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Diabetic retinopathy (DR) is recognized as one of the most prevalent complications of diabetes and a major cause of morbidity. Transcription factor 7-like 2 (TCF7L2), a pivotal component in the Wnt-signaling pathway, plays a significant role in β-cell development, blood-glucose homeostasis, cell survival, cell migration, and cell proliferation. Thus, this study aimed to assess the association between TCF7L2 variants (rs7903146, rs11196205, and rs12255372) with DR in a population-based association study. DNA was extracted from whole blood of all subjects by salting-out procedure. Total 524 T2DM patients including 234 T2DM individuals without DR and 290 T2DM individuals with DR were genotyped by TaqMan assay technology. Clinical characteristics of subjects were conducted to evaluate the plausible association between TCF7L2 variants and DR with univariate linear regression analysis. Demographic analysis between case and control groups revealed significant differences in FBS, HbA1c, lipidemia, heart disease, and family history of T2DM (p < 0.05). No significant difference was observed in either genotypes distribution or allele frequency (p > 0.05) between T2DM individuals with and without DR in any models of inheritance. Genotype-phenotype association showed no significant association. Result of analysis indicated that HbAlc with adjusted OR of 1.8 (p < 0.0001) and first-degree relatives of family history with adjusted OR of 3.04 (p < 0.0001) were significantly associated with DR. Finally, haplotype analysis showed no noticeable association. In conclusion, there was no significant genetic association between rs7903146, rs11196205, and rs12255372 with DR among T2DM Iranians; however, these variants may play unknown roles in other populations. [ABSTRACT FROM AUTHOR]

Gastric cancer is one of the most common malignancies worldwide and it is the fourth leading cause of cancer-related death. Staphylococcus aureus enterotoxin A (SEA) is one of the toxins affecting the expression of apoptotic-related genes. The aim of this research is to investigate the effects of S. aureus enterotoxin A on the expression of BAK, FAS, BAX, TNF-a, BCL-2 and Survivin in AGS cell lines. In this study, AGS cells were transfected with the pcDNA3.1(+)-enterotoxin A or empty pcDNA3.1(+) plasmids using Lipofectamine 2000. The cells were grown in Dulbecco's modified Eagle's medium (DMEM) with 10% FBS. Then, the mRNA expression level of BAK, FAS, BAX, TNF-a, BCL-2, and Survivin was measured by the qRT-PCR method. Our findings indicated that Staphylococcus aureus enterotoxin A markedly altered the expression level of the apoptotic-related gene of the AGS cell line. The mRNA expression of BAK, FAS, BAX, and TNF-a genes increased statistically significantly in enterotoxin A treated AGS cells compared with the control group. On the contrary, BCL2 and Survivin mRNA expression showed a significant decrease compared with AGS cells were transformed by empty pcDNA3.1(+) plasmid. We suggested that SEA could represent an agent that can significantly change apoptosis-related genes expression in the AGS cell line, leading to reduction of tumor cell proliferation. [ABSTRACT FROM AUTHOR]

Abstract Background Chromosome 15q14-22.1 has been linked to type 2 diabetes (T2D) and its related traits in Japanese and other populations. The presence of T2D disease susceptibility variant(s) was assessed in the 21.8 Mb region between D15S118 and D15S117 in a Japanese population using a region-wide case-control association test. Methods A two-stage association test was performed using Japanese subjects: The discovery panel (Stage 1) used 372 cases and 360 controls, while an independent replication panel (Stage 2) used 532 cases and 530 controls. A total of 1,317 evenly-spaced, common SNP markers with minor allele frequencies > 0.10 were typed for each stage. Captured genetic variation was examined in HapMap JPT SNPs, and a haplotype-based association test was performed. Results SNP2140 (rs2412747) (C/T) in intron 33 of the ubiquitin protein ligase E3 component n-recognin 1 (UBR1) gene was selected as a landmark SNP based on repeated significant associations in Stage 1 and Stage 2. However, the marginal p value (p = 0.0043 in the allelic test, OR = 1.26, 95% CI = 1.07–1.48 for combined samples) was weak in a single locus or haplotype-based association test. We failed to find any significant SNPs after correcting for multiple testing. Conclusion The two-stage association test did not reveal a strong association between T2D and any common variants on chromosome 15q14-22.1 in 1,794 Japanese subjects. A further association test with a larger sample size and denser SNP markers is required to confirm these observations.

Abstract Background Genome-wide maps of linkage disequilibrium (LD) and haplotypes have been created for different populations. Substantial sharing of the boundaries and haplotypes among populations was observed, but haplotype variations have also been reported across populations. Conflicting observations on the extent and distribution of haplotypes require careful examination. The mechanisms that shape haplotypes have not been fully explored, although the effect of sample size has been implicated. We present a close examination of the effect of sample size on haplotype blocks using an original computational simulation. Results A region spanning 19.31 Mb on chromosome 20q was genotyped for 1,147 SNPs in 725 Japanese subjects. One region of 445 kb exhibiting a single strong LD value (average |D'|; 0.94) was selected for the analysis of sample size effect on haplotype structure. Three different block definitions (recombination-based, LD-based, and diversity-based) were exploited to create simulations for block identification with θ value from real genotyping data. As a result, it was quite difficult to estimate a haplotype block for data with less than 200 samples. Attainment of a reliable haplotype structure with 50 samples was not possible, although the simulation was repeated 10,000 times. Conclusion These analyses underscored the difficulties of estimating haplotype blocks. To acquire a reliable result, it would be necessary to increase sample size more than 725 and to repeat the simulation 3,000 times. Even in one genomic region showing a high LD value, the haplotype block might be fragile. We emphasize the importance of applying careful confidence measures when using the estimated haplotype structure in biomedical research.

Background: Genetic factors like the allele for Brain-Derived Neurotrophic Factor (BDNF) are associated with the outcome of ischemic stroke most likely through affecting neural differentiation and synaptic plasticity. Studies of the association of BDNF G196A gene polymorphism and long-term ischemic stroke outcome in various populations have not been concordant. Objective: In this research, the association of BDNF G196A gene polymorphism and ischemic stroke occurrence were studied in a northern Iranian population with a glance to its 6-month outcome. Methods: The genetic variant of BDNF G196A was examined in Ischemic Stroke (IS) patients (n = 206) and control group (n = 200). In IS individuals, outcome variables such as stroke severity, functional disability, and cognitive impairment were examined, respectively, by NIHSS, Barthel Index, and MoCA in an average of 202 days after the stroke occurrence. Results: The frequency of risk allele G was 12.1% in IS patients and 5.5% in healthy individuals; and the difference was statistically significant (p < 0.0001). The frequency of risk genotype GG, heterozygote and homozygote were 0% and 1%, 24.3% and 9%, 75.7% and 90%, respectively, for IS and control groups (p < 0.05). After controlling the phenotype confounding factors, logistic regression analysis showed that there was a borderline significant relationship between genotype BDNF GA + GG and IS occurrence (AOR = 1.997,95% CI: 0.252-1.010, p = 0.051). There was no significant difference between the various genotypic groups regarding the severity of the stroke and functional disability. Yet, G allele carriers had more cognitive impairment after IS (p = 0.002). Conclusion: For the first time in an Iranian population, it was demonstrated that BDNF G196A variant plays a major role in stroke occurrence and consequences. It is suggested that, after IS, G allele carriers should have precedence for medicinal and rehabilitation interventions, in order to reduce their cognitive deficiency. [ABSTRACT FROM AUTHOR]

The AMP-activated protein kinase (AMPK) signaling pathway controls whole-body glucose homeostasis by regulating metabolisms in multiple peripheral tissues, such as liver, skeletal muscle and adipose tissues - key tissues in the pathogenesis of type 2 diabetes (T2D). The oral antidiabetic agent metformin acts at least partially through an activation of AMPK in liver and muscle cells. Recent studies have demonstrated that, in the liver, the tumor suppressor LKB1 is the main upstream activating kinase for AMPK, whereas the CREB (cyclic-AMP-response-element-binding protein) coactivator TORC2 (transducer of regulated CREB activity-2) is a crucial downstream target of AMPK signaling in the control of gluconeogenesis. To test the hypothesis that single nucleotide polymorphisms (SNPs) of genes encoding the LKB1-AMPK-TORC2 proteins could confer susceptibility to T2D, we carried out a large-scale association study in the Japanese population. To identify SNPs within the LKB1 and TORC2 gene loci, all exons and exon-intron boundaries were screened by direct-sequencing in 32 randomly selected T2D patients. Additional SNPs were obtained from the public SNP databases. For the AMPK α2 subunit gene, SNPs were picked from previous reports. Based on their allelic frequency, level of linkage disequilibrium (LD) with neighboring markers and their potential to alter function, eight SNPs in the LKB1 gene, twelve in the TORC2 gene and six in the AMPK α2 subunit gene were selected and used for a case-control study of 1,787 Japanese subjects participating in a multicenter research protocol (911 cases, 876 controls). Analysis of individual SNPs revealed weak disease associations of a LKB1 SNP (rs741765, genotypic P-value=0.01) and two AMPK α2 SNPs in complete LD (rs1418442 and rs932447, genotypic P-value=0.03 under a dominant model). None of the TORC2 SNPs showed evidence of significant association. Haplotype-based analysis showed that a single haplotype of the LKB1 gene was weakly associated with T2D (P-value=0.04). Our data are inconsistent with the data reported by Horikoshi et al. (Diabetes, 2006), who observed a significant association between the AMPK α2 gene haplotypes and T2D in a Japanese population. Overall, our results indicate that the LKB1-AMPK (α2)-TORC2 genes are unlikely to play a major role in the genetic susceptibility to T2D. [ABSTRACT FROM AUTHOR]

Background: Exact mechanisms of fetal harm following vitrification are still unknown. This study was conducted to evaluate the cryopreservation impact on the expression of Epidermal Growth Factor Receptor (EGFR) gene in mouse 2-cell and blastocysts. Methods: To stimulate ovulation in mice, hCG was injected, followed by collecting 2-cells and blastocysts after 44-46 and 88-89 hr, respectively. These embryos were divided into two case and control groups. The fresh case group was cryopreserved using cryotop and warmed after 4 mounts. Normal 2-cells were selected based on their morphology and their RNA was extracted. Quantitative expression of EGFR gene in both groups was investigated by applying real time-PCR. Results: The statistical Real-Time (RT)-PCR analyses performed using SPSS revealed that the expression level of EGFR gene was diminished in the case group compared to the control group. Conclusion: The current study indicated the negative effect of cryopreservation on expression amount of EGFR gene in 2-cell and blastocyst mouse embryos. [ABSTRACT FROM AUTHOR]

The global public health addiction crisis has been stark, with over 932,400 deaths in the USA and Canada from opioid overdose since 1999-2020, surpassing the mortality rates at the top of the HIV/AIDS epidemic. Both nations exhibit opioid consumption rates significantly above the norm for developed countries. Analgesic type of opioids present both therapeutic benefits and substantial health risks, necessitating balanced drug regulation, careful prescribing, and dedicated opioid stewardship. The role of the cytochrome P450 2D6 (CYP2D6) system (Enzymatic functions) in metabolizing opioids highlights the potential of genotype-guided analgesia. By integrating Pharmacogenomics (PGx), this approach aims to optimize pain management, enhance safety, and reduce addiction risks. This understanding prompted the utilization of multifactor dimensionality reduction (MDR) to explore a range of phenotypes including PGx and gene-gene interactions (GGI) in a healthy cohort, thereby personalizing pain management strategies. The study sampled 100 unrelated healthy Western Iranians and 100 individuals from the 1000 Genome Project. Pre-testing involved searching for PGx annotations (variants associated with drug-gene-diseases) related to pain sensitivity and inflammation using the PharmGKB database, which identified 128 relevant genes. A questionnaire helped select 100 participants who had never used potent opioids but also other psychoactive agents (e.g., nicotine, amphetamines, etc.) and disease-related drugs. Whole-exome sequencing (WES) was then employed to analyze these genes in an Iranian cohort. Further analyses included MDR for identifying synergistic gene annotations and GGI for exploring complex gene interactions through the Visualization of Statistical Epistasis Networks (ViSEN). The study identified a Pain, Anti-Inflammatory, and Immunomodulating agents (PAIma) panel from the 128 genes, resulting in 55,590 annotations across 21 curated pathways. After filtering, 54 significant structural or regulatory variants were identified. This research also highlighted novel gene relationships involving the CYP3A5 gene, hsa-miR-355-5p, Paliperidone, and CYP2D6, which warrant further investigation. This study offers a novel pharmacogenetic framework that could potentially transform opioid prescribing practices to mitigate misuse and enhance personalized pain management. Further validation of these findings from multi countries and ethnic groups could guide clinicians in implementing DNA-based opioid prescribing, aligning treatment more closely with individual genetic profiles., (© 2024. The Author(s).)

Purpose: The patients with more severe stroke, have more chance to develop higher levels of cognitive impairments; and family history of dementia as a genetic background, can give rise to an increased risk of the severity of cognitive deterioration. In this study, we sought to investigate whether the risk alleles of Val66Met of brain-derived neurotrophic factor (BDNF) polymorphism, has a destructive interaction with the stroke severity (SS) and family history of dementia (FHD) for cognitive impairments?, Method: In a case-control study, the carriers of at least one Val allele (n=56) were compared to the carriers of Met/Met homozygotes (n=156) in terms of FHD and SS (through National Institutes of Health Stroke Scale) on the north of Iran. To determine the cognitive functions, the third version of Addenbrooke's Cognitive Examination (ACE-III) was used., Result: The mean age of patients was 64.52±11.71, and in average 202 day had passed from their stroke. The interactive effects of genotypes Val66Met BDNF with SS[F=8.95, ή2=0.04, P=0.003] and FHD[F=4.59, ή2=0.02, P=0.03] were significant for total score of ACE-III. It means that the Met/ Met homozygosity, modulated the effect of risk factors of SS and FHD on the cognitive function. Such homozygosity protects the attentional function and language abilities against the SS and FHD(P≤0.05)., Conclusion: It can be speculated that presence of Val/Met heterozygosity has a destructive interaction with the SS and FHD for decreasing the cognitive function, particularly in attention and language domains. Our findings suggested that the inhibition of signaling and trafficking of Val/Met heterozygosity is possibly a practical strategy in reducing the cognitive impairments following the stroke.

The LKB1-AMPK-TORC2 signaling pathway controls glucose homeostasis in the liver, and mediates therapeutic effects of insulin-sensitizing antidiabetic agents. To examine whether genetic variations in genes encoding components of this signaling pathway contribute to increased susceptibility to type 2 diabetes, we screened STK11 (LKB1) and CRTC2 (TORC2) genes for genetic variants and conducted a case-control study in 1787 unrelated Japanese individuals. Additionally, the previously described association between the PRKAA2 (AMPK alpha2-subunit) haplotype and type 2 diabetes was tested for replication. We observed associations of nominal significance with two SNPs, an intronic SNP in the STK11 (rs741765; OR 1.33, 95% CI 1.05-1.67, p=0.017, under a recessive genetic model), and a non-synonymous SNP in the CRTC2 (6909C>T: Arg379Cys; OR 3.01, 95% CI 1.18-7.66, p=0.016, under a dominant model), although neither withstood correction for multiple testing. We were unable to replicate the association between the PRKAA2 haplotype and type 2 diabetes: however, in the single SNP evaluation, an intronic PRKAA2 SNP (rs1418442) that had previously been reported to be associated with serum cholesterol levels in Caucasian females showed a weak association (OR 0.62, 95% CI 0.40-0.96, p=0.030, under a recessive model). Among the three genes investigated herein, gene-gene (SNP-SNP) interaction studies provided evidence for an interaction between STK11 and CRTC2 influencing susceptibility to type 2 diabetes. Our findings suggest that genetic variants of LKB1-AMPK-TORC2 pathway components may exert a weak influence on the occurrence of type 2 diabetes in Japanese.