5 may alter response of hematopoietic cells to glucocorticoids. GAS5 can have interaction with the GR that encoded by NR3C1 gene and inhibit its transcriptional activity. To test whether the genetic variants can be associated with AML risk, we genotyped rs55829688 (T > C) polymorphism in GAS5 and three NR3C1 SNPs namely rs6195, rs41423247 and rs6189/rs6190 in a population of 100 Iranian AML patients and 100 healthy subjects. The analysis of the data showed the frequency of alleles and genotypes of rs55829688 and rs6189/rs6190 polymorphisms did not differ between patients and healthy subjects. But, rs41423247 and rs6195 demonstrated a significant correlation with AML risk. The rs6195 was associated with higher AML susceptibility in the co-dominant (OR = 4.58, 95% CI = 2.11-9.981, P < .0001), dominant (OR = 4.55, 95% CI = 2.155-9.613, P < .0001), and over-dominant (OR = 4.43, 95% CI = 2.042-9.621, P < .0001) models. Also, the rs41423247 polymorphism was associated with higher risk of AML in co-dominant (OR = 2.07, 95% CI = 1.171-4.242, P = .012) and dominant (OR = 2.47, 95% CI = 1.192-5.142, P = .010) models. Furthermore, haplotype analysis (rs41423247, rs6189.rs6190, rs6195, and rs55829688 respectively) demonstrated that GGAT, CGGT, and GGGT haplotypes were associated with higher risk of AML in the studied population (p-values = .007, 0.042 and 0.044, respectively). The present study reveals a possible role for NR3C1 in the pathogenesis of AML.
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http://dx.doi.org/10.1016/j.yexmp.2020.104399DOI Listing
June 2020

Role of and genes polymorphisms in multiple sclerosis.

Int J Neurosci 2020 Apr 26;130(4):407-412. Epub 2019 Nov 26.

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

Multiple sclerosis (MS) as a progressive chronic disease of the central nervous system (CNS) is characterized by demyelination and axonal loss. Results of genetic studies and clinical trials have proved a key role for the immune system in the pathogenesis of MS. Glucocorticoids (GR) are regarded as potent therapeutic compounds for autoimmune and inflammatory diseases which act through their receptors encoded by () gene. Meanwhile, the long non-coding RNA (lncRNA) () interacts with GR through binding to the DNA-binding domain (DBD) region and reduces GR transcriptional activity. The purpose of our study was to evaluate the association between MS and polymorphisms within (rs6189/6190, rs56149945, rs41423247) and (rs55829688) genes in 300 relapsing-remitting MS patients and 300 healthy subjects. We demonstrated significant differences in distribution of genotype, allele and haplotype frequencies of rs6189, rs41423247 and rs55829688 between the study groups. Our data may suggest that rs6189, rs41423247 and rs55829688 are associated with the increased risk of MS development. Future studies are needed to verify our results in larger sample sizes and elaborate the underlying mechanisms for contribution of these variants in MS disease.
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http://dx.doi.org/10.1080/00207454.2019.1694019DOI Listing
April 2020

Down-regulation of ERMN expression in relapsing remitting multiple sclerosis.

Metab Brain Dis 2019 10 23;34(5):1261-1266. Epub 2019 May 23.

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

Multiple Sclerosis (MS) is a chronic inflammatory disease causing demyelination and neurodegeneration in the central nervous system (CNS). Although the exact etiology of MS is still unclear, both genetic and environmental elements are regarded as causative factors. Environmental factors can induce a cascade of events in immune system leading to neuronal death and nerve demyelination. This paper aims to compare the peripheral transcript levels of Ermin (ERMN) (a gene with putative role in cytoskeletal rearrangements during myelinogenesis) and Listerin E3 Ubiquitin Protein Ligase 1 (LTN1) (a gene with functions in regulating innate immune system) between relapsing-remitting MS (RR-MS) patients and healthy controls. The results showed a significant decrease in ERMN expression (p = 0.022); whereas, no significant difference was detected in LTN1 expression between two groups (p = 0.935). The reduction in ERMN expression in leukocytes could be the cause of demyelinating process in RR-MS patients. Current findings might also have practical importance in prognosis and targeted therapies.
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http://dx.doi.org/10.1007/s11011-019-00429-wDOI Listing
October 2019

First Report of Congenital Short Bowel Syndrome in an Iranian Patient Caused by a Mutation in the Gene.

J Pediatr Genet 2019 Jun 26;8(2):73-80. Epub 2018 Oct 26.

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

Congenital short bowel syndrome (CSBS) is a rare congenital neonatal disorder. CSBS results from intestinal impairment during embryogenesis. Mutated ( ) and genes are involved in the cause of CSBS. In this study, due to our misdiagnosis, we had to perform whole exome sequencing on the patient, and also we implemented cosegregation analysis on his parents with consanguineous marriage and also parents' mothers. We identified a homozygous loss of function mutation in the gene in exon 5 (c.664C > T, p.R222X). Also, both parents and grandmothers of the proband were heterozygous for this mutation. Loss of function mutation in causes CSBS, leading to impaired intestinal development.
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http://dx.doi.org/10.1055/s-0038-1675339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6499612PMC
June 2019

The Neuronal Ceroid Lipofuscinoses-Linked Loss of Function CLN5 and CLN8 Variants Disrupt Normal Lysosomal Function.

Neuromolecular Med 2019 06 27;21(2):160-169. Epub 2019 Mar 27.

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

Neuronal ceroid lipofuscinoses (NCLs) are a group of neurodegenerative disorders caused by mutations in fourteen distinct ceroid lipofuscinoses, neuronal (CLN) genes described with various severe symptoms such as seizures, visual failure, motor decline, and progressive cognitive deterioration. The current research represents novel CLN5 (c.741G > A) and CLN8 (c.565delT) mutations in two different Iranian families with late-infantile NCL (LINCL) and their relatives by using whole-exome sequencing (WES). The first family had a 10-year-old male with consanguineous parents and severe NCL symptoms, including motor clumsiness, telangiectasia, and cerebellar atrophy. The second family with a child who suffered from nystagmus rotation, motor difficulties, and seizure was a 5-year-old male with consanguineous parent. WES of probands 1 and 2 revealed homozygotic mutations in exon 4 of CLN5 (c.741G > A, p.W247X) and deletion in exon 3 (c.565delT, p.F189fs) of CLN8, respectively. Both patients' parents were heterozygous for these alterations. In concordance with previous studies, our results indicate that pathogenic mutations in CLN genes, especially CLN5 and 8, are a main cause of LINCL; these results also suggest that LINCL is not a regionally or nationally dependent disorder and can occur in any ethnic group despite the fact that some populations may be more at risk. Consequently, CLN gene screening for patients with typical signs of LINCL is recommended.
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http://dx.doi.org/10.1007/s12017-019-08529-7DOI Listing
June 2019

Integrative analysis of OIP5-AS1/HUR1 to discover new potential biomarkers and therapeutic targets in multiple sclerosis.

J Cell Physiol 2019 08 27;234(10):17351-17360. Epub 2019 Feb 27.

Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Multiple sclerosis (MS) is a devastating autoimmune disease of the central nervous system associated with demyelination and axonal injury. This study was designed to find potential lncRNAs and their targets that are associated with the molecular basis of MS pathogenesis. In this study, peripheral blood samples were obtained from 50 relapsing-remitting MS (RR-MS) patients and 50 healthy controls. lncRNAs and their target were selected for validation using TaqMan Real-Time PCR. Interactions were studied based on approaches that used to investigation biological functions and signaling pathways affected by differentially expressed messenger RNAs (mRNAs). The results of this study indicate an increase in the expression of HUR1 (p = 0.0001), CPSF7 (p = 0.02), and reduction of CSTF2 expression (p = 0.04). Also, an increase in the expression of OIP5-AS1 (p = 0.01) was observed in men less than 30 years old. We performed a comparative analysis of the long noncoding RNAs (lncRNAs), and then we ranked them as candidate biomarkers according to a decreasing area under the receiver operating characteristic (ROC) curve (AUC) and plotted the results. Dysregulation of lncRNA expression has been linked to diseases. Further studies on the HUR1 gene can be used as diagnostic tools for the identification of high-risk individuals in families with a history of disease before, during, and even after treatment. Our data uncovered the expression profiles of lncRNAs and mRNAs in MS patients, which will help delineate the molecular mechanisms in MS pathogenesis. However, further studies need to determine the precise role of these genes in the pathological process in MS.
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http://dx.doi.org/10.1002/jcp.28355DOI Listing
August 2019

Genetic discoveries and advances in late-onset Alzheimer's disease.

J Cell Physiol 2019 08 20;234(10):16873-16884. Epub 2019 Feb 20.

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

Alzheimer's disease (AD) is a heterogeneous disorder with multiple patterns of clinical manifestations. Recently, due to the advance of linkage studies, next-generation sequencing and genome-wide association studies, a large number of putative risk genes for AD have been identified using acquired genome mega data. The genetic association between three causal genes, including amyloid precursor protein, presenilin1, and presenilin2 in early-onset AD (EOAD), was discovered over the past few decades. These discoveries showed that there should be additional genetic risk factors for both EOAD and late-onset AD (LOAD) to help fully explain the leading molecular mechanisms in a single pathophysiological entity. This study reviews the clinical features and genetic etiology of LOAD and discusses a variety of AD-mediated genes that are involved in cholesterol and lipid metabolism, endocytosis, and immune response according to their mutations for more efficient selection of functional candidate genes for LOAD. New mechanisms and pathways have been identified as a result.
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http://dx.doi.org/10.1002/jcp.28372DOI Listing
August 2019

Assessment of expression of RELN signaling pathway in multiple sclerosis patients.

Immunobiology 2019 05 12;224(3):402-407. Epub 2019 Feb 12.

Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address:

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system. Nearly 85% of MS patients are recognized with relapsing-remitting MS (RRMS), a typical clinical course of disease which is distinguished by several episodes of relapses, separated by remissions of neurological impairment. Failure of repair mechanisms is a main factor in progression of neurological dysfunction in MS. Several lines of evidence suggest that Reelin (RELN) signaling pathway can contribute in the regulation of repair mechanisms in MS patients. In the present study, we assessed expression levels of RELN and Disabled-1 (DAB1), two key genes in RELN signaling pathway, in peripheral blood of 50 RRMS patients and 50 matched healthy subjects. RELN was significantly down-regulated in total MS patients, and total female patients compared with the matched controls. However, no statistically significant difference was found in DAB1 mRNA expression between MS patients and controls. Furthermore, considerable correlations were detected between expression levels of RELN and DAB1 in the patients group. There were no significant correlations between expression levels of genes and EDSS, disease duration or age at onset. Our study provides evidences for the role of RELN signaling pathway in the pathogenesis of MS. Further studies are required to clarify the exact clinical significance of this pathway in MS patients.
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http://dx.doi.org/10.1016/j.imbio.2019.02.007DOI Listing
May 2019

A Novel Regulatory Function of Long Non-coding RNAs at Different Levels of Gene Expression in Multiple Sclerosis.

J Mol Neurosci 2019 Mar 4;67(3):434-440. Epub 2019 Jan 4.

Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Long non-coding RNAs (lncRNAs) play critical roles in regulation of immunological pathways. Consequently, their expression profile represents new biomarkers for susceptibility and progression of immunological disorders. However, their role in chronic inflammatory diseases such as multiple sclerosis (MS) remained unknown. Here, we assessed the expression of lncRNAs MALAT1 and HOTAIRM1 as well as their target genes in peripheral blood of MS patients to show their possible roles in disease initiation and progression. In this study, 50 patients with relapsing-remitting MS and 50 healthy matched controls were enrolled. Comparative Ct method via TaqMan assay was used to quantify transcript levels of MALAT1, HOTAIRM1, AGO2, CSTF2, CPSF7, and WDR33. Our analysis depicted significant differences in lncRNAs and their target genes expression levels. AGO2 expression was significantly elevated in MS patients (P < 0.001) whereas, CSTF2 expiration was considerably down-regulated (P < 0.042). These findings suggest that AGO2 and CSTF2 can be considered as potential theoretical biomarkers for MS and can be helpful for diagnosis and prognosis of responding patients to interferon.
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http://dx.doi.org/10.1007/s12031-018-1248-2DOI Listing
March 2019

The Growth Arrest-Specific Transcript 5 (GAS5) and Nuclear Receptor Subfamily 3 Group C Member 1 (NR3C1): Novel Markers Involved in Multiple Sclerosis.

Int J Mol Cell Med 2018 7;7(2):102-110. Epub 2018 May 7.

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

Recent studies have revealed that long noncoding RNAs (lncRNAs) are connected with pathogenesis of neurodegenerative diseases. Additionally, glucocorticoids have fundamental regulatory roles on the immune system, and act as potent therapeutic compounds for autoimmune and inflammatory diseases. The long noncoding RNA growth arrest-specific 5 () which accumulates inside the cells in response to cellular starvation/growth arrest, acts as a potent repressor of the glucocorticoid receptor (GR) through its glucocorticoid response element (GRE). The aim of the present study was to investigate the role of lncRNA and its downstream target Nuclear Receptor Subfamily 3 Group C Member 1() in the pathogenesis of multiple sclerosis (MS), and to define the role of in the regulation of expression. Quantitative polymerase chain reaction was performed for investigating the expression of and in MS patients and healthy subjects. We found that levels were up-regulated in the MS patients, blood compared with healthy subjects in correlation with expression. Our findings suggest that may play on important role in the molecular etiology and treatment of MS.
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http://dx.doi.org/10.22088/IJMCM.BUMS.7.2.102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6148504PMC
May 2018

Association Study of ANRIL Genetic Variants and Multiple Sclerosis.

J Mol Neurosci 2018 May 30;65(1):54-59. Epub 2018 Apr 30.

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

Multiple sclerosis (MS) is an autoimmune disorder of central nervous system with several genetic and environmental risk factors. Genes with regulatory roles on immune system have been implicated in its pathogenesis. Recently, long non-coding RNAs (lncRNAs) have been demonstrated to control some aspects of immune response. Among them is antisense non-coding RNA in the INK4 locus (ANRIL) whose involvement in NF-κB signaling pathway has been highlighted. In the current study, we evaluated the association between rs1333045, rs4977574, rs1333048, and rs10757278 variants of ANRIL and MS risk in a population of 410 Iranian MS patients and 410 healthy subjects. There was no significant difference in allele and genotype frequencies between MS patients and healthy subjects. However, haplotype analysis (rs1333045, rs1333048, rs4977574, and rs10757278 respectively) demonstrated protective effect of CCGG and TAAA haplotypes against MS (P values of 0.043 and 0.0026 respectively). In addition, TAGG and CCGA haplotypes were significantly associated with MS risk in the studied population (P values of 0.0065 and 0.024 respectively). The present study reveals a possible role for ANRIL in the pathogenesis of MS.
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http://dx.doi.org/10.1007/s12031-018-1069-3DOI Listing
May 2018

Genetic study of the PAH locus in the Iranian population: familial gene mutations and minihaplotypes.

Metab Brain Dis 2017 10 4;32(5):1685-1691. Epub 2017 Jul 4.

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

Phenylketonuria (PKU), one of the most common inborn errors of amino acid metabolism, is caused by mutations in the phenylalanine hydroxylase (PAH) gene (PAH). PKU has wide allelic heterogeneity, and over 600 different disease-causing mutations in PAH have been detected to date. Up to now, there have been no reports on the minihaplotype (VNTR/STR) analysis of PAH locus in the Iranian population. The aims of the present study were to determine PAH mutations and minihaplotypes in Iranian families with PAH deficiency and to investigate the correlation between them. A total of 81 Iranian families with PAH deficiency were examined using PCR-sequencing of all 13 PAH exons and their flanking intron regions to identify sequence variations. Fragment analysis of the PAH minihaplotypes was performed by capillary electrophoresis for 59 families. In our study, 33 different mutations were found accounting for 95% of the total mutant alleles. The majority of these mutations (72%) were distributed across exons 7, 11, 2 and their flanking intronic regions. Mutation c.1066-11G > A was the most common with a frequency of 20.37%. The less frequent mutations, p.Arg261Gln (8%), p.Arg243Ter (7.4%), p.Leu48Ser (7.4%), p.Lys363Asnfs*37 (6.79%), c.969 + 5G > A (6.17%), p.Pro281Leu (5.56), c.168 + 5G > C (5.56), and p.Arg261Ter (4.94) together comprised about 52% of all mutant alleles. In this study, a total of seventeen PAH gene minihaplotypes were detected, six of which associated exclusively with particular mutations. Our findings indicate a broad PAH mutation spectrum in the Iranian population, which is consistent with previous studies reporting a wide range of PAH mutations, most likely due to ethnic heterogeneity. High prevalence of c.1066-11G > A mutation linked to minihaplotype 7/250 among both Iranian and Mediterranean populations is indicative of historical and geographical links between them. Also, strong association between particular mutations and minihaplotypes could be useful for prenatal diagnosis (PND) and preimplantation genetic diagnosis (PGD) in affected families.
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http://dx.doi.org/10.1007/s11011-017-0048-7DOI Listing
October 2017

Expression analysis of long non-coding ATB and its putative target in breast cancer.

Breast Dis 2017 ;37(1):11-20

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

Background: A long noncoding RNA (lncRNA) activated by transforming growth factor (TGF)-β (lncRNA-ATB) has been recently shown to promote the invasion-metastasis cascade in various types of cancers via upregulation of some targets including ZEB1.

Objectives: The aim of the present study was to elucidate the expression of lncRNA-ATB and ZEB in breast cancer patients.

Methods: The expression of these genes was evaluated by real-time reverse transcription polymerase chain reaction in tumor samples form 50 newly diagnosed breast cancer patients as well as their corresponding adjacent non-cancerous tissues (ANCTs). Patients were divided into subsequent groups according to the median lncRNA-ATB expression.

Results: LncRNA-ATB has been shown to be downregulated in about two third of tumor samples compared with their ANCTs.A significant association has been found between ZEB1 expression and Ki-67 status. In addition, we demonstrated a correlation between expression of lncRNA-ATB and ZEB1 in tumor samples and not in ANCTs.

Conclusion: Collectively, out data show downregulation of lncRNA-ATB in a significant number of breast tumor tissues compared with ANCTs and imply that lncRNA-ATB might have distinct roles in the pathogenesis of different cancers or even different subtypes of a certain cancer which should be evaluated in future studies.
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http://dx.doi.org/10.3233/BD-160264DOI Listing
August 2018

Expression Study and Clinical Correlations of MYC and CCAT2 in Breast Cancer Patients

Iran Biomed J 2017 09 8;21(5):303-11. Epub 2017 May 8.

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

Background: Colon cancer-associated transcript 2 (CCAT2) is a newly recognized lncRNA transcribed from the 8q24 genomic region. It functions as an oncogene in various types of cancers including breast cancer, in which it affects Wnt/β-catenin pathway. Previous studies have shown a putative interaction between this lncRNA and MYC proto-oncogene.

Methods: In the current study, we evaluated the expression of CCAT2 in breast cancer tissues with regards to the expression of its target MYC. In addition, we assessed the relationship between CCAT2 and MYC expression levels in tumor tissues and the clinical prognostic characteristics of breast cancer patients.

Results: MYC expression levels were significantly up-regulated in tumor tissues compared with adjacent non-cancerous tissues (ANCTs), while such analysis showed no statistically significant difference between these two tissue types in CCAT2 expression. Starkly increased CCAT2 gene expression levels were found in 12/48 (25%) of cancer tissue samples compared with their corresponding ANCTs. Furthermore, significant inverse correlations were found between CCAT2 expression and stage, as well as lymph node involvement. Besides, a significant inverse correlation was found between the relative MYC expression in tumor tissues compared with their corresponding ANCTs and disease stage.

Conclusion: These results highlight the significance of MYC and CCAT2 expressions in the early stages of breast cancer development and suggest a potentially significant role for CCAT2 in a subset of breast cancer patients, which could be applied as a potential therapeutic target in these patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5548962PMC
http://dx.doi.org/10.18869/acadpub.ibj.21.5.303DOI Listing
September 2017

The Importance of VEGF-KDR Signaling Pathway Genes should Not Be Ignored When the Risk of Developing Multiple Sclerosis is Taken into Consideration.

J Mol Neurosci 2017 May 11;62(1):73-78. Epub 2017 Apr 11.

Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, 8th Floor, SBUMS Bldg., Next to Ayatollah Taleghani Hospital, Evin, Tehran, 198396-3113, Iran.

Vascular endothelial growth factor (VEGF) and its receptor kinase insert domain-containing receptor (KDR) pathway trigger the process of angiogenesis as well as inflammation, which contributes to the development and progression of demyelinating lesions in multiple sclerosis. This work is a case-control study comprising of a total of 400 subjects with multiple sclerosis and 400 healthy controls. Participants were subjected to neurological examination and peripheral blood sampling for genotyping. Polymorphisms in the VEGF and KDR genes were assessed using the restriction fragment length polymorphism (RFLP-PCR) method. A significantly higher frequency of the T allele and TT genotype of the VEGF 936C > T (rs3025039) polymorphism was found in the multiple sclerosis group than in the healthy control group (P = 0.01 [OR = 1.41] and P = 0.01 [OR = 3.12], respectively). In addition, VEGF 936C  >  T showed an association with patients in a recessive model. However, the KDR -604T > C (rs2071559) polymorphism showed no significant difference in either allelic or genotype frequency between the two groups. Taken together, the results of the present study suggests that the T allele of the rs3025039 in VEGF gene could be considered a risk factor for developing multiple sclerosis in the Iranian population.
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http://dx.doi.org/10.1007/s12031-017-0912-2DOI Listing
May 2017

Ras-like without CAAX 2 (RIT2): a susceptibility gene for autism spectrum disorder.

Metab Brain Dis 2017 06 11;32(3):751-755. Epub 2017 Feb 11.

Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, 8th Floor, SBUMS Bldg., Next to Ayatollah Taleghani Hospital, Evin, Tehran, 198396-3113, Iran.

Ras-like without CAAX2 (RIT2) which encodes a GTP-binding protein has recently been reported as a new susceptibility gene for Autism Spectrum Disorders (ASD) in a genome-wide association study. Since the gene is suggested to be involved in the pathogenesis of different neurological diseases, we investigated the association of two single nucleotide polymorphisms (SNP) rs16976358 and rs4130047 of this gene with ASD in Iranian patients. A total of 1004 individuals, comprising 532 ASD cases and 472 healthy subjects participated in this study. Allele frequency analyses showed significant over-presentation of rs16976358-C allele in cases versus controls (P < 0.0001). In addition, rs16976358 CC genotype (OR (95% CI) =3.57(1.72-7.69) and P < 0.0001) and rs4130047 CC genotype (OR (95% CI) =0.64(0.43-0.97) and P = 0.035) were associated with ASD in recessive inheritance model. Besides, haplotype analysis demonstrated an association between the C/T haplotype block (rs16976358/rs4130047) and ASD (OR (95%CI) = 0.44 (0.31-0.62), P < 0.0001). Altogether, our findings provided additional confirmation for the RIT2 gene participation in ASD risk and suggested the rs16976358 variant as a possible genetic risk factor for this disorder.
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http://dx.doi.org/10.1007/s11011-017-9969-4DOI Listing
June 2017

DNA methylation assessment as a prognostic factor in invasive breast cancer using methylation-specific multiplex ligation dependent probe amplification.

EXCLI J 2016 11;15:11-20. Epub 2016 Jan 11.

Hematology & Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Biochemistry and Clinical Laboratories, Division of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.

DNA methylation of promoter regions is a common molecular mechanism for inactivation of tumor suppressor genes that participates in carcinogenesis. Determining the methylation status of genes in cancer and their association with clinical features play an essential role in early diagnosis, prognosis and determine appropriate treatment for patients. The purpose of the present study was to evaluate the methylation of tumor suppressor genes in patients with invasive ductal carcinoma (IDC). Furthermore, we evaluated the association between clinical parameters and DNA methylation as a biomarker in diagnostic IDC patients. The methylation-specific multiplex ligation dependent probe amplification (MS-MLPA) assay was used to analyze the methylation profile of 24 genes in formalin-fixed paraffin embedded (FFPE) tissue samples from 75 patients with IDC. Each of the patients showed a distinctive methylation profile. We observed higher methylation in the RASSF1 (48 %), CDH13 (44 %) and GSTP1 (36 %) genes. Some of the methylated genes were associated with clinical features. Methylation of GSTP1 (P=0.028) and RASSF1 (P=0.012) were related with lymph node metastasis. Methylation of GSTP1 (P=0.005) was associated with high histological grade. Moreover, concurrent methylation of GSTP1 and CDH13 was observed in IDC patients (p<0.001). Hierarchical cluster analysis based on the methylation profile revealed two main clusters of patients, the highly methylated cluster being significantly associated with high histological grade and lymph node metastasis. The results of this study indicate that the methylation status of RASSF1 and CDH13 and GSTP1 can be a prognostic marker to better management of IDC patients.
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http://dx.doi.org/10.17179/excli2015-485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4822054PMC
April 2016

Association of CLU and TLR2 gene polymorphisms with late-onset Alzheimer disease in a northwestern Iranian population.

Turk J Med Sci 2015 ;45(5):1082-6

Background/aim: A number of genetic variants from different genes have been reported to be related to late-onset Alzheimer disease (LOAD) susceptibility. From these genes, polymorphisms in CLU and TLR2 have been replicated in several studies. In this study we examined the association of rs11136000 in CLU and the TLR2 -196 to -174 del polymorphism with the risk of LOAD in a northwestern Iranian population.

Materials And Methods: We conducted a case-control study with a dataset of 160 LOAD patients and 163 healthy controls. To examine polymorphisms of CLU and TLR2 in LOAD we used the PCR/RFLP method and genotype frequencies were statistically determined.

Results: There was no association between CLU polymorphism and the risk of LOAD, but for deletion in TLR2 we found significant differences between LOAD and the control group (P > 0.001, OR = 0.55).

Conclusion: This result suggests that the TLR2 -196 to -174 del polymorphism is an additional risk factor for LOAD. Allelic frequencies of CLU may have no effect on risk of LOAD.
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http://dx.doi.org/10.3906/sag-1406-64DOI Listing
February 2016

C-kit Mutations in Endometrial Cancer: Correlation with Tumor Histologic Type.

Asian Pac J Cancer Prev 2015 ;16(17):7449-52

Women's Reproductive Health Research Center, Tabriz, Iran E-mail :

Objective: Endometrial cancer is the fourth most common cancer among women in developed countries. Affected patients may benefit from systemic chemotherapy, alone or in combination with targeted therapies if the disease is clinically diagnosed prior to expansion and metastasis to other organs.The aim of this study was to evaluate the prognostic role of c-kit mutations and comparision with tumor type and grade in human uterine endometrial carcinomas.

Materials And Methods: Seventy five patients with endometrial carcinoma and seventy five normal controls were studied for possible mutations in exon 17 of the c-kit gene using single strand conformational polymorphisms and sequencing.

Results: c-kit mutation in exon 17 appeared to be significantly different between endometrial carcinoma and normal endometrium. The pattern and frequency of the mutations was also shown to be different between tumors from different stages.
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http://dx.doi.org/10.7314/apjcp.2015.16.17.7449DOI Listing
September 2016

Genetic Factors Affecting Late-Onset Alzheimer's Disease Susceptibility.

Neuromolecular Med 2016 Mar 9;18(1):37-49. Epub 2015 Nov 9.

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

Alzheimer's disease is considered a progressive brain disease in the older population. Late-onset Alzheimer's disease (LOAD) as a multifactorial dementia has a polygenic inheritance. Age, environment, and lifestyle along with a growing number of genetic factors have been reported as risk factors for LOAD. Our aim was to present results of LOAD association studies that have been done in northwestern Iran, and we also explored possible interactions with apolipoprotein E (APOE) status. We re-evaluated the association of these markers in dominant, recessive, and additive models. In all, 160 LOAD and 163 healthy control subjects of Azeri Turkish ethnicity were studied. The Chi-square test with Yates' correction and Fisher's exact test were used for statistical analysis. A Bonferroni-corrected p value, based on the number of statistical tests, was considered significant. Our results confirmed that chemokine receptor type 2 (CCR2), estrogen receptor 1 (ESR1), toll-like receptor 2 (TLR2), tumor necrosis factor alpha (TNF α), APOE, bridging integrator 1 (BIN1), and phosphatidylinositol-binding clathrin assembly protein (PICALM) are LOAD susceptibility loci in Azeri Turk ancestry populations. Among them, variants of CCR2, ESR1, TNF α, and APOE revealed associations in three different genetic models. After adjusting for APOE, the association (both allelic and genotypic) with CCR2, BIN1, and ESRα (PvuII) was evident only among subjects without the APOE ε4, whereas the association with CCR5, without Bonferroni correction, was significant only among subjects carrying the APOE ε4 allele. This result is an evidence of a synergistic and antagonistic effect of APOE on variant associations with LOAD.
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http://dx.doi.org/10.1007/s12017-015-8376-4DOI Listing
March 2016

Age-related decrease in mtDNA content as a consequence of mtDNA 4977 bp deletion.

Mitochondrial DNA A DNA Mapp Seq Anal 2016 07 7;27(4):3008-12. Epub 2015 Jul 7.

b Department of Medical Genetics , National Institute for Genetic Engineering and Biotechnology , Tehran , Iran.

As one of the most frequent somatic mutations accumulated during aging in human mitochondrial DNA, the 4977 bp deletion has intrigued scientific interest in recent years. Although many studies have shown a significant increase in the amount of 4977 bp deletion, the findings with respect to an age-dependent escalate of ΔmtDNA4977 bp in blood are still disputatious. Therefore, we investigated the presence of common deletion and mtDNA deletion level in whole blood samples of 100 old individuals (60-90 years). We detected the accumulation of common deletion in 46 old individuals. Consequently, there was statistically significant difference between the aged and young individuals in mitochondrial content (p = 0.01) and deletion levels ranged from 2% to 17% of the total mtDNA (mean: 10% ± 0.02%). We conclude that common deletion has decreased the mtDNA content; however, it is not clearly detectable in the blood as one of the fast replicating tissues comparing with tissues with low mitotic activity.
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http://dx.doi.org/10.3109/19401736.2015.1063046DOI Listing
July 2016

Role of exon 7 PTEN Gene in Endometrial Carcinoma.

Asian Pac J Cancer Prev 2015 ;16(11):4521-4

Women's Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran E-mail :

Background: Endometrial carcinoma is the most common malignant tumor of the female genital tract and the fourth most common cancer in Iranian women after breast, colorectal and lung cancers. Various genetic alterations appear to be early events in the pathogenesis of endometrial carcinoma and it seems that PTEN is the most commonly mutated gene in the endometrioid subtype. The aim of the present study was to investigate the correlation between mutations in exon 7 of PTEN gene and endometrial carcinoma.

Materials And Methods: Seventy-five patients with endometrial carcinoma and 75 females whose underwent hysterectomy for non tumoral indication were selected for evaluation of PTEN mutations in exon 7 by PCR-SSCP and sequencing. Correlations between the frequency and type of mutation and the pathologic findings of the cancer (tumor subtype, stage and grade) were assessed.

Results: All of the samples were obtained from Iranian patients. 60 % (45 cases) of the tumors were endometriod and 40% (30 cases) were of serous type. The grade distributions of the 75 cases according to the FIGO staging system were as follows: low grade, 20 cases; high grade 55 cases, low stage, 41 cases; high stage 34 cases. For exon 7 of the PTEN gene, the analysis showed that there were no mutations in our cases.

Conclusions: Our findings in the present study suggest that exon 7 of PTEN does not play any significant role in the development of endometrial carcinoma in Iranian cases.
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http://dx.doi.org/10.7314/apjcp.2015.16.11.4521DOI Listing
March 2016

Lack of influence of TP53 Arg72Pro and 16bp duplication polymorphisms on risk of breast cancer in Iran.

Asian Pac J Cancer Prev 2015 ;16(7):2971-4

Department of Medical Genetics, School of Medicine, Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran E-mail :

TP53 is assumed to be a very important tumour suppressor gene, as illustrated by recent reports that have shown effects of its polymorphisms on breast cancer risk. Arg72Pro and PIN3(16bp duplication) polymorphisms are proposed to have an effective role in structural changes of p53 and have therefore attracted interest as a risk factor for breast cancer in different populations. The aim of this study was to examine and determine whether p53 codon 72 and PIN3 Ins16 bp may be associated with an increased risk for breast cancer in female patients from the northwest of Iran. Genotyping was performed by PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) method for a total of 100 women with breast cancer and 100 healthy women without any background of cancer, focusing on the TP53 Arg72Pro-16Del/Ins haplotypes and the combined genotypes. The results in this study established no statistical significant distinctions between the genotypes and allele frequency were found for Arg72Pro and PIN3 Ins 16 bp polymorphisms between patients and controls.
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http://dx.doi.org/10.7314/apjcp.2015.16.7.2971DOI Listing
December 2015

First case report of Rett syndrome in the Azeri Turkish population and brief review of the literature.

Epilepsy Behav Case Rep 2015 23;3:15-9. Epub 2015 Feb 23.

Liver and Gastrointestinal Disease Research Center, Tabriz Children's Hospital, Tabriz University of Medical Sciences, Tabriz, Iran.

Rett syndrome is a dominant X-linked male-lethal disorder largely caused by mutations in the gene encoding methyl-CpG binding protein 2 (MECP2). Clinical manifestations include neurodevelopmental disorder characterized by early-onset intractable seizures, severe developmental delay, intellectual disability, and abnormal electroencephalograms. Afflicted females show normal development until the age of 6 to 18 months, followed by gradual loss of speech abilities, microcephaly, social impairment, ataxia, and stereotypic hand movements. We report a 7-year-old girl who was born of a nonconsanguineous marriage presenting with mental retardation and delayed development. Physical examination revealed loss of speech, repetitive hand-wringing movement, short stature (120 cm), strabismus, microcephaly, and autistic behavior. The diagnosis was confirmed by sequencing MECP2 gene with heterozygous mutation C385A in exon 2. The current study aimed to report the first case of Rett syndrome in the Azeri Turkish population.
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http://dx.doi.org/10.1016/j.ebcr.2014.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4338853PMC
March 2015

The polymorphism of hypoxia-inducible factor-1a gene in endometrial cancer.

Asian Pac J Cancer Prev 2014 ;15(23):10393-6

Women's Reproductive Health Research Center, Department of Medical Genetics, Tabriz University of Medical Sciences, Tabriz, Iran E-mail : [email protected]

Background: Endometral carcinoma is the most common malignant tumor of the female genital tract and the fourth most common cancer in women after breast, colorectal and lung cancers Hypoxia-inducible factor -1 (HIF-1) is a key transcription factor that regulates cellular response to hypoxia HIF-1 plays important roles in the development and progression of cancer through activation of various genes that are involved in crucial aspects of cancer biology, including angiogenesis, energy metabolism, vasomotor function, erythropoiesis, and cell survival. In this study, we aimed to investigate the association between HIF-1 1772 C/T polymorphisms and endometrial cancer.

Materials And Methods: 75 patients with endometrial carcinoma and 75 patients whose underwent hysterectomy for non tumoral indication selected for evaluation of HIF-1 1772 C/T polymorphisms by PCR-RFLP and sequencing.

Results: For the 1772 C/T polymorphism, the analysis showed that the T allele and genotype TT were significantly associated with endometrial cancer risk.

Conclusions: Our results suggest that the C1772T polymorphism of the HIF-1a may be associated with endometrial cancers.
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http://dx.doi.org/10.7314/apjcp.2014.15.23.10393DOI Listing
September 2015
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