A narrow repertoire of transcriptional modules responsive to pyogenic bacteria is impaired in patients carrying loss-of-function mutations in MYD88 or IRAK4.

Loss of function of the kinase IRAK4 or the adaptor MyD88 in humans interrupts a pathway critical for pathogen sensing and ignition of inflammation. However, patients with loss-of-function mutations in the genes encoding these factors are, unexpectedly, susceptible to only a limited range of pathogens. We employed a systems approach to investigate transcriptome responses following in vitro exposure of patients' blood to agonists of Toll-like receptors (TLRs) and receptors for interleukin 1 (IL-1Rs) and to whole pathogens. Responses to purified agonists were globally abolished, but variable residual responses were present following exposure to whole pathogens. Further delineation of the latter responses identified a narrow repertoire of transcriptional programs affected by loss of MyD88 function or IRAK4 function. Our work introduces the use of a systems approach for the global assessment of innate immune responses and the characterization of human primary immunodeficiencies.

Association of DRD2, DRD4 and COMT genes variants and their gene-gene interactions with antipsychotic treatment response in patients with schizophrenia.

Antipsychotic drugs are the first line of treatment in schizophrenia; although antipsychotic responses indicate a wide interindividual variety in patients with schizophrenia. This study aimed to investigate the association between four polymorphisms in DRD2, DRD4 and COMT genes and their gene-gene interactions with antipsychotic treatment response in patients with schizophrenia. A total of 101 patients with schizophrenia were recruited and stratified in treatment responder and treatment resistant groups based on the published criteria of resistant to treatment using PANSS. Clinical and demographic factors were analyzed. Genomic DNA was extracted from whole blood and genotyping for the four polymorphisms were done by ARMS-PCR, PCR-RFLP and gap-PCR. Gene-gene interactions were analyzed by logistic regression. In case of DRD2 A-241G, G allele was significantly associated with resistant to treatment. Regarding DRD4 120-bp duplication, 240/240 genotype was significantly associated with resistant to treatment comparing to other genotypes in a dominant model. The genotype combination of DRD4 240/240 and COMT Val/Val was significantly associated with treatment resistant. Among DRD2 AA genotype, COMT met allele carriers which also had a 120 bp allele of DRD4 had a significantly better response to antipsychotics. Moreover, analysis of clinical and demographic factors demonstrated a significantly longer duration of hospitalization and higher chlorpromazine-equivalent daily dose in resistant to treatment patients. Discovering the polymorphisms which effect treatment response to antipsychotics will provide the possibility of genetic screening before starting an antipsychotic treatment which enhances the chance of responding to antipsychotics and decreases drugs side effects and costs.

Identification of Cytochrome b-245, beta-chain gene mutations, and clinical presentations in Iranian patients with X-linked chronic granulomatous disease.

BACKGROUND: X-linked chronic granulomatous disease (X-CGD) is an immunodeficiency disorder caused by defects in the gp91phox subunit that leads to life-threatening infections. We aimed to identify CYBB gene mutations and study clinical phenotypes in Iranian patients with probable X-CGD. METHODS: We studied four unrelated Iranian patients with probable X-CGD and their families recruited in several years. We isolated genomic DNA from whole blood and performed Sanger sequencing in the CYBB gene's coding and flanking regions. We also performed pathogenicity predictions using in silico tools. RESULTS: We detected four different mutations, including a novel insertion mutation in exon 5 (p.Ile117AsnfsX6), in the patient. Bioinformatics analysis confirmed the pathogenic effect of this mutation. We predicted protein modeling and demonstrated lost functional domains. The patient with the insertion mutation presented pneumonia and acute sinusitis during his life. We also detected three other known nonsense mutations (p.Arg157Ter, p.Arg226Ter, and p.Trp424Ter) in the CYBB gene. The patient with p.Arg157Ter developed lymphadenitis and pneumonia. Moreover, the patient with inflammatory bowel disease showed p.Arg226Ter and the patient with tuberculosis presented p.Trp424Ter. We detected different clinical features in the patients compared to other Iranian patients with the same mutations. CONCLUSION: Our results expand the genetic database of patients with X-CGD from Iran and make it much easier and faster to identify patients with X-CGD. Our results also help to detect carriers and enable prenatal diagnosis in high-risk families as a cost-effective strategy.

The first report of two homozygous sequence variants in FKRP and SELENON genes associated with syndromic congenital muscular dystrophy in Iran: Further expansion of the clinical phenotypes.

BACKGROUND: Congenital muscular dystrophy (CMD) refers to hypotonia and delayed motor development that is manifested at or near the birth. Additional presentations have been observed in CMD syndromes. METHODS: Thorough clinical examinations were performed on two unrelated Iranian families with typical symptoms of CMD and uncommon features such as intellectual disability and nephrolithiasis. The genomic DNA of probands were subjected to whole exome sequencing. Following the detection of candidate variants with a bioinformatic pipeline, the familial co-segregation analysis was carried out using polymerase chain reaction-based Sanger sequencing. RESULTS: We identified a missense homozygous variant in the fukutin-related protein (FKRP) gene (c.968G>A, p.Arg323His) related to CMD-dystroglycanopathy type B5 (MDDGB5) and a frameshift homozygous variant in the selenoprotein N (SELENON) gene (c.1446delC, p.Asn483Thrfs*11) associated with congenital rigid-spine muscular dystrophy 1 (RSMD1), which were completely segregated with the phenotypes in the families. These variants were not found in either the 1000 Genomes Project or the Exome Aggregation Consortium. The present study provides the first report of these homozygous sequence variants in Iran. Moreover, our study was the first observation of nephrolithiasis in FKRP-related dystroglycanopathy and intellectual disability in SELENON-related myopathies. Based on in silico studies and molecular docking, these variations induced pathogenic effects on the proteins. CONCLUSIONS: Our findings extend the genetic database of Iranian patients with CMD and, in general, the phenotypical spectrum of syndromic CMD. It is recommended to consider these variants for a more accurate clinical interpretation, prenatal diagnosis and genetic counseling in families with a history of CMD, especially in those combined with cognitive impairments or renal dysfunctions.

A novel homozygous variant in an Iranian pedigree with cerebellar ataxia, mental retardation, and dysequilibrium syndrome type 4.

BACKGROUND: Cerebellar ataxia, mental retardation, and dysequilibrium (CAMRQ) syndrome is a rare and early-onset neurodevelopmental disorder. Four subtypes of this syndrome have been identified, which are clinically and genetically different. To date, altogether 32 patients have been described with ATP8A2 mutations and phenotypic features assigned to CAMRQ type 4. Herein, three additional patients in an Iranian consanguineous family with non-progressive cerebellar ataxia, severe hypotonia, intellectual disability, dysarthria, and cerebellar atrophy have been identified. METHODS: Following the thorough clinical examination, consecutive detections including chromosome karyotyping, chromosomal microarray analysis, and whole exome sequencing (WES) were performed on the proband. The sequence variants derived from WES interpreted by a standard bioinformatics pipeline. Pathogenicity assessment of candidate variant was done by in silico analysis. The familial cosegregation of the WES finding was carried out by PCR-based Sanger sequencing. RESULTS: A novel homozygous missense variant (c.1339G > A, p.Gly447Arg) in the ATP8A2 gene was identified and completely segregated with the phenotype in the family. In silico analysis and structural modeling revealed that the p.G477R substitution is deleterious and induced undesired effects on the protein stability and residue distribution in the ligand-binding pocket. The novel sequence variant occurred within an extremely conserved subregion of the ATP-binding domain. CONCLUSION: Our findings expand the spectrum of ATP8A2 mutations and confirm the reported genotype-phenotype correlation. These results could improve genetic counseling and prenatal diagnosis in families with clinical presentations related to CAMRQ4 syndrome.

Association of vascular endothelial growth factor A polymorphisms and aberrant expression of connexin 43 and VEGFA with idiopathic recurrent spontaneous miscarriage.

AIM: Idiopathic recurrent spontaneous miscarriage (IRSM) is one of the pregnancy outcomes that affects 1-2% of women trying to conceive. Specific genotype or aberrant expression of vascular endothelial growth factor A (VEGFA) and connexin 43 (Cx43) as two important genes for embryonic development are deemed to increase the risk of IRSM. METHODS: To investigate any possible association of VEGFA polymorphisms and aberrant expression of Cx43 and VEGFA with IRSM, we carried out a case-control study including embryo chorionic villus tissues of 100 pregnant women with IRSM and 100 embryo chorionic villus tissues of healthy pregnant women without history of miscarriage. Restriction fragment length polymorphism was used for genotyping of rs699947 (-2578C/A) and rs2010963 (-634G/C) polymorphisms in VEGFA. Besides, quantitative real-time PCR was performed for VEGFA and Cx43 expression analysis. RESULTS: The results showed that the frequency of -634G/C and C/C genotypes was significantly higher in aborted fetuses (P = 0.001 and P < 0.001, respectively) compared to the control group's. However, the frequency of -2578C/A genotypes was not significantly different between the cases and controls. Moreover, a significant higher expression of VEGF (P = 0.0005) and Cx43 (P = 0.0011) was observed in chorionic villus tissues of women with IRSM. CONCLUSION: The finding demonstrated that IRSM frequency may depend on GC and CC genotypes of rs2010963 VEGF polymorphism and expression level of VEGF and Cx43 in IRSM patients was increased.

Identification of the PRM1 gene mutations in oligoasthenoteratozoospermic men.

Mutations or altered expression of PRM1 gene have been associated with male infertility. This study aimed to analyse pathogenic variations of PRM1 gene in Iranian Arab infertile men with oligoasthenoteratozoospermia that was carried out for the first time in this population. Genomic DNA was used to perform PCR sequencing in PRM1 untranslated regions, exons and intron. Also, bioinformatics analysis was recruited to discover the possible effect of detected variations. Two pathogenic variations were seen in two men with oligoasthenoteratozoospermia, which were not found in the control group. The cDNA.384G>C variation is novel and was located in the 3' untranslated region, and cDNA.42G>A variation is reported for the first time related to male infertility and was found in 5' untranslated regions. Bioinformatics analysis showed that the minimum free energy was increased from -19.9kcal/mol to -13.1kcal/mol due to the cDNA.384G>C variation at hsa-miR-4326's seed site. More analysis revealed cDNA.42G>A located in transcription factors binding site, E1 and MYOD, which was detected as a promoter-associated region, and generally have regulatory features for acetylation and methylation. In conclusion, two pathogenic variations were recognised in regulatory areas of PRM1 gene, which might interfere with some critical factors related to PRM1 gene expression, hence cause male infertility.

Mechanism of dysfunction of human variants of the IRAK4 kinase and a role for its kinase activity in interleukin-1 receptor signaling.

Interleukin-1 receptor (IL1R)-associated kinase 4 (IRAK4) is a central regulator of innate immune signaling, controlling IL1R and Toll-like receptor (TLR)-mediated responses and containing both scaffolding and kinase activities. Humans deficient in IRAK4 activity have autosomal recessive primary immune deficiency (PID). Here, we characterized the molecular mechanism of dysfunction of two IRAK4 PID variants, G298D and the compound variant R12C (R12C/R391H/T458I). Using these variants and the kinase-inactive D329A variant to delineate the contributions of IRAK4's scaffolding and kinase activities to IL1R signaling, we found that the G298D variant is kinase-inactive and expressed at extremely low levels, acting functionally as a null mutation. The R12C compound variant possessed WT kinase activity, but could not interact with myeloid differentiation primary response 88 (MyD88) and IRAK1, causing impairment of IL-1-induced signaling and cytokine production. Quantitation of IL-1 signaling in IRAK4-deficient cells complemented with either WT or the R12C or D329A variant indicated that the loss of MyD88 interaction had a greater impact on IL-1-induced signaling and cytokine expression than the loss of IRAK4 kinase activity. Importantly, kinase-inactive IRAK4 exhibited a greater association with MyD88 and a weaker association with IRAK1 in IRAK4-deficient cells expressing kinase-inactive IRAK4 and in primary cells treated with a selective IRAK4 inhibitor. Loss of IRAK4 kinase activity only partially inhibited IL-1-induced cytokine and NF-κB signaling. Therefore, the IRAK4-MyD88 scaffolding function is essential for IL-1 signaling, but IRAK4 kinase activity can control IL-1 signal strength by modulating the association of IRAK4, MyD88, and IRAK1.

Association study between two polymorphisms of tumor necrosis factor ligand superfamily member 15 (TNFSF15) gene and ulcerative colitis in south-west of Iran.

BACKGROUND AND AIMS: Ulcerative colitis (UC) is the most prevalent clinical manifestation of the inflammatory bowel disease (IBD). Several candidate genes have been suggested to be involved in the genetic susceptibility or resistance in the development of UC. Among them, tumor necrosis factor ligand superfamily member 15 (TNFSF15) have been reported in association with IBD in several studies. The aim of this study was to investigate the association of TNFSF15 gene polymorphisms located in the promoter region, including rs6478108 (G/A -9706) and rs3810936 (G/A -15524) in Iranian patients with UC. METHODS: In this way, the two single nucleotide polymorphisms were studied in 115 patients with UC and 115 healthy controls with the same ethnic group from south-west of Iran. The genomic DNA of samples was genotyped using TaqMan Real-time PCR assay. This case-control study was conducted at the Department of Immunology, Jundishapur University of Medical Sciences, Ahvaz, Iran. RESULTS AND CONCLUSION: Our results did not confirm the formerly reported association of the studied polymorphisms with UC disease in comparison with healthy controls, neither with the type of the clinical forms of Colitis in the studied Iranian population. Comparing the genotype frequency of single nucleotide polymorphism (SNP) rs6478108, wild-type homozygous and heterozygote and mutant homozygote were 33%, 55.7%, and 11.3% in cases vs. 34.8%, 50.4%, and 14.8% in the controls (P = 0.6). The genotype frequency of SNP rs3810936 were 20.9%, 40.9%, and 38.2% in the cases compared to 18.3%, 44.3%, and 37.4% in controls, which was not significant ( P = 0.8). As multiple ethnic groups reside in all around the country, further studies using different ethnicities and/or larger sample size are required to clarify the role of these polymorphisms in the genetic susceptibility of UC in Iranian populations.

Effect of herbal antioxidant-rich formula on improvement of antioxidant defense system and heat shock protein-70 expression in recreational female athletes: A randomized controlled trial.

BACKGROUND: The aim of the present study was to evaluate the effect of natural antioxidant formula (blend of herbs: ginger root, cinnamon bark and raw almond fruit powder, rosemary leaf powder, and honey) on oxidative status, antioxidant enzyme activity, and relative heat shock protein (HSP-70) expression in recreational female athletes. MATERIALS AND METHODS: Eighteen female participants trained for 4 weeks and randomly received either antioxidant formula (FormEX) (n = 8) or placebo (PlcEX) (n = 10) in a randomized controlled trial. Blood samples were obtained 1-h before, 1 h and 24 h postexercise to measure malondialdehyde (MDA), total antioxidant capacity (TAC), superoxide dismutase (SOD), glutathione peroxidases (GPx), and HSP70 mRNA expression. Data analysis was performed using 2 (treatment = grouping factor) ×6 (time = within-factor) repeated measurements analysis of variance or generalized estimating equations (GEE) test. We used the independent t-test to evaluate any significant differences for real-time polymerase chain reaction data. RESULTS: Antioxidant formula increased the relative HSP-70 mRNA expression more than Plc-EX group in all time points (P = 0.001). The time main effect was significant with regard to TAC and SOD concentrations (P = 0.001 and 0.002, respectively). However, there were no statistically significant differences between groups for TAC, SOD, and MDA (P = 0.25, 0.06, and 0.38, respectively). Neither the time main effect for MDA nor time and intervention interaction was not statistically significant for MDA, TAC, and SOD (P = 0.19, 0.13, and 0.10, respectively). GEE results for GPx showed that there were no significant differences between the groups (P = 0.11). CONCLUSION: The results presented herein revealed that natural antioxidant rich formula had variable effects on oxidative status. However, in contrast to many antioxidant supplements, this formulation increases the HSP-70 mRNA expression which might improve the antioxidant ability of cells in the long-term period and exercise-induced adaptation.

Association between HLA-G 14bp Gene Polymorphism and Serum sHLA-G Protein Concentrations in Preeclamptic Patients and Normal Pregnant Women.

BACKGROUND: Preeclampsia (PE) is a multisystem syndrome that is a primary source of fetal-maternal morbidity and mortality. Human leukocyte antigen-G (HLA-G) is a nonclassical Major histocompatibility complex (MHC) class-Ib molecule expressed on the extravillous trophoblast and seems to have immunomodulatory functions during pregnancy. The purpose of our study was to investigate whether HLA-G may be a vital marker in the modulation of the pregnancy. METHODS: In this case-control study, a number of 150 healthy pregnant women and 150 patients with PE had been genotyped for the 14 base-pair (bp) insertion/deletion polymorphism in exon 8 of the HLA-G gene, and the serum level of soluble HLA-G (sHLA-G) protein was measured using the enzyme-linked immunosorbent assay. RESULTS: Data showed that the PE syndrome was not related to the HLA-G 14 bp genotype. But, the serum level of sHLA-G in PE patients was significantly lower than that in healthy pregnant women in the third trimester (11.74 and 24.48 U/ml, respectively, p < 0.001). However, no significant association was observed between the HLA-G 14 bp genotype and serum sHLA-G level. CONCLUSION: Our results demonstrate that measurement of sHLA-G protein level may be helpful as a primary diagnosis for the pathogenesis of PE. Overall, this study suggests that the association between HLA-G 14 bp polymorphism and serum sHLA-G level in different ethnic populations of PE should be taken into consideration.

Folate gene polymorphisms CBS 844ins68 and RFC1 A80G and risk of Down syndrome offspring in young Iranian women: A cross-sectional study.

Background: Cytogenetics and association studies showed that folate gene polymorphisms can increase the risk of chromosomal nondisjunction and aneuploidies. The folate-metabolizing gene polymorphisms in Down syndrome mothers (DSM) have been assessed in a variety of populations. Reduced folate carrier 1 (RFC1) and cystathionine beta-synthase (CBS) are key enzymes in folate metabolism. Objective: 2 common polymorphisms, CBS 844ins68 and RFC1 A80G, were analyzed to determine their probable risk for having Down syndrome (DS) babies in young mothers of Khuzestan province, Iran. Materials and Methods: This study was conducted on 100 mothers who had trisomy 21 DS children. 100 age- and ethnic-matched mothers with at least 2 healthy children and no history of abnormal pregnancies were considered as control. The samples were collected from all the mothers from June 2019 to April 2021. Genomic DNA was extracted from peripheral blood. The CBS-844ins68 and RFC1-A80G were genotyped using polymerase chain reaction-electrophoresis and restriction fragment length polymorphism, respectively. Results: The frequency of RFC1 AG and GG genotypes in DSM was significantly higher than the control mothers (odds ratio [OR] of 2.38 and 3.07, respectively). The heterozygote genotype of CBS 844ins68 was significantly more prevalent among DSM than the control (OR: 2.419). The OR was significantly increased to 6.667 when the homozygote of both variants was found together. Conclusion: Studying polymorphisms possibly increases the susceptibility of having a DS child. However, ethnicity, nutrition, and epistatic interactions are considerable factors to be evaluated in future studies.

Study of the genomics and transcriptomics profiles of male-infertility genes in human prostate cancer: an in silico analysis.

The World Health Organization has considered the infertility as an international public health problem. Infertility affect nearly 1 in 7 couples and male component contributes to 50% of infertility cases. There is a clear link between male infertility and some cancers such as testicular germ cell, prostate and colon cancers. Two possibilities support this finding: 1) Cancer treatments can affect the fertility factors 2) Genetic profile of infertility genes have been altered in cancer patients. Although the previously published researches have mostly focused on the first factor, no article has yet confirmed the role of genetic factors. In this in silico study, we collected the large number of genes (n = 17703) involved in infertility. These genes were collected from NGS panel tests of male infertility and comprehensive literature review or online data base. The Prostate Adenocarcinoma genomic and transcriptomics raw data were downloaded from the cBioPortal Cancer dataset. This included with 494 patients of Prostate Cancer with 494 mutation data, 489 with CNA and 493 with RNA seqV2 data. TCGA RNA-Seq raw data was extracted in R using the cgdsr extension package with a threshold of ±2 relative to normal samples. The observed data showed that male infertility genes have been distributed through the human genome. Among the 17703 analyzed genes of this study, the genomic profile of three genes including OR9Q1, H4C6 and PSG7 were changed approximately in 100% of (n = 493) patients. In most of patients (>98%), genetic alteration was related to change in gene expression. In conclusion, this study showed that the genomic and transcriptomics patterns of some male-infertility genes are notably altered in patients of prostate cancer and suggested a possible role of genetic factors in occurrence of infertility in cancer patients. Our information can be used as a source for the design of genetic database of male-infertility.

Genetic features of patients with MPS type IIIB: Description of five pathogenic gene variations.

BACKGROUND: There are four distinct forms of Sanfilippo syndrome (MPS type III), each of which is an autosomal lysosomal storage disorder. These forms are caused by abnormalities in one of four lysosomal enzymes. This study aimed to identify possible genetic variants that contribute to Sanfilippo IIIB in 14 independent families in Southwest Iran. METHODS: Patients were included if their clinical features and enzyme assay results were suggestive. The patients were subsequently subjected to Sanger Sequencing to screen for Sanfilippo-related genes. Additional investigations have been conducted using various computational analyses to determine the probable functional effects of diagnosed variants. RESULTS: Five distinct variations were identified in the NAGLU gene. This included two novel variants in two distinct families and three previously reported variants in 12 distinct families. All of these variations were recognized as pathogenic using the MutationTaster web server. In silico analysis showed that all detected variants affected protein structural stability; four destabilized protein structures, and the fifth variation had the opposite effect. CONCLUSION: In this study, two novel variations in the NAGLU gene were identified. The results of this study positively contribute to the mutation diversity of the NAGLU gene. To identify new disease biomarkers and therapeutic targets, precision medicine must precisely characterize and account for genetic variations. New harmful gene variants are valuable for updating gene databases concerning Sanfilippo disease variations and NGS gene panels. This may also improve genetic counselling for rapid risk examinations and disease surveillance.

Association of rs1570360 and rs2010963 in VEGF and rs2279744 in the MDM2 gene with Recurrent Implantation Failure in Iranian Women.

OBJECTIVE: The embryo implantation includes a complex sequence of signaling events, comprising numerous molecular mediators, such as ovarian hormones, cytokines, adhesion molecules and, growth factors. One of the critical factors in angiogenesis is the vascular endothelial growth factor (VEGF). The VEGF plays a pivotal role in embryonic development, decidua vascularization and placental angiogenesis. Furthermore, the P53 gene and its negative regulator, murine double minute 2 (MDM2), are major players in reproductive processes. This study aimed to assess the association of polymorphisms of the VEGF and the MDM2 genes with idiopathic recurrent implantation failure. METHODS: We genotyped 60 women with previous idiopathic recurrent implantation failures and 60 fertile women as controls. Restriction Fragment Length Polymorphism (RFLP) and Sanger sequencing were used for genotyping the rs2010963 and the rs1570360 polymorphisms in VEGF; and the rs2279744 in MDM2 genes. RESULTS: Results indicated a higher frequency of the VEGF rs1570360 AA genotype and A allele in patients with a history of idiopathic implantation failure [OR=6.4 (1.22 - 33.64), p-value=0.02)]. However, the frequency of VEGF +405 G/C and MDM2 SNP309 T/G [(OR=3 (0.5 - 16) p-value=0.2, OR=1.18 (0.3 - 3.7) p-value=0.7, respectively)] genotypes were not significantly different between cases and controls. CONCLUSIONS: The VEGF polymorphism may influence embryo implantation and the VEGF rs1570360 AA genotype may predispose to the risk of recurrent implantation failure after IVF.

Clinical and Molecular Spectrum of Muscular Dystrophies (MDs) with Intellectual Disability (ID): a Comprehensive Overview.

Muscular dystrophies encompass a wide and heterogeneous subset of hereditary myopathies that manifest by the structural or functional abnormalities in the skeletal muscle. Some pathogenic mutations induce a dysfunction or loss of proteins that are critical for the stability of muscle cells, leading to progressive muscle degradation and weakening. Several studies have well-established cognitive deficits in muscular dystrophies which are mainly due to the disruption of brain-specific expression of affected muscle proteins. We provide a comprehensive overview of the types of muscular dystrophies that are accompanied by intellectual disability by detailed consulting of the main libraries. The current paper focuses on the clinical and molecular evidence about Duchenne, congenital, limb-girdle, and facioscapulohumeral muscular dystrophies as well as myotonic dystrophies. Because these syndromes impose a heavy burden of psychological and financial problems on patients, their families, and the health care community, a thorough examination is necessary to perform timely psychological and medical interventions and thus improve the quality of life.

Effects of epigallocatechin gallate on total antioxidant capacity, biomarkers of systemic low-grade inflammation and metabolic risk factors in patients with type 2 diabetes mellitus: the role of FTO-rs9939609 polymorphism.

INTRODUCTION: Type 2 diabetes mellitus (T2DM) is known as one of the most common metabolic diseases and FTO polymorphism has been implicated in the susceptibility to this disease. Epigallocatechin-3-gallate (EGCG) has shown favorable effects on risk factors related to T2DM. The present study aimed to investigate the effects of EGCG on total antioxidant capacity, biomarkers of systemic low-grade inflammation and metabolic risk factors in patients with T2DM considering the role of FTO polymorphism. MATERIAL AND METHODS: In this double-blind randomized clinical trial, 60 patients with T2DM (20-60 years) were randomly allocated to three groups. Group 1 received 300 mg of EGCG (TT genotype). Group 2 received 300 mg of EGCG (AA + AT genotypes) and Group 3 received placebo. We genotyped FTO (rs9939609) and measured body mass index (BMI), blood pressure, profile lipid, interleukin-6, high sensitivity C-reactive protein and total antioxidant capacity, before and after the intervention, at 2 months. RESULTS: In carriers of A allele, EGCG intervention caused a significant decrease in BMI, diastolic blood pressure (DBP), mean arterial pressure and serum cholesterol level compared with placebo (p < 0.05). Also, we found a significant gene-treatment interaction effect between FTO-rs9939609 and EGCG on BMI and DBP (P > 0.05). CONCLUSIONS: These findings suggest that carriers of the risk alleles (A) of FTO-rs9939609 have a better response to EGCG in improving BMI and DBP in patients with T2DM.

Utilization of Whole Exome Sequencing in Non-Syndromic Premature Ovarian Failure: Ficolin-3 Gene Mutation in an Iranian Family

Background: Premature ovarian failure is a heterogeneous disorder, leading to early menopause. Several genes have been identified as the cause of non-syndromic premature ovarian failure (POF). Our aim was to explore the genetic defects in Iranian patients with POF. Methods: We studied a family with three females exhibiting non-syndromic POF. WES was performed for one of the affected individuals after ruling out the presence of CGG repeat expansion at fragile X mental retardation 1 gene in the family. Sanger sequencing was used to confirm the candidate sequence variants in the proband, and screening of the detected mutation was performed for the other affected and unaffected members of the family. Results: A homozygous frameshift mutation, c.349delC, was identified in ficolin-3 (FCN3) gene in the proband and two other patients. The parents and two healthy brothers were heterozygous for the mutation, and an unaffected sister was homozygous for wild type. Conclusion: This is the first report of a mutation in FCN3 gene in a family with POF. Our findings can lead to the enhancement of genetic databases of patients with POF, specifically for families with high-risk background.

Molecular diagnosis of maturity onset diabetes of the young in Iranian patients: improving management.

BACKGROUND: The purpose of this study is to identify the mutations of the most common form of maturity-onset diabetes of the young (MODY), also known as MODY3, in diabetic patients suspected of MODY. This can recommend appropriate medical surveillance of at-risk family members of MODY based on the genetic cause. METHODS: We analyzed the clinical course of 19 patients from 12 unrelated Iranian families with diabetes features. The coding regions and intron-exon boundaries of the hepatocyte nuclear factor 1 alpha (HNF1A) gene were studied by polymerase chain reaction (PCR) and sanger sequencing. Also, the detected mutation was analyzed by bioinformatics tools. RESULTS: One novel frameshift insertion mutation (p.Glu11Argfs*12) was detected in one of the probands and seven other patients of her family with the heterozygote state. The mutation is located in the exon1 of the dimerization domain of the HNF1A gene. According to the In Silico analysis, the detected mutation is predicted as a pathogenic one. CONCLUSIONS: Differential diagnosis between MODY3 and other forms of diabetes can be considered a necessity in terms of overlapping symptoms of MODY3 with type1 or 2 diabetes. Molecular genetic testing can provide an accurate diagnosis for optimal management.

Genetic association study of CTLA4 and FCεRIα polymorphisms in asthmatic patients in the southwestern region of Iran.

Asthma is a heterogeneous chronic pulmonary disease that develops due to the interaction of genetic and environmental factors. This study aimed to investigate the polymorphisms of CTLA4(SNP-318C > T, SNP + 49A > G) and FCεRIα(SNP-344T > C) genes in asthmatic patients in Southwest Iran. The study enrolled 200 patients with asthma of Arab and Bakhtiary descent and 200 healthy controls, where asthmatic patients and healthy controls were selected based on a spirometry test. Genomic DNA from whole blood samples using the TaqMan assay was used to study the genotypes of patients and healthy controls.The results indicated no statistically significant difference between cases and controls for the SNP-344C > T of the FCεR1α gene and the SNP + 49A > G, SNP-318C > T of the CTLA4 gene. There was a significant correlation between the CTLA4-318C > T allele frequency in both the case and control groups (OR = 1.83; 95%CI, 1.14-2.94; P = 0.01). We stratified genotypes according to age, gender, ethnicity, and smoking status and discovered a significant suggestive association between the SNP + 49A > G of the CTLA4 gene and smoking. Additionally, SNP + 49A > G was found to be associated with gender and age. The results indicated that the SNP-318C > T polymorphism in the CTLA4 gene might contribute to the development of asthma in the studied population. Meanwhile, smoking can exacerbate asthma in individuals with SNP + 49A > G of the CTLA4 gene.Supplemental data for this article is available online at https://doi.org/10.1080/15257770.2021.1964525 .