Replication of TCF7L2 rs7903146 association with type 2 diabetes in an Iranian population

The transcription factor 7-like 2 gene (TCF7L2) rs7903146 T allele is constantly associated with Type 2 diabetes in various populations and ethnic groups. Nevertheless, this has not been observed in two studies involving Arab populations. The aim of the present study was to investigate the association between TCF7L2 rs7903146 in an Iranian population. Type 2 diabetes patients (N = 258) and normal healthy control subjects (N = 168) from the same area, were examined. The ARMS- PCR (Amplification Refractory Mutation System) technique, subsequently validated by direct sequencing, was used for genotyping. Allele and genotype frequencies were significantly different between patients and controls TT vs. CT + CC [p 0.0081 OR 3.4 95%CI (1.27-11.9)] and T vs. C allele [p 0.02 OR 1.4 95%CI (1.03-1.9)]. Our data thus confirm the association between the rs7903146 T allele and T2D in an Iranian population, contrary to previous reports in Arab populations. This can possibly be attributed to differences in ethnic background or the effects of environmental factors

Ethnic differences in the +405 and -460 vascular endothelial growth factor polymorphisms and peripheral neuropathy in patients with diabetes residing in a North London, community in the United Kingdom.

BACKGROUND: There are marked ethnic differences in the susceptibility to the long-term diabetic vascular complications including sensory neuropathy. The vascular endothelial growth factor (VEGF) +405 (C/G) and -460 (T/C) polymorphisms are associated with retinopathy and possibly with nephropathy, however no information is available on their relationship with peripheral neuropathy. Therefore, we examined the prevalence of these VEGF genotypes in a multi-ethnic cohort of patients with diabetes and their relationship with evident peripheral diabetic neuropathy. METHODS: In the current investigation, we studied 313 patients with diabetes mellitus of African-Caribbean, Indo-Asian and Caucasian ethnic origin residing in an inner-city community in London, United Kingdom attending a single secondary care centre. Genotyping was performed for the VEGF +405 and VEGF -460 polymorphisms using a pyrosequencing technique. RESULTS: Forty-nine patients (15.6%) had clinical evidence of peripheral neuropathy. Compared to Caucasian patients, African-Caribbean and Indo-Asian patients had lower incidence of neuropathy (24.6%, 14.28%, 6.7%, respectively; P = 0.04). The frequency of the VEGF +405 GG genotype was more common in Indo-Asian patients compared to African-Caribbean and Caucasian patients (67.5%, 45.3%, 38.4%, respectively; p ≤ 0.02). The G allele was more common in patients with type 2 diabetes of Indo-Asian origin compared to African-Caribbean and Caucasian origin (p ≤ 0.02). There was no difference between the ethnic groups in VEGF -460 genotypes. The distributions of the VEGF +405 and VEGF -460 genotypes were similar between the diabetic patients with and without neuropathy. CONCLUSIONS: In this cohort of patients, VEGF +405 and VEGF -460 polymorphisms were not associated with evident diabetic peripheral neuropathy, however an association was found between VEGF +405 genotypes and Indo-Asian which might have relevance to their lower rates of ulceration and amputation. This finding highlights the need for further investigation of any possible relationship between VEGF genotype, circulating VEGF concentrations and differential vulnerability to peripheral neuropathy amongst diabetic patients of different ethnic backgrounds

Skewing of the genetic architecture at the ZMYM3 human-specific 5� UTR short tandem repeat in schizophrenia

Differential expansion of a number of human short tandem repeats (STRs) at the critical core promoter and 5� untranslated region (UTR) support the hypothesis that at least some of these STRs may provide a selective advantage in human evolution. Following a genome-wide screen of all human protein-coding gene 5� UTRs based on the Ensembl database (http://www.ensembl.org), we previously reported that the longest STR in this interval is a (GA)32, which belongs to the X-linked zinc finger MYM-type containing 3 (ZMYM3) gene. In the present study, we analyzed the evolutionary implication of this region across evolution and examined the allele and genotype distribution of the �exceptionally long� STR by direct sequencing of 486 Iranian unrelated male subjects consisting of 196 cases of schizophrenia (SCZ) and 290 controls. We found that the ZMYM3 transcript containing the STR is human-specific (ENST00000373998.5). A significant allele variance difference was observed between the cases and controls (Levene�s test for equality of variances F = 4.00, p < 0.03). In addition, six alleles were observed in the SCZ patients that were not detected in the control group (�disease-only� alleles) (mid p exact < 0.0003). Those alleles were at the extreme short and long ends of the allele distribution curve and composed 4 of the genotypes in the SCZ group. In conclusion, we found skewing of the genetic architecture at the ZMYM3 STR in SCZ. Further, we found a bell-shaped distribution of alleles and selection against alleles at the extreme ends of this STR. The ZMYM3 STR sets a prototype, the evolutionary course of which determines the range of alleles in a particular species. Extreme �disease-only� alleles and genotypes may change our perspective of adaptive evolution and complex disorders. The ZMYM3 gene �exceptionally long� STR should be sequenced in SCZ and other human-specific phenotypes/characteristics. © 2018, Springer-Verlag GmbH Germany, part of Springer Nature

Skewing of the genetic architecture at the ZMYM3 human-specific 5� UTR short tandem repeat in schizophrenia

Differential expansion of a number of human short tandem repeats (STRs) at the critical core promoter and 5� untranslated region (UTR) support the hypothesis that at least some of these STRs may provide a selective advantage in human evolution. Following a genome-wide screen of all human protein-coding gene 5� UTRs based on the Ensembl database (http://www.ensembl.org), we previously reported that the longest STR in this interval is a (GA)32, which belongs to the X-linked zinc finger MYM-type containing 3 (ZMYM3) gene. In the present study, we analyzed the evolutionary implication of this region across evolution and examined the allele and genotype distribution of the �exceptionally long� STR by direct sequencing of 486 Iranian unrelated male subjects consisting of 196 cases of schizophrenia (SCZ) and 290 controls. We found that the ZMYM3 transcript containing the STR is human-specific (ENST00000373998.5). A significant allele variance difference was observed between the cases and controls (Levene�s test for equality of variances F = 4.00, p < 0.03). In addition, six alleles were observed in the SCZ patients that were not detected in the control group (�disease-only� alleles) (mid p exact < 0.0003). Those alleles were at the extreme short and long ends of the allele distribution curve and composed 4 of the genotypes in the SCZ group. In conclusion, we found skewing of the genetic architecture at the ZMYM3 STR in SCZ. Further, we found a bell-shaped distribution of alleles and selection against alleles at the extreme ends of this STR. The ZMYM3 STR sets a prototype, the evolutionary course of which determines the range of alleles in a particular species. Extreme �disease-only� alleles and genotypes may change our perspective of adaptive evolution and complex disorders. The ZMYM3 gene �exceptionally long� STR should be sequenced in SCZ and other human-specific phenotypes/characteristics. © 2018, Springer-Verlag GmbH Germany, part of Springer Nature

A 15;15 Translocation in a couple with Repeated Abortions: Case report

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

Expression Levels of Two DNA Repairrelated Genes under 8 Gy Ionizing Radiation and 100 Mg/Kg Melatonin Delivery In Rat Peripheral Blood

Background: After radiation therapy (RT), some health hazards including DNA damages may occur where melatonin can play a protective role due to free radical generation. On the other hand, serious accidental overexposures may occur during RT due to nuclear accidents which necessitate the need for study on exposure to highdose radiations during treatments. Objective: The aim of this study was to study the expression level of two genes in non-homologous end joining (NHEJ) pathways named Xrcc4 and Xrcc6 (Ku70) in order to examine the effect of melatonin on repair of DNA double-strand breaks (BSBs) caused by 8Gy ionizing radiation. Methods: One hundred eight male Wistar rats were irradiated with a whole body gamma radiation dose of 8Gy with or without melatonin pretreatments. They were divided into six different groups of control, 100 mg/kg melatonin alone, 8Gy irradiation alone, vehicle alone, vehicle plus 8Gy irradiation and 100 mg/kg melatonin plus 8Gy irradiation. Peripheral blood samples were collected at 8, 24 and 48 h after irradiation. Ku70 and Xrcc4 gene expression were evaluated by real-time quantitative polymerase chain reaction (qPCR) technique and analyzed by one-way ANOVA test. Results: Expression of Ku70 and Xrcc4 genes normalized against Hprt gene showed significant difference in melatonin plus irradiation group at 8h compared to the control group (p<0.05). At 24h post irradiation, gene expression changes were significantly upregulated in irradiation-alone group as well as melatonin plus irradiation group (p<0.05). No significant change was found in any groups compared to control group at 48 h time point. Conclusion: We concluded that, by increasing expression level of Ku70 and Xrcc4 genes, 100 mg/kg melatonin administration 8 and 24 h before 8 Gyionizing radiation can significantly affect the repair of DNA DSBs in NHEJ pathway

Differential expression of FGFRs signaling pathway components in bladder cancer: A step toward personalized medicine

Variations Improper activation and inappropriate expression of fibroblast growth factor receptors (FGFRs) in cancer suggests that they can act as therapeutic targets. Fibroblast growth factor receptor inhibitors are currently employed in clinical trials of different cancers. Regarding the essence and the importance of the personalized medicine, mainly mirrored by remarkable inter-individual variations in different populations, we aimed to perform a pilot study to address FGFR1 and FGFR3 expression levels and their correlation with the clinicopathological features in Iranian patients with bladder cancer (BC). Paired tumor and adjacent non tumor tissue samples along with their clinico-pathological parameters were obtained from 50 cases diagnosed with BC in different stages and grades. The mRNA expressions of FGFR1 and FGFR3 in tissue samples were determined by real-time polymerase chain reaction (real-time PCR). The expression levels of FGFR3 were significantly higher in tumor tissues when compared to adjacent normal tissues (p = 0.007), regardless of the stages and grades of the tumor. Over expression was associated with cigarette smoking (p = 0.037) and family history for cancer (p = 0.004). Decreased expression of FGFR1 was observed, remarkably evident in high-grade tumors (p = 0.047), while over expression was detected in low-grade samples. This pilot study clearly suggests that in Iranian BC patients FGFR1 and FGFR3 expression patterns are different, and also highly distinctive with regard to the tumor’s stage and grade. Such particular expression patterns may indicate their special values to be employed for interventional studies aiming targeted therapy. Further studies with a larger sample size are needed to validate our results

The Association between PARP1 and LIG3 Expression Levels and Chromosomal Translocations in Acute Myeloid Leukemia Patients

Objective Chromosomal 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 Methods This experimental study used reverse transcription-quantitative polymerase chain reaction (RT- qPCR) to quantify the expression levels of PARP1 and LIG3 at the transcript level in AML patients (n=78) and healthy individuals (n=19). Results PARP1 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). Conclusion The 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