javad tavakkoly bazzaz
-
Introduction
Congenital ichthyosiform erythroderma (CIE) is a subtype of autosomal recessive congenital ichthyosis (ARCI), a group of ineffective keratinization disorders, which mainly results from missense mutations in the transglutaminase 1 (TGM1) gene.
Case PresentationHerein, a 9-year-old male case of CIE is presented, for whom we conducted genetic testing to uncover the underlying molecular cause of his condition. We performed whole-exome sequencing (WES) on the DNA extracted from blood, and the data was analyzed for checking pathogenic variants. Analysis of the WES data identified a novel missense variant, c.1165C >T (p. Arg389Cys), in the TGM1 gene. Evaluation of this variant via in silico tools showed its detrimental consequences on the stability and function of the encoded protein. The variant was characterized as likely pathogenic based on the American College of Medical Genetics and Genomics guidelines for variant interpretation. Analysis of all available family members confirmed the co-segregation of this novel variant with the CIE disease within the family.
ConclusionsThis study reported the successful application of WES and bioinformatics analysis to identify a novel mutation in a well-established ARCI-causing residue in an Iranian patient.
Keywords: Autosomal Recessive Congenital Ichthyoses, Congenital Ichthyosiform Erythroderma, Whole Exome Sequencing, TGM1 -
Gastroenterology and Hepatology From Bed to Bench Journal, Volume:14 Issue: 2, Spring 2021, PP 141 -153Aim
The aim of this study was to integrate both coding and non-coding available microarray data in the development of colorectal cancer (CRC) with bioinformatics analyses to attain a more inclusive pathobiologic map of their molecular interactions and functions.
BackgroundIdentification of competing endogenous RNAs (ceRNAs), especially circRNAs, has become a new hotspot in cancer research, although their roles and underlying mechanisms in CRC development remain mostly unknown.
MethodsMicroarray data was retrieved from the Gene Expression Omnibus (GEO) database and analyzed. Several bioinformatics tools and databases were applied for further elucidation. Principal component analysis (PCA) was run separately for four datasets. The dysregulated circRNA-miRNA-mRNA, co-expression, and protein-protein interaction (PPI) networks were established.
ResultsPCA discloses colorectal tumors; normal tissue can be distinguished not only by mRNAs expression profile, but also by both circRNA and miRNA expression profiles. In this study, 14 DE mRNAs, 85 DE miRNAs, and 36 DE circRNAs were identified in CRC tissue and compared with normal tissue. Taking their potential interactions into account, a circRNA-miRNA-mRNA network was constructed. The results disclosed some DE circRNAs with potential oncogenic (circ_0014879) or tumor suppressive (circ_0001666 and circ_0000977) effects. Finally, the PPI network suggests pivotal roles for DOCK2 and PTPRC dysregulation in the progression of CRC, possibly by facilitating tumor escape from immune surveillance.
ConclusionThe current study proposes a novel regulatory network consisting of DE circRNAs, miRNAs, and mRNAs in CRC development that highlights the roles of DE circRNAs at the upstream of oncotranscriptomic cascade in CRC development, suggesting their potential to be utilized as both prognostic and therapeutic biomarkers.
Keywords: circRNA, miRNA, Colorectal cancer, Microarray, Bioinformatics -
International Journal of Molecular and Cellular Medicine, Volume:8 Issue: 32, Autmn 2019, PP 258 -270
The acetylcholine receptor (AChR) is a member of the superfamily of transmitter-gated ion channels having a critical role in controlling electrical signals between nerves and muscle cells. Disruptive mutations in genes encoding different subunits of AChR result in multiple pterygium syndrome (MPS), which can be associated with a severe prenatally lethal presentation. This study aimed to investigate the etiology of lethal MPS (LMPS) in two consanguineous families with a history of miscarriages. DNA was extracted from a tissue sample of two aborted fetuses (probands) from two different families with a history of spontaneous miscarriages. Parental peripheral blood samples were collected for confirmatory analysis and follow-up testing. Whole-exome sequencing (WES) was performed on DNA from the probands. The results were confirmed and segregated by Sanger sequencing. Moreover, protein structure evaluations were accomplished. We identified a homozygous frameshift mutation of c.753_754delCT (p.V253fs*44) and a homozygous missense mutation of c.715C>T (p.Arg239Cys) in the CHRNG gene. Both aborted fetuses had pterygium, severe arthrogryposis, and fetal hydrops with cystic hygroma, being compatible with LMPS. The heterozygous state was confirmed in parents for both CHRNG variants. Likewise, CHRNG mutation was predicted to display the damaging effects by lowering the number of helixes and modifying the surface electrostatic potential. The present study identified rare sequence variants in the CHRNG gene in aborted fetuses from consanguineous couples with recurrent miscarriage history. WES is a comprehensive and cost-effective approach to study heterogeneous diseases including MPS. Such findings can improve our knowledge of MPS databases, particularly for genetic counseling of high-risk families and preimplantation genetic diagnosis.
Keywords: Multiple pterygium syndromes, whole-exome sequencing, CHRNG, recurrent abortion -
Journal of Research in Applied and Basic Medical Sciences, Volume:6 Issue: 1, Winter 2020, PP 14 -17
Carriers of structural chromosomal rearrangements such as Robertsonian or reciprocal translocations have an increased risk of spontaneous abortion and producing offspring with genetic abnormalities. Robertsonian translocations are present in 0.1% of the general population and 1% of the infertile population. Two types of Robertsonian translocations occur more frequently than all others, being 45,XX,rob(13;14)(q10;q10) and 45,XX,rob(14;21)(q10;q10) respectively. The history of repeated abortions could be the outcome of unbalanced gametes (either monosomy or trisomy) resulting during the meiotic segregation of the balanced heterozygote female carrier. In the present report, uncommon Robertsonian translocation in a couple with spontaneous repeated abortions is reported. Cytogenetic analysis of a couple revealed the presence of 45, XY, t (15; 15) (10q; 10q) chromosomal constitution in the male partner. The cytogenetic analysis of couples with repeated abortions is obligatory to identify any probable chromosomal aberrations. As far as we know this is the first instance reported in Iran.
Keywords: Carrier, Chromosomal rearrangements, Robertsonian translocations, Abortion -
Foodborne diseases are considered as one of the main problems of public health. Escherichia coli O157H7 are responsible for major outbreaks of bloody diarrhea and hemolytic uremic syndrome (HUS) throughout the world. The mortality is originated from the production of a Shiga toxin (Stx) by these bacteria. Garlic essential oil (GEO) has antibacterial effects on many food-borne pathogens. Therefore, this study was aimed to evaluate the antibacterial activity of the Allium sativum L. EO and its nanoliposomal form on the virulence of E. coli O157:H7. Reverse passive latex agglutination test was used to detect Shiga toxin2 (Stx2) production after exposure to sub-inhibitory concentrations of free and nanoencapsulated EO. Also, the effect of sub-inhibitory concentrations of free and nanoliposomal form of GEO was evaluated on Stx2 gene expression and the relative transcriptional level of Stx2 gene was determined by real-time PCR. It was found that the sub-inhibitory concentrations of liposomal form of EO (50 and 75%) had a significantly higher inhibitory effect on Stx2 titer than its free form (p<0.05). Also, increasing the concentration of EO and nanoencapsulated EO significantly reduced Shiga toxin 2 gene expression according to control. Using 75% sub-inhibitory value of free and nanoliposome GEO, the relative transcriptional level of Stx2A gene was reduced from 0.938 to 0.667 and 0.931 to 0.659, respectively. Based on our findings, different methods of nanoencapsulation should future study to improve nanoliposome efficacy to suppress toxin production on expression level.Keywords: Allium sativum L. essential oil, Nanoliposome, E. coli O157:H7, Shiga-toxin (Stx), Inhibitory effect
-
BackgroundYoung 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.MethodsFresh 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.ResultsOur results revealed that FOXA1 methylation level is significantly higher in early parous compared with nulliparous group (p = 0.041).ConclusionOur 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.Keywords: Breast cancer, DNA methylation, Epigenetics, FOXA1, Pregnancy
-
ObjectiveChromosomal translocations are among the most common mutational events in cancer development, especially in hematologic malignancies. However, the precise molecular mechanism of these events is still not clear. It has been recently shown that alternative non-homologous end-joining (alt-NHEJ), a newly described pathway for double-stranded DNA break repair, mediates the formation of chromosomal translocations. Here, we examined the expression levels of the main components of alt-NHEJ (PARP1 and LIG3) in acute myeloid leukemia (AML) patients and assessed their potential correlation
with the formation of chromosomal translocations.Materials And MethodsThis experimental study used reverse transcription-quantitative polymerase chain reaction (RTqPCR) to quantify the expression levels of PARP1 and LIG3 at the transcript level in AML patients (n=78) and healthy individuals (n=19).ResultsPARP1 was the only gene overexpressed in the AML group when compared with healthy individuals (P=0.0004), especially in the poor prognosis sub-group. Both genes were, however, found to be up-regulated in AML patients with chromosomal translocations (P=0.04 and 0.0004 respectively). Moreover, patients with one isolated translocation showed an over-expression of only LIG3 (P=0.005), whereas those with two or more translocations over-expressed both LIG3 (P=0.002) and PARP1 (P=0.02).ConclusionThe significant correlations observed between PARP1 and LIG3 expression and the rate of chromosomal translocations in AML patients provides a molecular context for further studies to investigate the causality of this association.Keywords: Acute Myeloid Leukemia, Chromosomal Translocation, LIG3, PARP1 -
BackgroundPrevious studies have suggested that BRCA1 dysregulation has been shown to have a role in triple-negative phenotypic manifestation. However, differences of BRCA1 expression, as a tumor suppressor gene, have rarely been investigated between luminal and triple-negative breast tumors. Therefore, the present study attempted to compare the BRCA1 expression in triple-negative with luminal breast tumors and its association with the clinicopathologic characteristics of patients.MethodsBRCA1 expression was evaluated by real-time PCR in 26 triple-negative and 27 luminal breast tumors.ResultsThe results revealed that there is a high frequency of BRCA1 underexpression in both triple-negative and luminal breast tumors. The BRCA1 underexpression was related to young age at diagnosis, lymph node involvement, and grade ІІІ tumors.ConclusionThe observations suggest that decreased BRCA1 expression, regardless of tumor subtype, has a general role in breast malignancy and associated with poor prognostic features in breast tumors.Keywords: Breast cancer, BRCA1, Triple, negative breast neoplasm
-
BackgroundThe epidermal growth factor receptor (EGFR) has critical roles in signal transduction pathways, leading to cell growth and differentiation. EGFR expression levels vary among different breast tumor subtypes and ethnic groups. On the other hand, the relationship between EGFR expression at the mRNA level with clinicopathological characteristics in breast cancer has rarely been reported.ObjectivesThe present study focuses on the assessment of EGFR mRNA expression in breast tumors and the association of its expression with various clinicopathological features in Iranian patients with breast cancer.MethodsIn this cross sectional study, the expression of EGFR was assessed by real time PCR technique in tumors of 52 Iranian women (27 luminal and 25 triple negative tumors) with primary breast cancer and 6 normal breast tissues.ResultsThe results of this study showed that EGFR mRNA was overexpressed only in triple negative tumors, and there is a high frequency of EGFR underexpression in luminal breast tumors, unlike triple negative tumors. We demonstrated that there is a significant positive correlation (r = 0.662) between EGFR expression and the size of luminal tumors. In the current study, the increased expression of EGFR is significantly associated with estrogen receptor (ER) negative, progesterone receptor (PR) negative, and grade III in breast tumors.ConclusionsThese findings suggest that the majority of patients with triple negative tumors are likely eligible to receive the anti-EGFR therapies. Also, it seems that EGFR expression probably has an association with tumor size in luminal subtype of breast tumors.Keywords: Breast Cancer, EGFR mRNA Expression, Luminal Subtype, Triple Negative Subtype
-
Long intergenic non-coding RNA (lincRNA) has been introduced as key regulators of diverse biological processes, including transcription, chromatin organization, cell growth and tumorigenesis. With regard to the potential role of lincRNAs in cancer development, one may postulate that differential expression of lincRNAs could be employed as a tool in cancer diagnosis, prognosis, and targeted therapy. In this study, we aimed to explore the putative correlation between the expression levels of two lincRNAs: LINC00152 and LINC01082 in the bladder cancer (BC), in comparison with its adjacent non-cancerous tissue. Fifty Iranian subjects diagnosed with BC, representing in different stages and grades participated in this study.. The mRNA expression levels of the above mentioned lincRNAs were analyzed comparatively in cancerous and their adjacent non-cancerous counterpart tissues, of each subject by Real-Time PCR. The expression levels of LINC00152, and LINC01082 were significantly lower in tumor tissues in comparison with their adjacent normal tissues (PKeywords: Bladder cancer, long intergenic non, coding RNA (lincRNA), LINC00152, LINC01082
-
مجله دانشکده پزشکی دانشگاه علوم پزشکی تهران، سال هفتاد و پنجم شماره 6 (پیاپی 198، شهریور 1396)، صص 408 -416زمینه و هدفپیرایش متناوب غیرمعمول در سلول های سرطانی، شایع بوده و ایزوفرم های حاصل می توانند به عنوان بیومارکر و یا هدف درمانی برای طراحی دارو مورد استفاده قرار گیرند. شناسایی ایزوفرم ها، جهت توسعه استراتژی های درمانی سرطان حایز اهمیت می باشد. هدف این مطالعه شناسایی ایزوفرم ها و بیان 3 ژن PIK3CA، FGFR3 و FGFR1 با استفاده از فناوری جدید تعیین توالی RNA و Real-Time PCR در سرطان مثانه بود.روش بررسیدر این مطالعه مقطعی، که در بازه زمانی شهریور 1393 تا مهر 1395 در مرکز تحقیقات اورولوژی دانشگاه علوم پزشکی تهران انجام گرفت. 30 نمونه بافت تازه تومور و 30 نمونه بافت نرمال مجاور تومور در فاصله مناسب، از افراد مبتلا به سرطان مثانه تهیه شد. RNA از بافت ها استخراج و پس از بررسی کمی و کیفی و ساخت کتابخانه cDNA، تعیین توالی RNA انجام و داده های حاصله توسط نرم افزارهای مربوطه آنالیز گردید.یافته هاایزوفرم های هر سه ژن در بافت نرمال و تومور از لحاظ تعداد و الگوی بیان تفاوت نشان دادند. ژن PIK3CA در بافت نرمال یک رونوشت و در بافت سرطانی سه ایزوفرم، ژن FGFR3 و FGFR1 در بافت تومور به ترتیب 6 و 12 و در بافت نرمال 7 و 9 رونوشت داشتند. افزایش بیان ژن (0/01P=)FGFR3 و کاهش بیان ژن (0/01P=) FGFR1 معنادار بود.نتیجه گیریپیرایش متناوب غیرمعمول در سلول های سرطانی مثانه منجر به ایجاد ایزوفرم هایی گردید که بعضی از آن ها در سلول های نرمال وجود نداشته و یا میزان بیان متفاوتی داشتند و به عنوان هدف درمانی و یا مارکر تشخیصی در مطالعات آتی قابل استفاده می باشند.کلید واژگان: پژوهش های مقطعی، تعیین توالی RNA، ترنسکریپتوم، گیرنده های فاکتور رشد فیبروبلاستBackgroundAberrant pre-mRNA alternative splicing is a common event in cancer cells. Many abnormally spliced RNA variants have been observed in tumor cells and they can be used as biomarkers or therapeutic targets in new drug design. Increasing our knowledge in understanding the mechanisms of alternative pre-mRNA splicing for cancer-related genes and determination of cancer specific isoforms are important for the development of new strategies in cancer therapy. The aim of this study was isoforms identification and expression of PIK3CA, FGFR3 and FGFR1 genes in bladder cancer by RNA Sequencing and Real-Time PCR.MethodsThis cross-sectional study was conducted at Urology Research Center of Sina Hospital, Tehran University of Medical Sciences, Tehran, from September 2014 to October 2016. Paired tumor and adjacent normal tissues samples were obtained from 30 bladder cancer subjects. Total RNAs were extracted from bladder tumor and normal tissues. Quantitative and qualitative examinations have been done. After quality control, fragmentation of RNAs and cDNA library construction, next-generation RNA sequencing was performed. Resulting raw data were analyzed with different bioinformatics software. Differential expression was confirmed by Real-Time PCR.ResultsRNA sequencing results showed the number of PIK3CA (1 vs 3), FGFR3 (7 vs 6) and FGFR1 (9 vs 12) isoforms and their expression were different in bladder normal tissues in comparison to tumor tissues. Overexpression of PIK3CA gene have been observed in 42% of tumor samples but statistically was not significant. Increased FGFR3 gene (P=0.01) and decreased FGFR1 (P=0.01) expression were significant. There was an association with overexpression of FGFR3 and cigarette smoking ((P=0.037) and family history (P=0.004).ConclusionRNA sequencing make possible to do the accurate assessment of transcript abundance and identification of different isoforms resulted from aberrant pre-mRNA alternative splicing, which is a crucial process for the maturation of transcripts of multi-exon genes. Regarding the differences in isoforms expression in tumor and normal tissues of bladder cancer, they have potential to be used as biomarkers and sensitive targets for cancer therapy.Keywords: cross-sectional studies, fibroblast growth factor receptors, PIK3CA, RNA sequenceing, transcriptome
-
Recognizing the importance of improvement of professionalism and ethics in medical students, the association of American medical colleges (AAMC) and the Liaison committee on medical education (LCME) and others have called for medical educators to pay attention to this critical competency and use different methods and tools for teaching professionalism in training. This article will share the authors experience using movies as a flexible and interactive teaching tool and technique. The taskforce, which aims to teach medical professionalism via movies, was established in 2012 at the Tehran University of Medical Sciences (TUMS). The researchers used movies for teaching professionalism and ethics in medical education as an optional program. First, they invited faculty members, who have expertise and interest in this field. The duration of the programs varied from 3 to 4 hours. During the programs, students received a brief introduction about the program objectives and after implementing the program, they criticized and analyzed them through reflection. An anonymous evaluation form was distributed to evaluate the effect of the program on the students motivation and satisfaction. These programs thus provided the opportunity for students to learn medical professionalism by observing and reflecting on movies.Keywords: Reflection, Professionalism, Education, Medical Student
-
BackgroundDisorders of sex development (DSDs) belong to uncommon pathologies and result from abnormalities during gonadal determination and differentiation. Various gene mutations involved in gonadal determination and differentiation have been associated with gonadal dysgenesis. Despite advances in exploration of genes and mechanisms involved in sex disorders, most children with severe 46,XY DSDs have no definitive etiological diagnoses; therefore, the possibility that other genes or loci might play important roles in these disorders needs to be explored.MethodsPatients (37) clinically suspicious for 46,XY gonadal dysgenesis (46,XY GD) of unknown etiology were studied. SRY, encoding the sex-determining region Y protein, NR5A1, encoding a transcription factor called steroidogenic factor 1, and DHH, encoding the desert hedgehog protein, were directly sequenced. Multiplex ligation-dependent probe amplification (MLPA) was used to detect deletions in NR0B1, encoding the DAX1 protein, and WNT4, encoding the WNT4 protein, and real-time PCR (qPCR) confirmed the MLPA data. Other potential loci have been investigated in the complete genome using Array-Comparative Genomic Hybridization, (Array CGH).ResultsThe SRY deletion was found in five patients. One each of previously described NR5A1, DHH, and AR (androgen receptor) allelic variants were identified. A pathogenic c.2522G>A AR mutation was found in two affected brothers. A heterozygous partial deletion was found in NR5A1 and heterozygous partial duplications were found in WNT4. These deletions and duplications (del/dup) were confirmed by qPCR. The Array CGH result demonstrated one partial deletion in SOX2-OT, which encodes a member of the SOX family of transcription factors, and the exact region of the rearrangements.ConclusionsAccording to our study, del/dup mutations could be checked prior to point mutations, SOX2-OT has a potential role in gonadal dysgenesis, and Array CGH has a prominent role in gonadal dysgenesis diagnosis.Keywords: Array-Comparative Genomic Hybridization, (Array-CGH), Disorders of sex development (DSDs), Mutation
-
Breast cancer is the most important and prevalent cancer in women that can be managed if detected in the early stages. Recently, there has been much focus on the use of epigenetic changes such as DNA methylation in early detection of cancer. As recent research has put forth DOK7 CpG Island methylation as an epimarker, in the present study, using a quantification method, a cohort of Iranian sporadic breast cancer patients are studied compared to healthy women. In this matched case-control study (by ethnicity andage), blood samples were collected and the extracted DNA was controlled and after sonication, the MeDIP process started. The enrichment estimation is the MeDIP control step and after that, all of the H19-ICR, GAPDH-promoter and DOK7-CpG were standardized with appropriate efficiency for Real-Time PCR relative quantification process. Comparison of the Relative Quantification (RQ) of the enriched methylated DNA in the DOK7 gene CpG island in the two groups showed a significant difference (P=0.01). The mean RQ was 0.961 (0.91) in patients and 0.44 (0.46) in the control group. The ROC curve analysis showed AUC= 0.671 and the estimated cut-off for this gene RQ was 1.136; in this cut-off, the odd sratio (OR) was 4.773 (95% CI; 1.52-14.98). It should be noted that the methylation level for DOK7-CpG in DCIS was significantly higher than ICD patients (P-Value= 0.023). Based on our results, we conclude that increased levels of DNA methylation in the DOK7-CpG in peripheral leukocyte associate with breast cancer and after further studies, it can be used as an early diagnostic indicator or a biomarker for breast cancer susceptibility.Keywords: Breast Cancer, Biomarkers, Early Detection of Cancer, DOK7 Gene
-
مقدمهتغییرات سطح سرمی IGF-I در زمینه بیماری دیابت، حتی در صورت عدم کاهش و احیانا افزایش سطوح تام آن، عملا با کاهش سطح آزاد و کاهش فراهمی زیستی (Bioavailability) این فاکتور رشد بروز می یابد. با توجه به پتانسیل های مثبت و تاثیرات حمایتی IGF-I در فرآیندهای ترمیم بافتی و باززایش (Regeneration) سلول های تحت آزار، کاهش سطح آزاد این ماده زمینه ساز بروز و یا تشدید اختلالات و عوارض مختلفی می گردد. جهت بررسی این نکته که آیا تفاوت های موجود در بروز و یا عدم بروز عارضه رتینوپاتی دیابتی در نزد بیماران مبتلا به دیابت نوع یک می تواند به نوعی مرتبط با تغییرات ساختمانی ژن IGF-I باشد، مطالعه حاضر برای نخستین بار به این موضوع می پردازد.روش هادر تحقیق حاضر فراوانی آلل های مربوط به دو پلی مورفیسم ژن IGF-I در موقعیت های*C/T383– و C/T*1089– در نزد 248 بیمار بریتانیایی- قفقازی مبتلا به دیابت نوع یک (135 نفر با رتینوپاتی و 113 نفر بدون رتینوپاتی) با استفاده از روش ARMS-PCRمورد بررسی قرار گرفت.یافته هاتوزیع فراوانی آلل ها و ژنوتیپ های مربوط به این دو پلی مورفیسم تفاوت معناداری را از نظر آماری بین دو جمعیت بیماران دیابتی با توجه به وجود یا فقدان رتینوپاتی نشان نداد)05/0.(P≥نتیجه گیریبا توجه به نقش برجسته IGF-I در پاتوفیزیولوژی عوارض دیررس بیماری دیابت به ویژه رتینوپاتی دیابتی، یافته های ما در وهله اول ممکن است بر فقدان عملکرد پلی مورفیسم های مطالعه شده دلالت نماید که به معنی تاثیرات غیرقابل ملاحظه این دو پلی مورفیسم بر میزان نسخه برداری از ژن IGF-I و در نهایت تعیین غلظت سرمی/ شبکیه ای پروتئین IGF-I است. پیام دیگر این تحقیق می تواند اشاره به عواملی باشد که علاوه بر ژن IGF-I، در عملکرد این محور نقش دارند. مطالعه مجدد فرضیه حاضر در قالبی جامع که دیگر متغیرهای سیستم IGF-I را نیز شامل گردد، قابل توصیه به نظر می رسد.
کلید واژگان: ژنتیک، پلی مورفیسم، رتینوپاتی دیابتی، IGF، 1BackgroundThe alteration of IGF-I systemic level in diabetes is typically characterized by depletion of free IGF-I plasma level and its decreased bioavailability. With regard to protective and advantageous effects of IGF-I on tissue healing and cellular regeneration such depletion could facilitate or accelerate tissue damages and complications. By contrast, the local concentration of IGF-I is reportedly increased in particular tissues during some occasions, which has also clinical implications as IGF-I could function in an autocrine and paracrine manner.The present study was conducted to assess that whether the differential outcome of diabetic subjects relative to diabetic retinopathy (DR) is linked to some extent to the structural variations of IGF-I gene.MethodsTwo polymorphisms of the IGF-I gene at positions -383*C/T and -1089*C/T were employed for genotyping analysis by ARMS-PCR assay and the data of genotype/allele distribution was compared between two subgroups of 248 British Caucasian type 1 diabetic subjects, 135 cases with DR and 113 controls (DR-).ResultsThe distribution of these polymorphisms did not associate significantly with presence or absence of DR (P≥ 0.05).ConclusionSince the involvement of IGF-I in development of DR is fairly rational, our results firstly may reflect some reservations about the functionality of the employed polymorphic markers and secondly may indicate that all regulators of IGF-I functionality or its local concentration level including IGFBPs and IGFRs should be taken into account, so their genes could be the subject of new study to accomplish current investigation. Keywords: -
مقدمهیکی از واسطه های التهابی مهم و ضروری در آغاز و بروز دیابت نوع 1 سایتوکین IFN-g می باشد. این سایتوکین که از گروه سایتوکین های Th1 محسوب می شود، نقش بسیار مهمی را در برانگیختن سلول های ایمنی بیطرف Th0)) و تبدیل آنها به سلول های Th1 و به طور متقابل مهار تکثیر سلول های Th2 دارد که در نهایت سبب القا و پیشبرد پاسخ های ایمنی سلولی می گردد. با توجه به آنکه الگوی پاسخ ایمنی در بیماری خودایمن دیابت نوع 1 از نوع سلولی است، این سایتوکین جایگاه مهمی را از نظر هدایت واکنش های خودایمن و بر هم زدن نظم عوامل سلولی و مولکولی درگیر داراست. از منظر مداخلات درمانی در بیماری دیابت نوع 1 نیز این سایتوکین موضوع تحقیقات متنوعی در سطوح مختلف بوده است.روش هادر قالب یک Candidate Gene Association Study میزان تاثیر پلی مورفیسم ژن IFN-g در موقعیت +874*T/A بر ایجاد و پیشرفت بیماری دیابت نوع 1 مطالعه شد. جمعیت مورد مطالعه شامل 248 نفر بیمار بریتانیایی- قفقازی با دیابت نوع 1 و 119 نفر بدون بیماری مشخص (سالم) بوده است. روش ARMS-PCR جهت تعیین آلل و ژنوتیپ مربوط به پلی مورفیسم مذکور انتخاب گردید.یافته هاتوزیع فراوانی آلل/ ژنوتیپ حاصله از پلی مورفیسم ژن IFN-g تفاوت معنی داری را از نظر آماری در بین دو جمعیت مقایسه شده کنترل و بیمار نداشت (P30.05).نتیجه گیریبا توجه به گزارش های قبلی که همراهی پلی مورفیسم مورد نظر با بیماری دیابت نوع 1 را گزارش نموده اند، یافته های ما چنین نتیجه ای را تایید نمی کند که می تواند دلالت بر این نکته نماید که پلی مورفیسم (های) ژنی دخیل در ایجاد دیابت نوع 1 در گزارش های قبلی، پلی مورفیسم (های) دیگری (یا در داخل ژن IFN-g یا در ساختمان ژن های مجاور) بوده اند که با پلی مورفیسم مورد مطالعه در Linkage Disequilibrium می باشند.
کلید واژگان: ژنتیک، پلی مورفیسم، دیابت، IFN، gBackgroundIFN-g is one of the most essential and fundamental player in initiation and development of T1DM. This mediator belongs to T Helper-1(Th1) class of cytokines and exerts stimulation and differentiation of naïve T cells towards Th1 cells and meanwhile inhibits differentiation and proliferation of Th2 cells. These effects are highly important in induction and progression of cell-mediated immune responses that is aberrantly operative in development of T1DM. Due to such outstanding role, numerous studies including genetic manipulation have focused on the role of this pro-inflammatory cytokine in T1DM.MethodsIn a genetic association study the influence of IFN-g gene variation in position +874*T/A on development of T1DM was analysed in 248 British Caucasian T1DM patients in comparison with 119 healthy matched controls. ARMS-PCR procedure was designed for detection of the variants at allele/genotype level.ResultsNo significant association between IFN-g gene polymorphism and T1DM was apparent (P≥ 0.05). The distribution of these polymorphic variants was in Hardy-Weinberg equilibrium.ConclusionWhile some studies have shown an association between the examined polymorphism of IFN-g and T1DM, our data do not support that. According to present study the selected polymorphic marker (+874*T/A) is not among the polymorphisms that governs in part genetic susceptibility to T1DM. That irreproducibility or controversial results is a common observation in genetic studies of complex traits such as T1DM, reflecting a fragile correlation between genotype and phenotype. This study also underlines the importance of replication of association studies to confirm the previous results/interpretations.Keywords: Genetic, Polymorphism, Diabetes, IFN -
مقدمهآدیپونکتین یک پپتید مترشحه از بافت چربی است که به خاطر ایجاد حساسیت به انسولین و اثرات ضدآتروژنی مورد توجه قرار گرفته است. پلی مورفیسم های ژن آدیپونکتین مرتبط با سطح سرمی آدیپونکتین، BMI، حساسیت به انسولین و دیابت نوع 2 می باشند. هدف از این مطالعه تعیین فراوانی ژنوتیپ ها و آلل های پلی مورفیسم ژن آدیپونکتین در موقعیت +45 T/G و بررسی ارتباط آن با دیابت نوع 2 در جمعیت تهران می باشد.روش هاافراد دیابتی از کلینیک دیابت و گروه کنترل غیردیابتی با محدوده سنی 64-25 سال بوده و از ناحیه 17 تهران انتخاب شدند. در این مطالعه بررسی فراوانی پلی مورفیسم +45 T/G آدیپونکتین در 70 فرد نرمال و 80 بیمار دیابتی چاق و 72 بیمار دیابتی غیر چاق انجام شد. آنالیز مولکولار ژن آدیپونکتین با PCR-RFLPانجام گرفت.یافته هادر این مطالعه مشاهده گردید که فراوانی ژنوتیپ TT جمعیت دیابتی غیرچاق %62.5 و در گروه کنترل 78% بود که این تفاوت از نظر آماری معنی دار بود CI: 0.9-5) و OR: 2.2 و (TT Vs TG+GG P=0.02 (همچنین تفاوت معنی داری در فراوانی آلل های T و G در مقایسه بین گروه دیابتی غیرچاق و گروه کنترل مشاهده گردید و آنالیز آماری نشان داد که فراوانی آلل G در گروه دیابتی غیرچاق (%20.1) نسبت به گروه کنترل (12%) افزایش یافته است CI%95: 0.9-3.7) و OR: 1.8 و (P=0.04.نتیجه گیریاین مطالعه نشان داد که ژنوتیپ TG و GG در مقابل TT شانس ایجاد دیابت را افزایش می دهد که این نقش غیروابسته به چاقی و BMI بالا بوده است.
کلید واژگان: پلی مورفیسم، آدیپونکتین، دیابت ملیتوسBackgroundSingle nucleotide polymorphisms of Adiponectin gene have been associated with BMI, insulin sensitivity and type 2 diabetes, reportedly. In present study we performed a genetic association study for Adiponectin gene at position +45*T/G in type 2 diabetes and normal subjects of Tehran population.MethodsDiabetic patients were selected from diabetes clinic and normal healthy control subjects aged between 25-64 years selected from zone 17 of Tehran. Adiponectin gene polymorphism was analyzed using PCR-RFLP method in normal healthy controls (N=70), obese diabetic patients (N=80) and non-obese diabetic patients (N=72).ResultsFrequency of TT genotype was 62.5% in non-obese diabetic patients and 78% in control group, that was statistically significant (TT vs TG+GG: P=0.02, OR=2.2, CI:0.98-5.00). There was also a significant difference for allele T and G frequencies when we compared between non-obese diabetic patients and controls group. The frequency of allele G was increased in non-obese diabetic (20.1%) patients compared to controls (12%) (P: 0.04 OR: 1.8 CI: 0.9-3.7).ConclusionThis study showed TG and GG alleles of Adiponectin gene polymorphism at position +45*T/G are risk factors for development of diabetes mellitus while this effect is independent from BMI and obesity.Keywords: Polymorphism, Adiponectin, Diabetes mellit -
CANDIDATE GENE ANALYSIS IN DIABETIC RETINOPATHY: IGF-I GENEBackgroundThe alteration of IGF-I systemic level in diabetes is typically characterized by depletion of free IGF-I plasma level and its decreased bioavailability. With regard to protective and advantageous effects of IGF-I on tissue healing and cellular regeneration such depletion could facilitate or accelerate tissue damages and complications. By contrast, the local concentration of IGF-I is reportedly increased in particular tissues during some occasions, which has also clinical implications as IGF-I could function in an autocrine and paracrine manner.
The present study was conducted to assess that whether the differential outcome of diabetic subjects relative to diabetic retinopathy (DR) is linked to some extent to the structural variations of IGF-I gene.MethodsTwo polymorphisms of the IGF-I gene at positions -383*C/T and -1089*C/T were employed for genotyping analysis by ARMS-PCR assay and the data of genotype/allele distribution was compared between two subgroups of 248 British Caucasian type 1 diabetic subjects, 135 cases with DR and 113 controls (DR-).ResultsThe distribution of these polymorphisms did not associate significantly with presence or absence of DR (P≥ 0.05).ConclusionSince the involvement of IGF-I in development of DR is fairly rational, our results firstly may reflect some reservations about the functionality of the employed polymorphic markers and secondly may indicate that all regulators of IGF-I functionality or its local concentration level including IGFBPs and IGFRs should be taken into account, so their genes could be the subject of new study to accomplish current investigation.Keywords: Genetic, Polymorphism, Diabetic Retinopathy, IGF-1 -
مقدمهVEGF فاکتور رشد نسبتا جدیدی است که قابلیت های بیولوژیک بسیار متنوعی را داراست. شان عمده این قابلیت ها، هدایت و تعیین مسیر سلسله واکنش هایی است که در بستر عروقی (به ویژه میکرو واسکولار) بافت ها و اندام های مختلف روی می دهند.روش هادر مطالعه حاضر طی روش ARMS-PCR، نقش تغییرات ساختمانی ژن VEGF در بروز استعداد یا مقاومت افراد دیابتی نسبت به رتینوپاتی دیابتی ارزیابی شده است. توزیع فراوانی چهار پلی مورفیسم در موقعیت های -7*C/T، -1001*G/C، -1154*G/A و -2578*C/A در بین بیماران مبتلا به T1DM (248 نفر) و زیرگروه های با رتینوپاتی (135 نفر) و بدون رتینوپاتی (113 نفر) آنها همراه با گروه شاهد (سالم) (95 نفر) که همگی از جمعیت «بریتانیایی- قفقازی» بوده اند، بررسی گردید.یافته هابا مقایسه توزیع فراوانی آلل ها/ ژنوتیپ های پلی مورفیک در میان جمعیت های بیمار، شاهد و همچنین در بین دو زیرگروه دیابتی های با و بدون رتینوپاتی، به طور خاص در مورد پلی مورفیسم -7*C/T و تنها در هنگام مقایسه دو زیرگروه اخیر (DR? و DR+) اختلاف قابل ملاحظه و معناداری قابل مشاهده بود (1.98=OR؛ 0.002=P).نتیجه گیریبا توجه به نقش محوری VEGF در پاتوفیزیولوژی رتینوپاتی های ایسکمیک، مطالعه حاضر در پی پاسخ به این پرسش بوده که آیا می توان این افزایش بیان را ثانویه به نوع آرایش ساختمانی ژن VEGF دانسته و آن را «وابسته به آلل» در نظر گرفت؟ نتیجه تحقیق حاضر چنین بیان می دارد که یکی از پلی مورفیسم های مورد بررسی، حداقل در بستر شرایط بیوشیمیایی دیابت، از چنان قابلیت «عملکردی» و یا پتانسیل فنوتیپیکی برخوردار است که بتواند احتمالا با کنترل سطح و کیفیت پاسخ ژن VEGF به محرکهای محیطی و تنظیم میزان بیان آن، نقش مهمی را در پاتوفیزیولوژی DR ایفا نماید. با توجه به نقش ضعیف تر عوامل ژنتیکی در DR - در مقایسه با سایر عوارض دیابت-، یافته های این مطالعه حاکی از وزن و اثر قابل ملاحظه سازوکارهای «وابسته به ساختمان» ژن VEGF در بروز DR دارند و البته بررسی مجدد فرضیه این مطالعه میان تعداد بیشتری از بیماران دیابتی (DR? و DR+)، می تواند مکمل تحقیق حاضر باشد.
کلید واژگان: رتینوپاتی، VEGF، پلی مورفیسمBackgroundVEGF is newly discovered growth factor that has diverse biologic properties. The bottom-line of these activities is conduction and orchestration of a series of reactions that are taking place at microvasculature of different tissues/organs. Among the growth factors, cytokines and other mediators that reflect meaningful alteration in their local/systemic level, VEGF is the distinct player which can explain by its own all hemodynamic and architectural manifestations present in diabetic retinopathy (DR). The present study was conducted to pursue the role of a candidate gene structure variation, VEGF gene polymorphisms, in genetic susceptibility/resistance to development of DR through a cross sectional case-control study.MethodsThe frequency of four SNPs in VEGF gene at positions –7*C/T, –1001*G/C, –1154*G/A and –2578*C/A has been traced among 248 type 1 diabetic subjects (135 DR+, 113 DR−) along with 95 healthy controls. The populations had "British-Caucasian" background and ARMS-PCR technique was employed for DNA genotyping.ResultsComparing the polymorphic variant's frequency at both allelic and genotypic levels among different groups/subgroups, significant difference was noticeable for –7*C/T polymorphism between diabetic patients with vs. without DR, while T allele conferred protective effect (p=0.002; OR=1.98).ConclusionContemplating that up-regulation/over-expression of VEGF (local/systemic) as a common pre-requisite for DR development, our hypothesis was that whether the VEGF gene structural variations is correlated with the magnitude of VEGF expression in response to different stimuli present in diabetic context, namely hypoxia and hyperglycemia. Our data indicate that among the examined polymorphisms of VEGF gene, only SNP at position –7*C/T harbored significant difference between DR+ vs. DR− cases, proposing phenotypic impact for that SNP illustrating by evolvement/impediment of DR. However, reminding the insubstantial role of genetic issues in development of DR relative to DN or DNU, replicating current hypothesis by providing larger sample size and also employing more polymorphic markers could shed more light on the subject of present study.Keywords: Retinopathy, VEGF, Polymorphism -
CANDIDATE GENE ANALYSIS IN T1DM: IFN-IFN-γ GENEBackgroundIFN-g is one of the most essential and fundamental player in initiation and development of T1DM. This mediator belongs to T Helper-1(Th1) class of cytokines and exerts stimulation and differentiation of naïve T cells towards Th1 cells and meanwhile inhibits differentiation and proliferation of Th2 cells. These effects are highly important in induction and progression of cell-mediated immune responses that is aberrantly operative in development of T1DM. Due to such outstanding role, numerous studies including genetic manipulation have focused on the role of this pro-inflammatory cytokine in T1DM.MethodsIn a genetic association study the influence of IFN-g gene variation in position *T/A on development of T1DM was analysed in 248 British Caucasian T1DM patients in comparison with 119 healthy matched controls. ARMS-PCR procedure was designed for detection of the variants at allele/genotype level.ResultsNo significant association between IFN-g gene polymorphism and T1DM was apparent (P≥ 0.05). The distribution of these polymorphic variants was in Hardy-Weinberg equilibrium.ConclusionWhile some studies have shown an association between the examined polymorphism of IFN-g and T1DM, our data do not support that. According to present study the selected polymorphic marker (*T/A) is not among the polymorphisms that governs in part genetic susceptibility to T1DM. That irreproducibility or controversial results is a common observation in genetic studies of complex traits such as T1DM, reflecting a fragile correlation between genotype and phenotype. This study also underlines the importance of replication of association studies to confirm the previous results/interpretations.Keywords: Genetic, Polymorphism, Diabetes, IFN-γ
-
ANALYSIS OF ADIPONECTIN GENE POLYMORPHISM IN TYPE 2 DIABETIC PATIENTS IN A POPULATION FROM TEHRANBackgroundSingle nucleotide polymorphisms of Adiponectin gene have been associated with BMI, insulin sensitivity and type 2 diabetes, reportedly. In present study we performed a genetic association study for Adiponectin gene at position *T/G in type 2 diabetes and normal subjects of Tehran population.MethodsDiabetic patients were selected from diabetes clinic and normal healthy control subjects aged between 25-64 years selected from zone 17 of Tehran. Adiponectin gene polymorphism was analyzed using PCR-RFLP method in normal healthy controls (N=70), obese diabetic patients (N=80) and non-obese diabetic patients (N=72).ResultsFrequency of TT genotype was 62.5% in non-obese diabetic patients and 78% in control group, that was statistically significant (TT vs TG: P=0.02, OR=2.2, CI:0.98-5.00). There was also a significant difference for allele T and G frequencies when we compared between non-obese diabetic patients and controls group. The frequency of allele G was increased in non-obese diabetic (20.1%) patients compared to controls (12%) (P: 0.04 OR: 1.8 CI: 0.9-3.7).ConclusionThis study showed TG and GG alleles of Adiponectin gene polymorphism at position *T/G are risk factors for development of diabetes mellitus while this effect is independent from BMI and obesity.Keywords: Polymorphism, Adiponectin, Diabetes mellitus
-
مقدمهنقش و اهمیت قابل ملاحظه عوامل عروقی اولا در اتیوپاتوژنز نوروپاتی دیابتی و ثانیا در مرحله پس از بروز این عارضه، در تعیین برآیند نهایی واکنش های نوروژنراتیو/ نورودژنراتیو، سبب شده تا مطالعات گسترده ای در این زمینه به ویژه در قالب درمان های مداخله ای صورت گیرد. در این راستا با توجه به ماهیت ایسکمیک نوروپاتی دیابتی و اهمیت فراوان برقراری مجدد تغذیه خونی در نسج عصبی مورد آزار در فرآیند ترمیم، VEGF به عنوان فاکتور رشدی که در کنار کارکردهای همودینامیک، قابلیت بالایی در ایجاد عروق دارد، جایگاه ویژه ای را داراست.روش هابا توجه به تاثیرات قابل ملاحظه زمینه های وراثتی و نژادی در میزان بروز و شدت علایم مربوط به نوروپاتی دیابتی، مطالعه حاضر تاثیرات مربوط به تغییرات ساختمانی ژن VEGF بر استعداد/ مقاومت بیماران دیابتی در ابتلا به نوروپاتی را در قالب یک «مطالعه پیوستگی» مورد بررسی قرار می دهد.یافته هاتوزیع فراوانی آلل ها/ ژنوتیپ های مربوط به چهار پلی مورفیسم ژن VEGF در موقعیت های 7*C/T-، 1001*G/C-، 1154*G/A- و 2578*C/A- بین 248 بیمار مبتلا به T1DM (81 نفر DNU+ و 167 نفر DNU-) و 113 فرد سالم (گروه شاهد) که همگی از جمعیت «بریتانیایی- قفقازی» بوده اند، ارزیابی شد. اختلاف معنادار تنها در یک مورد آن هم در سطح آللی - و نه ژنوتیپی- پلی مورفیسم ناحیه پروموتر در موقعیت 7*C/T- در مقایسه بین دو زیرگروه واجد و فاقد نوروپاتی (DNU-/ DNU+) مشاهده شد که آلل T دارای نقش حمایتی بود.(OR=0.03،OR=1.75)نتیجه گیریبا توجه به نقش حمایتی VEGF در نوروپاتی دیابتی، مطالعه حاضر نشان می دهد پلی مورفیسم ژن VEGF در موقعیت 7*C/T- با پتانسیل های «عملکردی» و فنوتیپیک خود و احتمالا با دخالت در تعیین سطح موضعی/ بافتی (عمدتا نسج عصبی) VEGF، می تواند به عنوان یکی از عوامل تعیین کننده میزان استعداد/ مقاومت ژنتیکی در برابر ابتلا به نوروپاتی دیابتی باشد. البته برای قضاوت بهتر تکرار این مطالعه در تعداد بیشتری از بیماران دیابتی (DNU-/ DNU+) قویا توصیه می شود.
کلید واژگان: VEGF، پلی مورفیسم، نوروپاتیBackgroundVascular factors in conjunction with metabolic issues are involved in both etiopathogenesis of diabetic neuropathy (DNU), and more remarkably in "repair" phase, when the net balance between neuroregenerative/degenerative reactions is dictated to some extent by these factors. The ischemic nature of DNU indicates the importance of re-establishment of blood vessels. VEGF, a growth factor which, in addition to its hemodynamic effects, possesses an "angiogenic" capacity has been the subject of extensive investigations in DNU, especially, interventional therapies. The impacts of racial and inherited backgrounds in the development of DNU suggest that the genetic issues partially govern the outcome of diabetic late complications, including DNU. By conducting a candidate gene case-control association study, present study explores the possibility if the inter-individual variations of VEGF gene structure by any means encode the genetic susceptibility/resistance in the course of DNU.MethodsThe distribution of VEGF gene polymorphisms frequencies were analyzed at positions –7*C/T, -1001*G/C, -1154*G/A and –2578*C/A and were evaluated by ARMS-PCR in 248 type 1 diabetic subjects (81 DNU+, 167 DNU−) and 113 healthy controls, all from "British-Caucasian" origin.ResultsWhen the frequency of the polymorphic alleles/genotypes between patients and controls, and also between two subgroups within patient's group with each other (DNU+ vs. DNU−) or with healthy controls were compared, only in one situation a significant difference was evident. The distribution of a VEGF gene polymorphism at promoter region (–7*C/T) at allelic (but not at genotypic) level was notably different between diabetics, with and without neuropathy, while the minor allele (T) conferred a protective effect (P=0.03; OR = 1.75).ConclusionThe present study may imply a prognostic value for VEGF gene polymorphism at promoter region (–7*C/T) in DNU. However, it requires further studies to appreciate better the phenotypic impact of this polymorphism in this chronic complication of diabetes. A catalog of candidate genes polymorphisms that functionally reflect a protection/predisposition to DNU can provide the genotypic profile that can be useful to reasonably predict the overall behavior of diabetic subjects to the metabolic derangements relative to development of DNU, which in turn may require adoption of relevant preventive and therapeutic measures.Keywords: VEGF, Polymorphism, Neuropathy -
GENETICS OF DIABETIC RETINOPATHY: STUDY OF VEGF GENEBackgroundVEGF is newly discovered growth factor that has diverse biologic properties. The bottom-line of these activities is conduction and orchestration of a series of reactions that are taking place at microvasculature of different tissues/organs. Among the growth factors, cytokines and other mediators that reflect meaningful alteration in their local/systemic level, VEGF is the distinct player which can explain by its own all hemodynamic and architectural manifestations present in diabetic retinopathy (DR). The present study was conducted to pursue the role of a candidate gene structure variation, VEGF gene polymorphisms, in genetic susceptibility/resistance to development of DR through a cross sectional case-control study.MethodsThe frequency of four SNPs in VEGF gene at positions -7*C/T, -1001*G/C, -1154*G/A and -2578*C/A has been traced among 248 type 1 diabetic subjects (135 DR, 113 DR-) along with 95 healthy controls. The populations had "British-Caucasian" background and ARMS-PCR technique was employed for DNA genotyping.ResultsComparing the polymorphic variant's frequency at both allelic and genotypic levels among different groups/subgroups, significant difference was noticeable for -7*C/T polymorphism between diabetic patients with vs. without DR, while T allele conferred protective effect (p=0.002; OR=1.98).ConclusionContemplating that up-regulation/over-expression of VEGF (local/systemic) as a common pre-requisite for DR development, our hypothesis was that whether the VEGF gene structural variations is correlated with the magnitude of VEGF expression in response to different stimuli present in diabetic context, namely hypoxia and hyperglycemia. Our data indicate that among the examined polymorphisms of VEGF gene, only SNP at position -7*C/T harbored significant difference between DR vs. DR- cases, proposing phenotypic impact for that SNP illustrating by evolvement/impediment of DR. However, reminding the insubstantial role of genetic issues in development of DR relative to DN or DNU, replicating current hypothesis by providing larger sample size and also employing more polymorphic markers could shed more light on the subject of present study.Keywords: Retinopathy, VEGF, Polymorphism
-
GENETICS OF DIABETIC NEUROPATHY: STUDY OF VEGF GENEBackgroundVascular factors in conjunction with metabolic issues are involved in both etiopathogenesis of diabetic neuropathy (DNU), and more remarkably in "repair" phase, when the net balance between neuroregenerative/degenerative reactions is dictated to some extent by these factors. The ischemic nature of DNU indicates the importance of re-establishment of blood vessels. VEGF, a growth factor which, in addition to its hemodynamic effects, possesses an "angiogenic" capacity has been the subject of extensive investigations in DNU, especially, interventional therapies. The impacts of racial and inherited backgrounds in the development of DNU suggest that the genetic issues partially govern the outcome of diabetic late complications, including DNU. By conducting a candidate gene case-control association study, present study explores the possibility if the inter-individual variations of VEGF gene structure by any means encode the genetic susceptibility/resistance in the course of DNU.MethodsThe distribution of VEGF gene polymorphisms frequencies were analyzed at positions -7*C/T, -1001*G/C, -1154*G/A and -2578*C/A and were evaluated by ARMS-PCR in 248 type 1 diabetic subjects (81 DNU, 167 DNU-) and 113 healthy controls, all from "British-Caucasian" origin.ResultsWhen the frequency of the polymorphic alleles/genotypes between patients and controls, and also between two subgroups within patient's group with each other (DNU vs. DNU-) or with healthy controls were compared, only in one situation a significant difference was evident. The distribution of a VEGF gene polymorphism at promoter region (-7*C/T) at allelic (but not at genotypic) level was notably different between diabetics, with and without neuropathy, while the minor allele (T) conferred a protective effect (P=0.03; OR = 1.75).ConclusionThe present study may imply a prognostic value for VEGF gene polymorphism at promoter region (-7*C/T) in DNU. However, it requires further studies to appreciate better the phenotypic impact of this polymorphism in this chronic complication of diabetes. A catalog of candidate genes polymorphisms that functionally reflect a protection/predisposition to DNU can provide the genotypic profile that can be useful to reasonably predict the overall behavior of diabetic subjects to the metabolic derangements relative to development of DNU, which in turn may require adoption of relevant preventive and therapeutic measures.Keywords: VEGF, Polymorphism, Neuropathy
-
مقدمهنفروپاتی دیابتی هنوز هم یکی از شایع ترین علل نارسایی پیشرفته کلیوی محسوب می گردد. یکی از موانع موجود در پیشگیری موثرتر از این عارضه، ماهیت پیچیده و نقش سیالی است که زمینه ژنتیکی افراد دیابتی در زمینه هدایت و هماهنگیOrchestrating)) میان علل شناخته و ناشناخته این عوارض در قالب استعداد و یا مقاومت میزبان از خود نشان می دهند.
بررسی تاثیرات منفرد هر ژن با اولویت ژن هایی که دخالت آنها در ایجاد و یا پیشرفت فنوتیپ مورد مطالعه، توجیه بیولوژیک دارد، تنها رویکرد مطالعاتی است که برای غلبه بر پیچیدگی(Complexity) و تجزیه (Dissection) زیرساخت ژنتیکی بیماری های کمپلکس (مثل نفروپاتی دیابتی)، در دسترس محققین قرار دارد.روش هادر قالب یک «Association Study»، تاثیرات و قابلیت های فنوتیپیک پلی مورفیسم های ژن TGF-β1در کدون های 10 T/C)*869 +) و G/C)*915+) 25 در پیدایش و کنترل شدت نفروپاتی دیابتی در بیماران مبتلا به دیابت نوع یک ((T1DM مورد مطالعه قرار گرفت. میزان فراوانی آلل/ ژنوتیپ حاصله از پلی مورفیسم های ژن مذکور که توسط روش PCR – ARMS تایپ گردید، در دو گروه بیمار (248 نفر:86 DN+ و162 DN−) و کنترل سالم (113 نفر) که همگی «بریتانیایی- قفقازی» بوده اند، بررسی گردید.یافته هاتفاوت معناداری در توزیع فراوانی آلل های پلی مورفیک ژن TGF-β1 بین گروه ها و زیرگروه های افراد مورد مطالعه مشاهده نشد P=NS)).نتیجه گیریاین عدم تفاوت در توزیع آلل ها/ ژنوتیپ ها، می تواند تا حدودی «قابلیت عملکردی» (Functionality) (و البته پتانسیل پروگنوستیک) پلی مورفیسم های مورد مطالعه را در سطح ژنی به عنوان نشانگرهایی «قابل اعتماد»، زیر سوال ببرد. تاکید مجدد برعدم وجود رابطه قطعی و دایمی بین «ژنوتیپ- فنوتیپ» در بیماری های پیچیده، می تواند پیام مطالعه حاضر باشد. البته این نتیجه (عدم پیوستگی) می تواند نتیجه ای «کاذب» نیز فرض گردد و آن حالتی است که به علت «کشنده» بودن نفروپاتی دیابتی، بخشی از بیمارانی که حامل «ژنوتیپ های پرخطر» بوده اند، به علت مرگ از جمعیت مورد مطالعه، حذف قبلی شده اند.
کلید واژگان: TGF، B1، ژنوتیپ، فنوتیپ، پلی مورفیسم، نفروپاتی دیابتیBackgroundDespite substantial progress in the clinical management of diabetes, diabetic nephropathy (DN) still occurs recurrently, implicating diabetes as the major underlying condition leading to the end stage renal disease. One of the main reasons is the influential role of genetic or inherited backgrounds of diabetics that are almost overlooked in daily practice. Owing to be orchestrated by the genetic makeup, cellular and molecular responses are different to similar metabolic disturbances. This in turn defines susceptibility/resistance state of the host to chronic diabetic complications, including DN. Separate analysis of every single gene that may be involved in genetics of a multi-factorial disease (such as DN) is the only available way to dissect the genetic basis of the disease and overcome its complexity. Among different genes accountable for DN, Transforming Growth Factor (TGF)-1 has an exceptional place. TGF-1 has profound impact on cell growth and proliferation, and in particular the regulation of extra cellular matrix deposition, branding it as a "pro-fibrotic" and "hypertrophic" mediator.MethodsBy employing ARMS-PCR technique, the genetic susceptibility to DN was studied in 248 patients with T1DM (86 DN+, 162 DN−) and 113 healthy controls, all from British Caucasian origin. The analysis of two functional TGF-1 gene variations, which change codons 10 (+869*C/T) and 25 (+915*G/C) was carried out.ResultsThere were some differences in alleles/genotypes distribution, but no significant association was apparent in patients as a whole or DN+/DN− subgroups and controls (P=NS).ConclusionThe negative result of this study may be false. As DN is a mortal disability, some fraction of risky genotypes associated with DN may previously be excluded by death. Such under-representation of the risky-genotypes (selective survivor effect) can be avoided by carrying out a prospective study. However, if the non-association result is true, it may question the functionality and reliability of the examined polymorphisms at least in the context of diabetes. Moreover, it does not underestimate the role of TGF-1 at the level of gene/protein themselves in development of DN.Keywords: TGF, 1, Genotype, Phenotype, Polymorphism, Diabetic nephropathy
- در این صفحه نام مورد نظر در اسامی نویسندگان مقالات جستجو میشود. ممکن است نتایج شامل مطالب نویسندگان هم نام و حتی در رشتههای مختلف باشد.
- همه مقالات ترجمه فارسی یا انگلیسی ندارند پس ممکن است مقالاتی باشند که نام نویسنده مورد نظر شما به صورت معادل فارسی یا انگلیسی آن درج شده باشد. در صفحه جستجوی پیشرفته میتوانید همزمان نام فارسی و انگلیسی نویسنده را درج نمایید.
- در صورتی که میخواهید جستجو را با شرایط متفاوت تکرار کنید به صفحه جستجوی پیشرفته مطالب نشریات مراجعه کنید.