Association of Genetic Polymorphisms in Long Noncoding RNA HOTTIP with Risk of Idiopathic Recurrent Spontaneous Abortion.

The clustered homeobox gene family known as the Hox family plays a fundamental role in the morphogenesis of the vertebrate's embryo. A long noncoding RNA (lncRNA), known as HOTTIP (HOXA transcript at the distal tip), has been functionally characterized and contributed to the pathogenesis of various conditions. The current case-control study was undertaken to examine the gene frequencies and shared alleles of the HOTTIP  gene in Iranian participants with or without idiopathic recurrent spontaneous abortion (RSA). Both ARMS-PCR reaction and RFLP-PCR techniques were employed to detect three HOTTIP polymorphisms (rs2023843C/T, rs78248039A/T, and rs1859168C/A) in a DNA sample of 161 women with RSA and 177 healthy women. We found that the TT genotype of the HOTTIP rs2023843 C/T polymorphism was associated with a lower risk for idiopathic RSA. In contrast, the TT genotype of the HOTTIP rs78248039 A/T polymorphism was correlated with an enhanced risk of RSA. The presence of the A-allele for HOTTIP rs1859168 C/A polymorphism was associated with an increased risk for idiopathic RSA. Haplotype analysis showed that the T/T/A, C/T/A, T/T/C, and T/A/A haplotypes of rs2023843/rs78248039/rs1859168 enhanced RSA susceptibility. Computational analysis predicted that this lncRNA might act as a potential sponge for some microRNAs; therefore, affecting the expression of genes being targeted by them. In addition, both rs2023843 and rs1859168 variants could alter the local secondary structure of HOTTIP. Our results showed that HOTTIP rs2023843C/T, rs78248039A/T, and rs1859168C/A polymorphisms may confer genetic susceptibility to idiopathic RSA in an Iranian population.

Association of SLC11A1 polymorphisms with anthropometric and biochemical parameters describing Type 2 Diabetes Mellitus.

Diabetes, a leading cause of death globally, has different types, with Type 2 Diabetes Mellitus (T2DM) being the most prevalent one. It has been established that variations in the SLC11A1 gene impact risk of developing infectious, inflammatory, and endocrine disorders. This study is aimed to investigate the association between the SLC11A1 gene polymorphisms (rs3731864 G/A, rs3731865 C/G, and rs17235416 + TGTG/- TGTG) and anthropometric and biochemical parameters describing T2DM. Eight hundred participants (400 in each case and control group) were genotyped using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and amplification-refractory mutation system-PCR (ARMS-PCR) methods. Lipid profile, fasting blood sugar (FBS), hemoglobin A1c level, and anthropometric indices were also recorded for each subject. Findings revealed that SLC11A1-rs3731864 G/A, -rs17235416 (+ TGTG/- TGTG) were associated with T2DM susceptibility, providing protection against the disease. In contrast, SLC11A1-rs3731865 G/C conferred an increased risk of T2DM. We also noticed a significant association between SLC11A1-rs3731864 G/A and triglyceride levels in patients with T2DM. In silico evaluations demonstrated that the SLC11A2 and ATP7A proteins also interact directly with the SLC11A1 protein in Homo sapiens. In addition, allelic substitutions for both intronic variants disrupt or create binding sites for splicing factors and serve a functional effect. Overall, our findings highlighted the role of SLC11A1 gene variations might have positive (rs3731865 G/C) or negative (rs3731864 G/A and rs17235416 + TGTG/- TGTG) associations with a predisposition to T2DM.

Association study to evaluate Foxo1 and Foxo3 gene polymorphisms in polycystic ovary syndrome: a preliminary case-control study and in silico analysis.

BACKGROUND: Polycystic ovary syndrome (PCOS) is known as a multifactorial and multi-gene-mediated endocrine disorder among women of reproductive age. FoxO1 and FoxO3 are members of the forkhead transcriptional factors family that play a pivotal role in the function of ovaries. The current work is aimed at investigating the association between gene variants of FoxO1 and FoxO3 and the risk of PCOS in a sample of the Iranian population. METHODS AND RESULTS: We recruited 200 women diagnosed with PCOS and 200 healthy women. Both polymerase PCR-RFLP and ARMS-PCR methods were used for genotyping. Sanger sequencing was recruited to confirm the genotyping results. The T allele of rs17592236 and the C allele of rs12585277 decreased PCOS risk by 29 and 28%, respectively. In contrast, the C allele of rs2253310 and G allele of rs2802292 increased the risk of PCOS by 1.39 and 1.63 folds, correspondingly. Bioinformatics results showed that some genes, including matrix metallopeptidase 9 (MMP-9), phosphoinositide-3-Kinase Regulatory Subunit 224 1 (PIK3R1), peroxisome proliferator-activated receptor Gamma (PPARG), and glycogen synthase 225 kinase-3 beta (GSK-3 beta) have significant interactions with FoxO1, suggesting that FoxO1 might have crucial roles in regulating different signaling pathways in ovarian cells. CONCLUSION: We found that FoxO1 rs17592236C > T and rs12585277C > T had a protective role against PCOS, while FoxO3 rs2253310C > G and rs2802292G > T  enhanced the risk of this metabolic disorder in our population. Additional studies on larger populations with varying races are needed to confirm these findings.

Genetic Polymorphisms in miR-137 and Its Target Genes, TCF4 and CACNA1C, Contribute to the Risk of Bipolar Disorder: A Preliminary Case-Control Study and Bioinformatics Analysis.

Accumulating evidence has suggested that miR-137 and its target genes, CACNA1C, and TCF4, are amongst the most robustly implicated genes in psychiatric disorders. This preliminary study is aimed at investigating the effects of genetic variations in miR-137 (rs1625579A/C), TCF4 (rs1261084C/T), and CACNA1C (rs10774053A/G and rs10466907G/T) on BD susceptibility. We recruited 252 BD patients and 213 healthy subjects as the control group. Genotyping was performed using PCR-RFLP and ARMS-PCR methods. Enhanced risk of BD was found under the codominant homozygous, dominant, and allelic models of TCF4 rs1261084C/T, codominant homozygous and allelic models of CACNA1C rs10466907G/T polymorphisms, as well as codominant homozygous, dominant, recessive, and allelic models of the CACNA1C rs10774053A/G. Moreover, both TT/AG/GT/AA and TT/GG/GT/AC genotype combinations strongly increased the risk of BD in the participants. The bioinformatics analyses revealed that rs1261084C/T and rs10466907G/T created and disrupted binding sites of some miRNAs in the 3'-untranslated region of TCF4 and CACNA1C genes. In contrast, the rs10774053A/G created a new binding site for a major splicing factor and might have an effective role in the function of the CACNA1C protein. We have found that all the studied SNPs are positively associated with BD susceptibility. Replicated studies on different ethnicities are required to confirm these findings.

Single nucleotide polymorphisms located in TNFA, IL1RN, IL6R, and IL6 genes are associated with COVID-19 risk and severity in an Iranian population.

Cytokines play pivotal functions in coronavirus disease 2019 (COVID-19) pathogenesis. However, little is known about the rationale and importance of genetic variations associated with immune system responses, so-called "immunogenetic profiling." We studied whether polymorphisms of IL6, IL6R, TNFA, and IL1RN affect the disorder severity and outcome in patients infected with COVID19. We recruited 317 hospitalized patients with laboratory-confirmed COVID-19 from Bu-Ali hospital and 317 high-risk participants who had high exposure to COVID-19 patients but with a negative real-time-polymerase chain reaction (PCR) test. Multiple regression analyses were applied. We indicated that participants carrying the A allele in TNFA-rs361525, G>A (p < .004), the C allele in IL1RN-rs419598 T>C (p < .004), the A allele in IL6R-rs2228145, A>C (p = .047) are more susceptible to develop COVID-19. In contrast, those who carry the G allele of IL6-rs2069827, G>T (p = .01), are more protected from COVID-19. Also, we compared the various genotypes regarding the disorder severity and poor prognosis; we found that the AA genotype in TNFA is related to more aggressive illness and bad prognostic in contrast to the other inflammatory cytokines' genotypes. In addition, a high level of inflammatory indications, such as neutrophil-to-lymphocyte ratio and systemic immune-inflammation index, was observed in deceased patients compared with the survived subjects (p < .0001). We advised considering inflammatory cytokines polymorphisms as the main item to realize the therapeutic response against the acute respiratory distress syndrome induced by the SARS-CoV-2 virus.

Association of Polymorphisms in miR146a, an Inflammation-Associated MicroRNA, with the Risk of Idiopathic Recurrent Spontaneous Miscarriage: A Case-Control Study.

It has been established that microRNAs (miRNAs) are involved in the regulation of immune responses and serve as biomarkers of inflammatory diseases as well as recurrent spontaneous miscarriage (RSM). Herein, we aimed to study the relationship between three functional miR146a gene polymorphisms with idiopathic RSM (IRSM) susceptibility. We recruited 161 patients with IRSM and 177 healthy women with at least one live birth and without a history of abortion. Genotyping was performed using RFLP-PCR and ARMS-PCR methods. We found that the rs6864584 T/C decreased the risk of IRSM under dominant TT+TC vs. CC (OR = 0.029) and allelic C vs. T (OR = 0.028) contrast models. Regarding rs2961920 A/C and rs57095329 A/G polymorphisms, the enhanced risk of IRSM was observed under different genetic contrasted models, including the codominant CC vs. AA (OR = 2.81 for rs2961920) and codominant GG vs. AA (OR = 2.36 for rs57095329). After applying a Bonferroni correction, haplotype analysis revealed a 51% decreased risk of IRSM regarding the ACA genotype combination. This is the first study reporting that miR146a rs57095329 A/G, rs2961920A/C, and rs6864584 T/C polymorphisms are associated with the risk of IRSM in a southern Iranian population. Performing replicated case-control studies on other ethnicities is warranted to outline the precise effects of the studied variants on the risk of gestational trophoblastic disorders.

Long noncoding RNA HOTAIR polymorphisms and susceptibility to bipolar disorder: a preliminary case-control study.

Recent studies have shown that long noncoding RNAs contribute to the pathogenesis of bipolar disorder (BD). In this study, we genotyped four HOX Transcript Antisense Intergenic RNA (HOTAIR) gene polymorphisms to investigate if these variations could affect the risk of BD and its clinical subtypes. A total of 357 subjects, comprised of 194 BD patients and 163 age-matched healthy controls, were enrolled. Genotyping was carried out using PCR-RFLP and ARMS-PCR methods. We detected significant associations between the HOTAIR gene rs1899663 G/T, rs12826786 C/T, rs4759314 A/G, and rs920778 C/T polymorphism and the risk of BD under allelic, recessive, dominant, and codominant contrasted genetic models. The CT genotype of rs920778 C/T, GT genotype of rs1899663 G/T, and CT genotype of rs12826786 C/T polymorphisms enhanced the risk of BD type II (BDII). In contrast, the GG genotype of rs4759314 A/G polymorphism significantly diminished BDII risk by 83%. A positive association was noticed between CTTA and CTCG haplotypes of rs920778/rs1899663/rs12826786/rs4759314 and BD risk. Our findings reveal an interactive effect of HOTAIR polymorphisms on the development of BD and its subtypes. Further functional studies are needed to elucidate the role of these variations on HOTAIR expression and epigenetic status.

Association of TMPRSS2 Gene Polymorphisms with COVID-19 Severity and Mortality: a Case-Control Study with Computational Analyses.

Coronavirus disease 2019 (COVID-19) is a severe disease caused by a new variant of beta-coronavirus that first appeared in China. Human genetic factors, including polymorphisms, serve pivotal roles in the high transmission of SARS-CoV-2 and the stubbornly progressing sickness seen in a small but significant percentage of infected people; however, but these factors remain ill-defined. A total of 288 COVID-19 patients and 288 controls were genotyped for TMPRSS2 polymorphisms using both restriction fragment length polymorphism polymerase chain reaction (RFLP-PCR) and amplification refractory mutation system (ARMS)-PCR techniques. Different genotypes of TMPRSS2 polymorphisms were compared in terms of disease susceptibility and mortality. The statistical analysis showed that minor alleles of all studied variants statistically increased the risk of COVID-19, except for the rs75603675 C > A variant. The T allele of rs12329760 conferred an increased risk of COVID-19. Moreover, the AG/AC/TT/AG combination of genotypes significantly enhanced the risk of COVID-19 in our population. Different haplotypes of rs17854725/rs75603675/rs12329760/rs4303795 polymorphisms, including GACA, GACG, GATG, GATA, AATA, ACCG, ACTG, ACTA, GCCA, and GCTG, were found to be associated with increased risk of the disease (odds ratio > 1). Regarding the clinical and paraclinical characteristics, a statistically significant difference was found between non-severe and severe forms except for gender, platelet, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and underlying diseases. In addition, case genotypes of TMPRSS2 rs17854725 A > G, rs12329760 C > T, and rs4303795 A > G were significantly different regarding severe and non-severe forms of the disease (P-value < 0.001). Specifically, death was more frequent in carriers of the AG genotype of rs17854725 A > G (P-value = 0.022). Patients who carry the minor alleles of the four studied TMPRSS2 variants were rather vulnerable to COVID-19 infection. Our findings indicated that rs17854725 A > G (AA vs. AG and AA vs. GG), rs12329760 C > T (CC vs. CT and CC vs. TT), and rs4303795 A > G (AA vs. AG) genotypes of TMPRSS2 variations are associated with a more invasive disorder pattern. More studies on larger populations are needed to confirm our results.

Relationship between GABRB2 gene polymorphisms and schizophrenia susceptibility: a case-control study and in silico analyses.

PURPOSE: Converging evidence has recently established the significance of γ-aminobutyric acid neurotransmitter (GABA) system in the development of schizophrenia (SCZ). We aimed to determine the association of two markers of the GABAA receptor ß2 subunit gene (GABRB2), rs12187676 G/C and rs1816072 T/C, with the risk of SCZ in Iranian population. MATERIALS AND METHODS: In this case-control study, 190 patients with SCZ and 200 healthy controls were recruited from December 2018 to February 2020. Genotyping was done using the Tetra-ARMS-PCR technique. In silico analyses were performed to determine the potential effects of the variants. RESULTS: The C allele and genotypes of codominant CC vs.TT and CT vs.TT, dominant TT vs. TC + CC, recessive TT + TC vs. CC of rs1816072 polymorphism, as well as codominant CC vs. GG and recessive GG + GC vs. CC genetic models of rs12187676 polymorphism were significantly associated with SCZ susceptibility. Compared to the TC/GC model, we have found that the TC/CC combination significantly increased the risk of SCZ by 4.32 fold while the TT/GG combination conferred a protective role against SCZ. Haplotypes analysis indicated that GABRB2 polymorphisms are in weak linkage disequilibrium with each other (LD = 0.1). However, bioinformatics analyses predicted that these polymorphisms do not have significant effects on the secondary structure and the splicing of GABRB2-mRNA. CONCLUSIONS: We found that intronic GABRB2 polymorphisms were associated with SCZ risk in a sample of the Iranian population. These findings provided proof of concept for the involvement of the GABAergic neurotransmission system in SCZ development. These observations should be validated across other ethnicities and clinical subtypes.

Functional Variants of miR-143 Are Associated with Schizophrenia Susceptibility: A Preliminary Population-Based Study and Bioinformatics Analysis.

Single nucleotide polymorphisms within genes encoding microRNAs may alter the expression of microRNAs and their target genes, contributing to the etiology of psychiatric disorders. We aimed to investigate the link between rs4705342T/C and rs4705343T/C polymorphisms in the promoter region of miR-143 and the risk of schizophrenia (SCZ) in a sample of an Iranian population. In this experimental study, a total of 398 subjects were recruited. Genotyping carried out using allele-specific PCR (AS-PCR) method. Different bioinformatics databases and Cytoscape V3.4.0 software were used for the analysis of the gene-miRNA interaction network. The genotypic analysis of rs4705342C/T showed that CC genotype in the co-dominant model significantly decreased the risk of SCZ (p < 0.001). Also, a significantly reduced risk of SCZ was observed under allelic (p < 0.001), dominant (p = 0.007), and recessive (p = 0.001) models of this variant. As regards rs4705343T/C, significantly enhanced risk of SCZ was found under the co-dominant CC (p = 0.01) and recessive (p = 0.007) contrasted genetic models. For this variant, the C allele conferred an increased risk of SCZ by 1.41 fold. Haplotype analysis showed that the Crs4705342 Trs4705343 haplotype significantly diminished SCZ susceptibility. The result of the bioinformatics analysis showed that miR-143, as a critical miRNA, targets ERK5, ERBB3, HK2, and PKCε, the four major genes involved in SCZ development. Our findings suggest that these two polymorphisms might affect SCZ susceptibility. Elucidating the precise regulatory mechanisms of gene expression in the development of SCZ will help researchers discover a novel target for therapeutic interventions.

Association of polymorphisms in tumor necrosis factors with SARS-CoV-2 infection and mortality rate: A case-control study and in silico analyses.

The present coronavirus disease 2019 (COVID-19) is spreading rapidly and existing data has suggested a number of susceptibility factors for developing a severe course of the disease.  The current case-control experiment is aimed to study the associations of genetic polymorphisms in tumor necrosis factors (TNFs) with COVID-19 and its mortality rate. A total of 550 participants (275 subjects and 275 controls) were enrolled. The tetra-amplification refractory mutation system polymerase chain reaction technique was recruited to detect -308G>A TNFα and +252A>G TNFß polymorphisms among the Iranian subjects. We demonstrated that carriers of the G allele of TNFß-252A/G, rs909253 A>G were more frequent in COVID-19 subjects compared to the healthy group and this allele statistically increased the disease risk (odds ratio [OR] = 1.55, 95% confidence interval [CI] = 1.23-1.96, p < 0.0001). At the same time, the A allele of TNFα-311A/G, rs1800629 G>A moderately decreased the risk of COVID-19 (OR = 0.68, 95% CI = 0.53-0.86, p < 0.002). Also, we analyzed the various genotypes regarding the para-clinical and disorder severity; we found that in the AA genotype of TNFß-252A/G (rs909253 A>G), the computed tomography scan pattern was different in comparison to cases carrying the AG genotype with p1 < 0.001. In addition, in the severe cases of COVID-19, leukocyte and neutrophil count and duration of intensive care unit hospitalization in the deceased patients were significantly increased (p < 0.001). Moreover, the TNFα-311A/G (rs1800629 G>A) variant is likely to change the pattern of splicing factor sites. Our findings provided deep insights into the relationship between TNFα/TNFß polymorphisms and severe acute respiratory syndrome coronavirus 2. Replicated studies may give scientific evidence for exploring molecular mechanisms of COVID-19 in other ethnicities.

Genetic variants of HOTAIR are associated with susceptibility to recurrent spontaneous abortion: A preliminary case-control study.

AIM: To investigate the association between Hox transcript antisenses RNA (HOTAIR) polymorphisms, rs12826786 C/T, rs920778 T/C, rs4759314 A/G, and rs1899663 G/T, with recurrent spontaneous abortion (RSA) susceptibility in the Iranian women. METHODS: We enrolled 161 patients diagnosed with RSA and 177 healthy women with at least one live birth without a history of abortion. Genotyping of HOTAIR polymorphisms was carried out using both restriction fragment length polymorphism-polymerase chain reaction and amplification refractory mutation system-polymerase chain reaction methods. Odds ratios (ORs) with 95% confidence intervals (CIs) were assessed to estimate the strength of association. RESULTS: Different inheritance models of rs12826786 C/T, rs920778 T/C, and rs1899663 G/T polymorphisms significantly enhanced the risk of RSA (p < 0.05), whereas the rs4759314 A/G polymorphism was correlated with diminished risk of developing RSA under recessive AA versus GA + GG (OR 0.42 [95% CI = 0.19-0.91]), log-additive GG versus GA vs. GG (OR 0.67 [95% CI = 0.48-0.93]), and allelic A versus G (OR 0.65 [95% CI = 0.47-0.92]) models. Moreover, the TGTC, TTCT, TTTC, CGTC, CGTT, CTCC, CTCT, CTTC, and CTTT haplotypes of rs920778/rs1899663/rs12826786/ significantly increased the risk of RSA. The studied variants were not in strong linkage disequilibrium. CONCLUSIONS: Our results indicated that variations in the HOTAIR gene might serve as beneficial biomarkers for determining susceptibility to RSA. To confirm these findings, replication studies with a larger population and different races are needed.

Relationship between Functional miR-143/145 Cluster Variants and Susceptibility to Type 2 Diabetes Mellitus: A Preliminary Case-Control Study and Bioinformatics Analyses.

Purpose: To investigate the link between two variants (rs4705342 and rs4705343) in the promoter of the miR-143/145 cluster with Type 2 diabetes mellitus (T2DM) risk. Methods:A total of 1200 subjects were genotyped using the ARMS-PCR method. Results: The rs4705342 variant enhanced the risk of T2DM under codominant CC (OR = 3.24; 95% CI: 1.89-5.60), recessive TT+TC (OR = 3.02; 95% CI: 1.77-5.17), and dominant TC+CC (OR = 1.35; 95% CI: 1.08-1.71) genetic models. Individuals carrying the C allele of rs4705342 conferred a 1.43 fold increased risk of T2DM. As regards rs4705343, decreased risk of T2DM was observed under codominant TC (OR = 0.53; 95% CI: 0.42-0.67), over-dominant TT+CC (OR = 0.51; 95% CI: 0.40-0.64), and dominant TC+CC (OR = 0.59; 95% CI: 0.48-0.75) models. Haplotype analysis of the variants showed a 1.941-fold increased risk of T2DM regarding the C T combination. Significant associations were noticed between different haplotypes and lipid indices of T2DM patients. There were no notable changes in p-values after adjustment for BMI. Computational analysis revealed that miR143 and/or miR145 target important genes involved in glucose and lipid metabolism. Conclusions: Functional miR-143/145 variants might influence the risk of T2DM. Hence, clarifying the precise regulatory mechanisms of gene expression in the development of T2DM will significantly guide researchers to find a novel target for therapeutic intervention.

Association of a Novel KIF26B Gene Polymorphism with Susceptibility to Schizophrenia and Breast Cancer: A Case-Control Study.

BACKGROUND: KIF26B gene is found to play essential roles in regulating different aspects of cell proliferation and development of the nervous system. We aimed to determine if rs12407427 T/C polymorphism could affect susceptibility to schizophrenia (SZN) and breast cancer (BC), the two genetically correlated diseases. METHODS: The current case-control study was performed from Aug 2018 to Dec 2018. Briefly, 159 female pathologically confirmed BC cases referring to Alzahra Hospital, Isfahan, Iran, and 102 psychologically confirmed SZN patients (60 males and 42 females) admitted to Baharan Hospital, Zahedan, Iran, were enrolled. Using the salting-out method, genomic DNA was extracted, and variants were genotyped using allele-specific amplification refractory mutation system polymerase chain reaction (ARMS-PCR) method. RESULTS: The results revealed a significant association between the KIF26B rs12407427 codominant CT (P=0.001), CC (P=0.0001), dominant CT+CC, and recessive CC (P=0.001) genotypes with the risk of developing SZN. Significant correlations were also found regarding rs12407427 and BC susceptibility in different inheritance models, including over-dominant CT (P=0.026), dominant CT+CC (P=0.001), recessive CC (P=0.009), and codominant CT and CC (P=0.001) genotypes. The over-presence of the C allele was also correlated with an increased risk for SZN (P=0.0001) and BC (P=0.0001). Finally, computational analysis predicted that T/C variation in this polymorphism could change the binding sites in proteins involved in splicing. CONCLUSION: rs12407427 T/C as a de novo KIF26B variant might be a novel genetic biomarker for SZN and/or BC susceptibility in a sample of the Iranian population.

Functional miR143/145 Cluster Variants and Haplotypes Are Associated with Chronic Kidney Disease: a Preliminary Case-Control Study and Computational Analyses.

MiR-143/145 cluster is a novel transcriptional target of many signaling pathways, with variations within this cluster contributed to the risk of multiple diseases. To date, no data regarding the link between miR143/145 cluster polymorphisms and the risk of developing chronic kidney disease (CKD) has been reported. Hence, we aimed to examine such association in a population of Iranian ancestry. In this preliminary study, 276 CKD patients and 300 unrelated age and sex-matched healthy controls were recruited. Genotyping was performed by PCR-RFLP and allele-specific-PCR methods. Computational analyses were performed to predict the potential effects of the variants. Our findings indicated that rs41291957, rs12659504, and rs353292 polymorphisms were positively associated with CKD, while rs4705342 and rs4705343 polymorphisms demonstrated a significant negative association with the disease. Moreover, a significant association was observed between CC + TC and TT genotypes and CKD stages. We found that AACTT, AATTC, AATTT, GATTC, GATTT, and GGCTT haplotypes significantly enhanced the risk of CKD compared with the Grs41291957AArs12659504Crs353292Trs4705342Trs4705343 haplotype. Computational analysis showed that rs353292, rs4705342, and rs4705343 might alter the binding of the transcription factors in this gene cluster. We found that miR-143/145 cluster polymorphisms were associated with CKD risk in a sample of the Iranian population. Replicated studies on different ethnicities are necessary to investigate the association between these promoter variants and clinical outcomes.

Impact of Proliferator-Activated Receptor γ Gene Polymorphisms on Risk of Schizophrenia: A Case-Control Study and Computational Analyses.

Objective: Schizophrenia (SCZ) is a common psychiatric disorder characterized by a complex mode of inheritance. Peroxisome proliferator-activated receptor-γ (PPARG) mainly regulates lipid and glucose metabolisms while it is constitutively expressed in rat primary microglial cultures. This preliminary study was aimed to investigate the relationship of two polymorphisms in the PPARG gene, rs1801282 C/G, and rs3856806 C/T, to the risk of SCZ in the southeast Iranian population. Method : A total of 300 participants (150 patients with SCZ and 150 healthy controls) were enrolled. Genotyping was done using the amplification refractory mutation system polymerase chain reaction (ARMS-PCR) technique. Computational analyses were carried out to predict the potential effects of the studied polymorphisms. Results: A significant link was found between genotypes of rs1801282 and SCZ susceptibility. The G allele of rs1801282 in CG and GG form of the codominant model increased the risk of SCZ by 2.49 and 2.64 folds, respectively. With regards to rs3856806, enhanced risk of SCZ was also observed under different inheritance models except for the overdominant model. Also, the T allele of rs3856806 enhanced the risk of SCZ by 3.19 fold. Computational analyses predicted that rs1801282 polymorphism might alter the secondary structure of PPARG-mRNA and protein function. At the same time, the other variant created the binding sites for some enhancer and silencer motifs. Conclusion: Our findings showed that PPARG rs1821282 and rs3856806 polymorphisms associate with SCZ susceptibility. Replication studies in different ethnicities with a larger population are needed to validate our findings.

Relationship between Single Nucleotide Polymorphisms of GRHL3 and Schizophrenia Susceptibility: A Preliminary Case-Control Study and Bioinformatics Analysis.

Grainyhead-like (GRHL) transcription factors were recently linked to the etiology of neural tube defects (NTDs). Overlapping patterns in the variation of schizophrenia (SCZ) incidence with that of NTDs suggests the presence of common etiological risk factors. This preliminary study was designed to examine the relationship between two missense variants of GRHL3 gene (rs2486668C/G and rs545809A/T) and SCZ susceptibility among Iranians. Three hundred ninety subjects (192 patients confirmed with SCZ, and 198 healthy controls) were enrolled and genotyped. Statistical and bioinformatics analyzes were performed to determine the effects of the variants. In silico analyzes were performed to determine the effects of the variants on the secondary structure of GRHL3 protein and prediction of silencer motifs for each variation. Statistically significant differences were observed between the studied groups under codominant AA, dominant AT+AA, and recessive AA genetic contrast models for rs545809A/T. The presence of the A allele of rs545809A/T enhanced SCZ risk by 2.33 fold. In contrast, rs2486668C/G was not linked to SCZ susceptibility (P > 0.05). Bioinformatics analysis revealed that both missense SNPs caused substantial changes in the secondary structure of GRHL3-mRNA. Screening of the flanking sequences of rs545809A/T predicted silencer motifs for this SNP. Our results demonstrated that the rs545809A/T of GRHL3 gene could affect the risk of SCZ in Iranian populations. Replication studies are warranted to confirm these results.

An association study of polymorphisms in the H19 imprinted gene in an Iranian population with the risk of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies that causes problems in female fertility at the reproductive age. PCOS is a multifactorial disease, with genetic factors playing a crucial role in its development. H19 is a long non-coding RNA (lncRNA) expressed from the maternal chromosome, which is correlated with PCOS. In this study, 115 women suffering from PCOS and 130 healthy women with regular menstrual cycles were recruited as case and control groups, respectively. After the extraction of genomic DNA, the restriction fragment length polymorphism polymerase chain reaction was employed for genotyping of rs2067051G>A and rs3741219T>C. Statistical analysis was done using SPSS package V.22 for Windows. In silico analysis was recruited to determine the effects of SNPs on the secondary structure of gene transcript as well as miRNA binding sites. The obtained data showed that the A allele of rs2067051G>A was associated with the high risk of PCOS (OR = 2.00, 95%CI = 1.38-2.91, P = 0.00). AG and AA genotypes led to a 3.64- and (about) a five-fold increase in the risk of PCOS, respectively (95%CI = 2.02-6.54, P = 0.00, and 95%CI = 1.51-16.52, P = 0.00, respectively). These variants caused a significant increase in the risk of this disorder in all genotype models except in the recessive model. However, no association was found between rs3741219T>C and the increased risk of PCOS, either in the allele or in the genotype models. According to the findings, rs2067051G>A is associated with an increased risk of PCOS in the Iranian population.

Polymorphism in the 3'-UTR of LIF but Not in the ATF6B Gene Associates with Schizophrenia Susceptibility: a Case-Control Study and In Silico Analyses.

Schizophrenia (SCZ) is a multifactorial disorder caused by environmental and genetic factors. Studies have shown that various single-nucleotide polymorphisms (SNPs) in the binding sites of microRNAs contribute to the risk of developing SCZ. We aimed to investigate whether the variants located in the 3'-UTR region of LIF (rs929271T>G) and ATF6B (rs8283G>A) were associated with increased susceptibility to SCZ in a population from the south-east of Iran. In this case-control study, a total of 396 subjects were recruited. SNPs were genotyped via polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Genotyping results showed that the G allele of rs929271 significantly increased the risk of SCZ (OR = 1.58 95%CI = 1.19-2.10, p = 0.001). As for rs929271, the GG genotype of co-dominant (OR = 2.54 95%CI = 1.39-4.64, p = 0.002) and recessive (OR = 2.91 95%CI = 1.77-4.80, p < 0.001) models were strongly linked to SCZ. No significant differences were observed between rs8283 polymorphism and predisposition to SCZ. In silico analyses predicted that rs929271 might alter the binding sites of microRNAs, which was believed to have an unclear role in the development of SCZ. Moreover, rs929271 polymorphism changed the LIF-mRNA folding structure. These findings provide fine pieces of evidence regarding the possible effects of LIF polymorphism in the development of SCZ and regulation of the LIF gene targeted by microRNAs.

SNPs in the 3'-untranslated region of SLC30A8 confer risk of type 2 diabetes mellitus in a south-east Iranian population: Evidences from case-control and bioinformatics studies.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a heterogenic disease with increasing incidence. The SLC30A8 gene encodes an islet zinc transporter (ZnT8), and its variants have been associated with glucose and pro-insulin levels. This study was aimed to examine the effects of a missense variant (rs13266634 C/T), and two 3'UTR variants (rs2466294 C/G and rs2466293 T/C) in SLC30A8 gene on T2DM risk in a south-east Iranian population. METHODS: In this experiment, 450 patients diagnosed with T2DM and 453 healthy subjects from the same geographic area were enrolled. Genotypes were amplified using the ARMS-PCR method. In silico analyses were performed to determine the effects of the variants on the local structure of mRNA, splicing patterns, and potential miRNA-gene interactions as well. RESULTS: Significant differences were noticed between cases and controls regarding the genotypic and allelic distribution of the studied variants. As regards rs2466293 and rs2466294 variants, enhanced risk of T2DM was found under allelic, dominant, recessive, and codominant models (OR > 1). Besides, different genetic models of rs13266634 were associated with decreased risk of T2DM (OR < 1). Bioinformatics analyses indicated that the rs2466293 variant might influence the binding of some miRNAs, while the G-allele of rs2466294 decreased the stability of SLC30A8-mRNA. CONCLUSIONS: In our population, both SNPs in the 3'-untranslated region of SLC30A8 increased the risk of T2DM, while the rs13266634 variant showed a protective association against T2DM susceptibility. Investigating the effects of other variants in this gene or other ZnTs can further indicate such associations in subjects from the same ethnicity.