Effects of immunorelated gene polymorphisms on trastuzumab targeting breast cancer cell in vitro.

Aim: To investigate the associations between genetic polymorphisms in immunorelated genes and PBMC-induced cytotoxicity to breast cancer cell with the treatment of trastuzumab in vitro.Methods: Trastuzumab-mediated cytotoxicity of peripheral blood mononuclear cells (PBMC) from 148 healthy donors and 13 BC patients was analyzed by flow cytometry. 16 SNPs in 7 immunorelated genes were genotyped by Sequenom Mass Array Genotype Platform.Results: Cytotoxicity in the trastuzumab treated PBMCs were significantly higher than those of the basal group. A wide variability in trastuzumab-mediated cytotoxicity was observed, and PBMC from individuals with the CD247 rs16859030 T genotype generated increased cytotoxicity than those with the CC genotype.Conclusion: The CD247 rs16859030 polymorphism affects trastuzumab-mediated cytotoxicity in vitro.

[Box: see text].

Genetic polymorphism of Duffy binding protein in Pakistan Plasmodium vivax isolates.

Plasmodium vivax Duffy binding protein (PvDBP) is crucial for erythrocyte invasion, interacting with the Duffy Antigen Receptor for Chemokines (DARC) on the erythrocyte surface. The amino-terminal cysteine-rich region II of PvDBP (PvDBPII) is a promising blood stage vaccine candidate, yet the genetic polymorphisms of this protein in global P. vivax isolates complicate the design of effective vaccines against vivax malaria. This study analyzed the genetic polymorphism of PvDBPII in Pakistan P. vivax isolates. A total of 29 single nucleotide polymorphisms (SNPs), including 22 nonsynonymous SNPs, were identified in 118 Pakistan PvDBPII. Most amino acid substitutions occurred in subdomains II and III, with six commonly observed in the global PvDBPII population. The amino acid change patterns in Pakistan PvDBPII generally mirrored those in global PvDBPII, although the frequencies of amino acid changes varied by country. Nucleotide diversity in Pakistan PvDBPII was comparable to that found in global PvDBPII. Evidence of natural selection and recombination in Pakistan PvDBPII aligned with observations in global PvDBPII. Analysis of the haplotype network of global PvDBPII revealed a complexed network of 167 haplotypes, but no geographical clustering was observed. The findings are crucial for understanding the genetic characteristics of Pakistan PvDBPII. A comprehensive analysis of nucleotide diversity and evolutionary trends in the global PvDBPII population offers valuable insights for the development of vivax malaria vaccines based on this antigen.

Population Pharmacokinetic and Pharmacodynamic of Atorvastatin in Chinese Lung Transplant Recipients.

Atorvastatin is a widely prescribed cholesterol-lowering drug that inhibits 3-hydroxy-3-methylglutaryl coenzyme A reductase to reduce lipid levels. This study aimed to establish a population pharmacokinetic and pharmacodynamic model for atorvastatin in Chinese lung transplant recipients (LTRs), particularly those using voriconazole (VOR) and with different genotypes. It evaluated precise dosing regimens and analyzed the correlation between atorvastatin exposure and clinical outcomes. A nonlinear mixed-effects model was used for the population pharmacokinetic/pharmacodynamic (PK/PD) analysis. A one-compartment population PK model was developed, incorporating VOR, SLCO2A1 rs76906503, and SLC22A8 rs2187383 to assess apparent clearance and volume of distribution. LDL-C was modeled as a biomarker to evaluate atorvastatin efficacy. A Monte Carlo simulation was conducted to assess various dosing schemes and the effects of different covariates on achieving the target LDL concentration. The correlation between atorvastatin exposure and clinical outcomes was also evaluated. Results indicated that the average probability of target attainment for optimal dosing regimens across various covariate results exceeded 45.8%. Dosages of 10, 20, and 40 mg were deemed suitable for LTRs. A lower dose was recommended for LTRs taking VOR or with mutant-type genotypes to avoid overexposure and adverse reactions. The population PK/PD model offers valuable guidance for evaluating atorvastatin dosing regimens in clinical settings, particularly for LTRs using VOR and those with different genotypes.

[Vitamin D status in connection with VDR and GC genes polymorphism in coal mining workers].

Vitamin D is a unique compound that can enter the human body not only with food, but also be synthesized in the skin under the influence of ultraviolet radiation. Individual differences in the need for this vitamin may be associated with the carriage of polymorphic variants of genes that implement its biological effects, which include VDR BsmI C>T (rs1544410), VDR TaqI A>G (rs731236) and GC rs2282679 T>G. At risk for vitamin D deficiency are workers in the coal mining industry, whose working conditions combine limited insolation and a pronounced deficiency of vitamins in the diet. The purpose of the study was to assess vitamin D plasma level in coal mining workers depending on the carriage of polymorphic variants of the VDR BsmI C>T (rs1544410), VDR TaqI A>G (rs731236) and GC rs2282679 T>G genes and professional working conditions. Material and methods. The study included 154 coal mining workers. The main group consisted of 100 workers associated with the underground nature of work, the comparison group - 54 ground workers of the enterprise. In all individuals, the level of 25-hydroxyvitamin D in blood plasma was determined by enzyme-linked immunosorbent assay and genotyping was performed for three polymorphic loci: VDR rs1544410, rs731236, GC rs2282679 by real-time PCR. Results. A statistically significant decrease in the concentration of plasma vitamin D in the underground workers was revealed, compared with the level of this vitamin in ground workers of the enterprise (p=0.037). Underground workers - carriers of the CT genotype of the VDR rs1544410 gene, AG of the VDR rs731236 gene and TT of the GC rs2282679 gene had a lower 25(OH)D level in blood plasma compared to owners of similar genotype variants in the comparison group (p<0.05). Among ground workers, carriers of the TT genotype of the GC rs2282679 gene had a significantly higher vitamin D plasma level compared to carriers of the TG and GG genotypes (p=0.02). An association of the GC gene with vitamin D level in blood plasma was revealed according to a dominant model of inheritance (OR=0.47, 95% CI 0.23-0.97; p=0.037, for owners of the TT genotype, compared with carriers of the TG+GG genotypes). Conclusion. The development of personalized diets based on individual genetic status may be of great importance for the prevention of diseases associated with vitamin D deficiency in individuals at risk.

Sub- and supratherapeutic efavirenz plasma concentrations with risk for HIV therapy failure are mainly genetically explained in Ugandan children: The prospective GENEFA cohort study.

AIMS: Interindividual variations in efavirenz (EFV) plasma concentrations are extensive, but paediatric data on its consequences for viral control are scarce. The aim of this study was to explore the role of genetic variation in achieving therapeutic efavirenz plasma concentrations in a cohort of Ugandan children and the linkage between genetic CYP2B6 variants, EFV plasma variability, viral resistance and viral outcome. METHODS: Ninety-nine treatment-naïve children, aged 3-12 years and living with HIV, were followed for 24 weeks after ART initiation assessing mid-dose efavirenz plasma concentrations, HIV RNA, HIV drug resistance and adherence. Polymorphisms in genes coding for drug-metabolizing enzymes were genotyped. Efavirenz concentrations were determined by liquid chromatography coupled with high-resolution tandem mass spectrometry. Metabolizer phenotype was predicted from composite genotypes of CYP2B6 (c.516G>T and c.983 T>C). A mixed effects restricted maximum likelihood regression model was used to identify important factors for efavirenz exposure. RESULTS: Efavirenz plasma concentrations were below the therapeutic interval (1000-4000 mg/mL) in 12-17% and above in 21-24% of measurements. Eight children had persisting subtherapeutic concentrations, five of which failed virologically and three acquired at least one new resistant mutation. Multivariate modelling explained 70% of interindividual variation in plasma concentration, with treatment duration, adherence, CYP2B6c.136A>G, and metabolizer phenotype as independent predictors of EFV concentration. In univariate analysis, metabolizer phenotype explained 50% of interindividual variation. CONCLUSIONS: Metabolizer phenotype explained 50% of interindividual variation in efavirenz plasma concentration. Autoinduction was not confirmed and >33% of the concentrations were outside the therapeutic interval. Subtherapeutic concentrations worsened virological resistance and outcomes. Genotype-based dosing may help avert both sub- and supratherapeutic efavirenz plasma concentrations in Ugandan children.

The relationship between CYP2C9 gene polymorphisms and azilsartan metabolism in vitro.

BACKGROUND: The gene polymorphisms of the CYP2C9, as well as the substrate specificity of the enzyme, result in different clearances for different substrates by CYP2C9 variants. RESEARCH DESIGNAND METHODS: The CYP2C9 wild type and 38 CYP2C9 variants, expressed in insectmicrosomes, were incubated with azilsartan. The resulting metabolite,O-desethyl azilsartan, was determined by HPLC-MS/MS. The enzyme kineticparameters of the 38 variants were calculated and compared with the wild type.Subsequently, we selected CYP2C9*1, *2, and *3 as target proteins for molecular docking with azilsartan to elucidate the mechanisms underlying changes in enzyme function. RESULTS: Compared with CYP2C9*1, three variants (CYP2C9*29, *39, and *49) exhibited markedlyincreased CLint values (from 170%-275%, *p < 0.05), whereas 28 variants exhibited significantly decreased CLint values (from 3-63%,*p < 0.05). The molecular docking results showed that the binding energy of CYP2C9*2 and *3 was lower than that of the wild type. CONCLUSION: Thisassessment revealed the effect of CYP2C9 gene polymorphisms on azilsartan metabolism, establishing a theoretical basis for further in-vivo studies and clinical applications. This study will help expand the database of CYP2C9 gene-drug pairs and identify appropriate treatment strategies for azilsartan, contributing to the field of precision medicine.

Genetic Variants in Vitamin-D Metabolism Genes (rs1155563, rs12785878 and rs10500804) among Females with Type-2 Diabetes Mellitus in Saudi Arabia.

Background & Objective: Hypovitaminosis D has shown to be linked with T2DM development and control in numerous studies. The association of SNPs in genes related to VitD metabolism with T2DM has not been sufficiently studied. Consequently, our aim in the present study was to explore the association between genetic variants in genes connected with VitD, mainly a SNP in GC (rs1155563), a SNP in DHCR7 (rs12785878) and a SNP in CYP2R1 (rs10500804) with glycaemic parameters in females with T2DM in Saudi Arabia. Methods: The cross-sectional study included 149 females (age 38-52 years) with T2DM from Jeddah, Saudi Arabia (September 2022-March 2023). Blood was extracted from the participants for biochemical tests including measuring VitD [25(OH)D] concentration, parameters of glycaemia (HbA1c, insulin, fasting glucose and insulin sensitivity indices including HOMA2-IR and HOMA2-%ß), and for genomic DNA isolation. Sanger DNA sequencing was used to screen for VitD genetic polymorphisms (rs1155563, rs12785878 and rs10500804). Results: Minor allele frequency for rs1155563C, rs12785878T and rs10500804G was 0.21, 0.23 and 0.37, respectively. Levels of 25(OH)D and glycaemic parameters as well did not show any significant difference between the genotypes of each SNP. Conclusion: This study showed lack of association of rs1155563 in GC, rs12785878 in DHCR7 and rs10500804 in CYP2R1 with VitD level primarily and with glycaemic parameters secondarily. Additional research is required to explore further other VitD genetic polymorphisms influencing T2DM which might lead consequently to genetically-based personalized management for T2DM.

CYP2D6, CYP2E1 Gene Polymorphisms and Gastrointestinal Cancer Risk in Rural Maharashtra: A Hospital Based Case-Control Study.

BACKGROUND: Cytochrome P450 (CYP) is a family phase I metabolizing enzymes important in xenobiotics metabolism. Genetic polymorphisms of CYPs have been comprehensively studied for their association with a range of diseases including cancer risk. In this study we assessed single nucleotide polymorphism (SNP) CYP2D6 and CYP2E1 genes and their role in gastrointestinal (GI) cancer susceptibility in the rural population of Maharashtra. METHODS: Genotyping of CYP2D6*4, CYP2E1*5B, CYP2E1*6, CYP2E1*7B genes among 200 GI cancer cases and equal number of controls was studied by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The Odds ratio (OR) with 95% confidence interval and p-value were evaluated to get the level of association of polymorphisms with risk of GI cancer, where p ≤0.005 was considered as statistically significant. RESULTS: After the analysis of CYP2D6 and CYP2E1 gene polymorphisms, we noticed that CYP2D6*4 (rs3892097) with heterozygous genotype (G/C) showed negative association with GI cancer risk (OR=0.43, 95% CI: 0.25-0.74; p=0.002) and CYP2E1*6 (rs6413432) variant genotype showed positive association (OR=2.85, 95% CI: 1.40-5.81; p=0.003) showed positive association with GI cancer risk in studied population. CONCLUSION: The findings obtained from this study concluded that the polymorphic CYP2D6 was negatively associated; however CYP2E1*6 polymorphism was significantly associated with GI cancer risk in studied population.

Advantages of using Genetically Elevated Lipoprotein(a) Levels in Predicting 5-Year Major Adverse Cardiovascular Events Relating to Coronary Artery Disease in Women.

Background: This study aimed to investigate major adverse cardiovascular events (MACE) in patients with coronary artery disease (CAD) over 5 years, in general, and depending on sex, lipoprotein(a) level, and number of kringle IV type 2 (KIV-2) repeats in the Lipoprotein(A) (LPA) gene. Methods: This study comprised 216 patients (120 women and 96 men) hospitalized with a diagnosis of "CAD, unstable angina IIB class". The three-point risk of MACEs was assessed over 5 years: cardiovascular death, non-fatal myocardial infarction, and stroke. The number of KIV-2 repeats in the LPA gene was determined by quantitative real-time polymerase chain reaction (qPCR). Results: The relative risk of MACE in patients with elevated lipoprotein(a) (Lp(a)) was 2.0 (95% CI 1.04-3.87, p < 0.05) for quartile 4 (Q4) ≥ 48 mg/dL versus quartile 1 (Q1) ≤ 6 mg/dL. This was mainly attributable to an increase in men-relative risk (RR) 2.6 (95% CI 1.10-6.16, p < 0.05)-but not in women: RR 1.4 (95% CI 0.50-3.92). Mean lipoprotein(a) levels were inversely correlated with 42.5 and 7.5 for Q1 and Q4 KIV-2 repeat numbers, respectively. The relative risks of MACE for Q1 vs. Q4 KIV-2 repeats were as follows: 3.0 (95% CI 1.48-6.08, p < 0.001) for all patients; 3.0 (95% CI 1.20-6.55, p < 0.01) for men; 3.3 (95% CI 1.02-10.4, p < 0.05) for women. Conclusions: Quantifying kringle IV type 2 repeat copy number in the LPA gene using qPCR more accurately reflects the risk of major adverse cardiovascular events within 5 years in women with coronary artery disease.

Exploring Genetic Variants and Platinum Chemotherapy Response in Indonesian Non-Small Cell Lung Cancer Patients: Insights from ERCC2 rs13181.

Purpose: Individual responses to platinum-based treatment for Non-Small Cell Lung Cancer (NSCLC) are influenced by genetic polymorphisms, including Single Nucleotide Polymorphisms (SNPs). This study aimed to explore the role of ERCC2 in the Nucleotide Excision Repair (NER) pathway for platinum-based chemotherapy in NSCLC. While ERCC2 is widely studied, data for Southeast Asian populations are lacking. Addressing this gap could improve personalized treatment strategies for NSCLC in this demographic. Patients and Methods: This study recruited 82 NSCLC patients with wildtype mutations of EGFR at Dr. H.A. Rotinsulu Lung Hospital, Bandung, and Dharmais Cancer Hospital, Jakarta. Data were collected prospectively from whole blood samples and medical records, while the effectiveness of chemotherapy was assessed by evaluating the response using RECIST 1.1 criteria on fourth cycle of chemotherapy. Results: The results of this study showed the presence of genotype variation among the subjects, with frequency distribution as follows: AA genotype (82.9%), AC genotype (15.9%), and CC genotype (1.2%). The analysis of the association between ERCC2 rs13181 CC + AC versus AA with RECIST 1.1 yielded an odds ratio (OR) of 1.042 (95% CI: 0.292-3.715; p=0.950). A multivariate analysis that included cancer stage and chemotherapy regimen as additional variables produced an adjusted odds ratio (aOR) of 0.970 (95% CI: 0.263-3.568; p=0.963). Conclusion: This study did not find statistically significant associations between ERCC2 rs13181 polymorphisms and chemotherapy responses. However, this research highlights the presence of genetic variation within the Indonesian population, with the AA genotype being the most prevalent, which may influence chemotherapy responses. The results provided preliminary data and lay the foundation for future comprehensive cohort observational investigations.

[Genetic polymorphisms of common sandflies in selected areas of Henan Province based on DNA barcoding].

OBJECTIVE: To characterize the species of common sandflies in Henan Province using DNA barcoding with cytochrome c oxidase subunit I (COI) gene as the molecular marker, and to analyze the genetic polymorphisms of sandflies, so as to provide insights into visceral leishmaniasis prevention and control in Henan Province. METHODS: Sandfly specimens were sampled from 13 sandflies surveillance sites from 2021 to 2023 in Anyang City, Zhengzhou, Luoyang and Xuchang cities (Zhengzhou-Luoyang-Xuchang areas) where visceral leishmaniasis cases were reported and in Jiaozuo and Xinxiang cities (Jiaozuo-Xinxiang areas) without visceral leishmaniasis cases reported. Genomic DNA was extracted from a single sandfly, and COI gene was amplified. The amplification product was subjected to bidirectional sequencing. Following sequence assembly, the species of sandflies was characterized through sequence alignment using the BLAST tool. The intra-specific and inter-specific genetic distances of sandflies were estimated among different areas using the software Mega 11, and phylogenetic trees were created. The polymorphisms of nucleotide sequences in the sandflies COI gene were estimated using the software DnaSP. The fixation index (FST) of different geographical isolates of sandflies was calculated using the Arlequin software, and the gene flow value (Nm) was used to measure the gene flow in the sandflies populations. In addition, the population genetic structure of different geographical populations of Phlebotomus chinensis was analyzed using the STRUCTURE software. RESULTS: A total of 978 sandflies were collected from 13 sandflies surveillance sites in Zhengzhou-Luoyang-Xuchang areas, Jiaozuo-Xinxiang areas and Anyang City of Henan Province from 2021 to 2023, and 475 sandflies were randomly sampled for subsequent detections. A total of 304 Ph. chinensis, 162 Se. squamirostris and 9 Se. bailyi were identified based on molecular biological detection of the COI gene, and Se. bailyi was reported for the first time in Henan Province. The intraspecific genetic distances of sandflies were 0.000 to 0.040, and the inter-specific genetic distances ranged from 0.133 to 0.161. Phylogenetic analysis revealed that each of the three sandfly species was clustered into a clade. The genetic polymorphisms of Ph. chinensis populations varied among different areas, with the highest haplotype diversity (0.966 ± 0.007) and the greatest nucleotide diversity (0.011) in Zhengzhou-Luoyang-Xuchang areas, and the lowest haplotype diversity (0.720 ± 0.091) and nucleotide diversity (0.004) in Anyang City. The dominant haplotype of Ph. chinensis populations was Pch_Hap_2 in Anyang City and Jiaozuo-Xinxiang areas, with moderate genetic differentiation (0.05 < FST < 0.15) and frequent gene exchange (Nm value > 1) between Ph. chinensis populations sampled from Anyang City, and Jiaozuo-Xinxiang areas. Population genetic structure analysis showed that the dominant component of Ph. chinensis populations was K5 in Anyang City and Jiaozuo-Xinxiang areas. No obvious dominant haplotype was observed in Ph. chinensis populations sampled from Zhengzhou-Luoyang-Xuchang areas, which had very high genetic differentiation (FST > 0.25) and little gene exchange (Nm value < 1) with Ph. chinensis populations from Anyang City, and Jiaozuo-Xinxiang areas, with K3 as the dominant component. In addition, there was no significant difference in the genetic polymorphism level among Se. squamirostris populations from the three areas. CONCLUSIONS: There are Ph. chinensis, Se. squamirostris and Se. bailyi in Henan Province, and S. bailyi is recorded for the first time in Henan Province by molecular biological assays. There are different levels of genetic differentiation and gene exchange among P. chinensis populations in different areas of Henan Province.

Association of MTHFR rs9651118 and TYMS rs2790 Polymorphisms with Risk of Cancers: A Case-Control Study and Meta-analysis.

Recently, rs9651118 in the MTHFR gene and rs2790 in the TYMS gene have been repeatedly studied for their contribution to cancer risk. However, the results remain conflicting rather than conclusive. Therefore, we here conducted a replication case-control study and a meta-analysis to comprehensively examine the contribution of rs9651118 and rs2790 to cancer risk. A total of 1727 patients with colorectal/gastric/liver (787/460/480) cancer and 800 healthy controls were recruited, and the Sanger sequencing was applied to genotype rs9651118 and rs2790. Besides, a total of 23 eligible studies were included in the following meta-analysis. After Bonferroni correction, the results of case-control study suggested that significant associations between rs9651118 and colorectal cancer (CRC) risk, rs9651118 and gastric cancer (GC) risk, and rs2790 and liver cancer (LC) risk were identified in Hubei Chinese population. The results of meta-analysis indicated that after Bonferroni correction, both rs9651118 and rs2790 were significantly associated with total cancer risk especially in Asian population and based on Sanger sequencing method, rs9651118 was significantly associated with breast cancer (BC) risk, and rs2790 was significantly associated with the risk of CRC and GC. In conclusion, the present findings revealed that the MTHFR gene rs9651118 may participate in the risk of total cancer (especially BC) in Asian population, and the TYMS gene rs2790 may be associated with the risk of total cancer (especially CRC) in Asian population and also the risk of GC in total population.

Association of serum level of TGF-B1 and its genetic polymorphisms (C509T and T869C) with Ischemic heart disease in Iraqi population.

Transforming growth factor beta 1 (TGF-ß1) is considered a pleotropic cytokine involved in the progression of cardiovascular disease. The purpose of the current study was to identify the relationship between serum levels of TGF-ß1, the genetic variations (C509T rs1800469, T869C rs1800470) and their constructed haplotypes with the susceptibility of ischemic heart disease (IHD) in the Iraqi population.The case-control study enrolled 200 participants, including 100 patients with IHD and 100 healthy controls. Genotypes of (TGF-ß1) polymorphisms were performed by TaqMan allele-specific probes detected by real-time PCR (RT-PCR). The serum level of TGF-ß1 was measured by an ELISA assay. The obtained results showed that the two minor alleles of C509T rs1800469 and T869C rs1800470 were associated with a decreased risk of IHD, preventive fraction (PF%) = 11.6 %; 23.9 %, respectively. Genotype distribution was significantly noted in the TT genotype of C509T rs1800469 (p = 0.033) and in the TC genotype of T869C rs1800470 (p = 0.006) between patients and control groups. A significant distribution was seen in the C allele of T869C rs1800470 (p = 0.002) between the studied groups. The carriers of the TT genotype in the C509T rs1800469 and the TC; CC genotypes in the T869C rs1800470 decreased the chance of having IHD, (hazard ratio HR<1). Furthermore, the haplotype analysis observed that H1 (C-T) was significantly associated with the development of IHD (HR=1.66; 95 % CI=1.10-2.51; p = 0.021) and the inverse effect of H4 (T-C), (HR=0.36; 95 % CI=0.20-0.65; p = 0.001). The TGF-ß1 alleles of both SNPs, TT genotype of C509T rs1800469, TC, CC of T869C rs1800470 and H4 locus of haplotypes were suggested to be protective biomarkers against IHD in Iraqi population.

Association between partial remission phase in type 1 diabetes and vitamin D receptor Fok1 rs2228570 polymorphism.

OBJECTIVES: The aim of the current study was to assess the natural course of partial remission (PR) phase of type 1 diabetes (T1D) and to highlight the putative association between vitamin D receptor (VDR) (Fok1) gene polymorphism and PR phase. METHODS: Ninety participants with newly diagnosed T1D were followed up for a total of 12 months. The VDR (Fok1) rs2228570 gene polymorphism was genotyped using allelic discrimination (AD) assay. RESULTS: Fifty-four patients (60 %) reached PR with an average duration of 5.63 ± 2.9 months. Among remitters, the frequency of CC "FF" genotype and allelic frequency of C "F" were significantly higher (p<0.001). Furthermore, participants expressing "CC" genotype had earlier onset of PR and spent a significantly longer duration in remission (p<0.001). Younger age (p<0.001; OR 41.6; CI 12.12-142.99), absence of DKA (p<0.001; OR 16, CI 4.36-50.74), higher C-peptide levels (p<0.001; OR 19.55; CI 6.52-58.63), and presence of CC "FF" genotype of VDR (p<0.001; OR 6.74; CI 2.41-18.86) best predicted the overall occurrence of PR. CONCLUSIONS: Younger age, less extent of metabolic derangements, and expression of a CC "FF" genotype were found to influence the occurrence of PR. Data from the current study showed that the "C" allele could have a protective role on preserving residual ß-cell mass and could predict both onset and duration of PR among newly diagnosed T1D. These findings support the growing concept of future tailored precision medicine.

Influence of H19 polymorphisms on breast cancer: risk assessment and prognostic implications via LincRNA H19/miR-675 and downstream pathways.

Introduction: Breast cancer, as the most prevalent malignancy among women globally, continues to exhibit rising incidence rates, particularly in China. The disease predominantly affects women aged 40 to 60 and is influenced by both genetic and environmental factors. This study focuses on the role of H19 gene polymorphisms, investigating their impact on breast cancer susceptibility, clinical outcomes, and response to treatment. Methods: We engaged 581 breast cancer patients and 558 healthy controls, using TaqMan assays and DNA sequencing to determine genotypes at specific loci (rs11042167, rs2071095, rs2251375). We employed in situ hybridization and immunohistochemistry to measure the expression levels of LincRNA H19, miR-675, MRP3, HOXA1, and MMP16 in formalin-fixed, paraffin-embedded samples. Statistical analyses included chi-squared tests, logistic regression, and Kaplan-Meier survival curves to evaluate associations between genetic variations, gene expression, and clinical outcomes. Results: Genotypes AG at rs11042167, GT at rs2071095, and AC at rs2251375 were significantly associated with increased risk of breast cancer. Notably, the AA genotype at rs11042167 and TT genotype at rs2071095 were linked to favorable prognosis. High expression levels of LincRNA H19, miR-675, MRP3, HOXA1, and MMP16 in cancer tissues correlated with advanced disease stages and poorer survival rates. Spearman correlation analysis revealed significant positive correlations between the expression of LincRNA H19 and miR-675 and specific genotypes, highlighting their potential regulatory roles in tumor progression. Discussion: The study underscores the critical roles of LincRNA H19 and miR-675 as prognostic biomarkers in breast cancer, with their overexpression associated with disease progression and adverse outcomes. The H19/LincRNA H19/miR-675/MRP3-HOXA1-MMP16 axis offers promising targets for new therapeutic strategies, reflecting the complex interplay between genetic markers and breast cancer pathology. Conclusion: The findings confirm that certain H19 SNPs are associated with heightened breast cancer risk and that the expression profiles of related genetic markers can significantly influence prognosis and treatment response. These biomarkers hold potential as targets for personalized therapy and early detection strategies in breast cancer, underscoring the importance of genetic research in understanding and managing this disease.

Do aluminum, boron, arsenic, cadmium, lipoperoxidation, and genetic polymorphism determine male fertility?

Male infertility is a world multifactorial problem modulated by environmental and genetic factors. Male aspects account for 20-50 % of infertility cases. Our results are unique because they treat the importance of components participating in the determination of male infertility (environmental and immunogenetic determinants, seminological analysis, lipoperoxidation, genetic determinants, role of aluminum, arsenic, cadmium and boron). We analyzed agents affecting male reproductive potential (aluminum, boron, cadmium, arsenic, lipid peroxidation, gene polymorphisms (MTHFRv.C677T (rs1801133) (chromosome-1) and IL-4v.C589T (rs2243250) (chromosome-5) in men with semen disorders (n=76) and with normozoospermia (n=87) from Central Poland. Polymorphisms of MTHFRv.C677T and IL-4v.C589T genes indirectly shape toxic metals concentration and lipoperoxidation but do not exert direct influence on male fertility disorders (monomorphism and lack of differences in genotypes frequency). Men with genotype TT or CC (IL-4v.C589T) show some differentiation in elements concentration and intensity of lipoperoxidation. Analysis of TT or CC (IL-4v.C589T) genotype brought correlations with B, Al, Cd, and lipoperoxidation (P<0.05) and suggesting that mentioned factors jointly shape male reproductive capability. Toxic metals may play an important role in shaping of men genetic polymorphisms, since Cd was identified as a factor increasing risk of qualification to infertile group, predisposing to fertility disorders. B, Al and Cd may be considered as important modulators of reproductive condition. However, lipoperoxidation as an isolated predictive parameter does not produce convincing results in male reproductive potential (higher MDA concentration in healthy men). Our results may be helpful in the diagnosis of male infertility, in the reduction of idiopathic cases of unknown origin and in implementation of targeted and more effective treatment (pharmacological, hormonal). Identification of environmental stressors and their correlations with fertility disorders can help to eliminate or reduce the impact of factors unfavorable to fertility. Our results highlight the importance of environmental and immunogenetic factors in shaping of defensive potential against destruction of spermatozoa and infer a role of oxidative stress in the induction of gene polymorphisms, affecting male fertility.

Association between 5-HT1A receptor C-1019G, 5-HTTLPR polymorphisms and panic disorder: a meta-analysis.

HTR1A C-1019G polymorphism (rs6295) and serotonin transporter promoter polymorphism (5-HTTLPR) have been linked with panic disorder (PD) in different ethnic backgrounds. Both these polymorphisms are in the promoter regions. However, results are inconsistent and contrasting evidence makes reliable conclusions even more challenging. A meta-analysis was conducted to test whether C-1019G polymorphism and 5-HTTLPR were involved in the etiology of PD. Articles researching the link between C-1019G, 5-HTTLPR polymorphisms, and PD were retrieved by database searching and systematically selected on the basis of selected inclusion parameters. 21 studies were included that examined the relationship of rs6295,5-HTTLPR polymorphisms with PD risk susceptibility (rs62957 polymorphism - 7 articles, and 5-HTTLPR polymorphism - 14 articles). A significant association was seen between the rs6295 polymorphism and PD pathogenesis, especially in Caucasian PD patients. No significant genetic linkage was found between the 5-HTTLPR polymorphism and PD. C-1019G polymorphism was involved in the etiology of PD in Caucasian patients. The 5-HTTLPR polymorphism was not a susceptibility factor of PD.

Evaluation of SLC6A2 and CYP2D6 polymorphisms' effects on atomoxetine treatment in attention deficit and hyperactivity disorder.

BACKGROUND: There is insufficient replicated data to establish a relationship between the polymorphisms of SLC6A2 and CYP2D6 and the treatment responses of atomoxetine (ATX) in ADHD. We focused on evaluating the effect of top-line single nucleotide polymorphisms (SNPs) in SLC6A2 and CYP2D6 on the ATX treatment response in attention deficit and hyperactivity disorder (ADHD). METHODS: Of 160 patient records, 34 patients who met the inclusion criteria were evaluated to determine the relationship between genotypes of ten SNPs (six of SLC6A2 and four of CYP2D6) and ATX treatment response. Additionally, the connection between SNPs of CYP2D6 and the severity of side effects associated with ATX was analyzed in 37 patients, including the 34 study patients, and three patients discontinued because of ATX-dependent side effects. RESULTS: All six polymorphisms we studied in SLC6A2 were associated with the treatment response of ATX. Clinical improvement in oppositional defiant disorder symptoms of patients with ADHD was only observed in carriers of the homozygous "C" allele of rs3785143 (podd = 0.026). We detected an association between higher CGI-side-effect severity scores and the "TT" genotype of rs1065852 polymorphism in CYP2D6 (p = 0.043). CONCLUSIONS: The findings of this study suggest that genotypes of polymorphisms within the SLC6A2 and CYP2D6 may play an influential role in treatment response or the severity of side effects associated with ATX in ADHD patients.

NQO1 polymorphism and susceptibility to ischemic stroke in a Chinese population.

BACKGROUND: Ischemic stroke (IS) is a major cause of death and disability worldwide. Genetic factors are important risk factors for the development of IS. The quinone oxidoreductase 1 gene (NQO1) has antioxidant, anti-inflammatory, and cytoprotective properties. Thus, in this study, we investigated the relationship between NQO1 gene polymorphism and the risk of IS. METHODS: Peripheral blood was collected from 143 patients with IS and 124 the control groups in Yunnan, China, and NQO1 rs2917673, rs689455, and rs1800566 were genotyped. Logistic regression was used to analyze the relationship between the three NQO1 loci and IS susceptibility. The difference in the expression levels of NQO1 between the control groups and IS groups was verified using public databases and enzyme-linked immunosorbent assay. RESULTS: The rs2917673 locus increased the risk of IS by 2.375 times in TT genotype carriers under the co-dominance model compared with CC carriers and was statistically associated with the risk of IS (OR = 2.375, 95% CI = 1.017-5.546, P = 0.046). In the recessive model, TT genotype carriers increased IS risk by 2.407 times compared with CC/CT carriers and were statistically associated with the risk of IS (OR = 2.407, 95% CI = 1.073-5.396, P = 0.033). CONCLUSIONS: NQO1 rs2917673 polymorphism is significantly associated with IS. Mutant TT carriers are risk factors for IS.

Positive correlation between Bax and Bcl-2 gene polymorphisms with the risk of endometriosis: A case-control study.

Background: Endometriosis is a chronic, gynecological disorder, and the disease's pathogenesis is still debatable. Genes related to apoptosis have been revealed to be deregulated in endometriosis. Objective: This study investigates the relationship between polymorphic variants of Bax -248G > A and Bcl-2 -938C > A promoter regions with endometriosis risk in an Iranian population. Materials and Methods: In this case-control study, the polymorphisms of Bax -248G > A and Bcl-2 -938C > A promoter regions were analyzed in 127 Iranian cases and 125 controls who were referred to Ali-ibn-Abi Taleb Educational hospital, Zahedan, Iran between May 2022 and February 2023. The genotypic analysis was performed for all the subjects using the polymerase chain reaction-restriction fragment length polymorphism method. Results: The frequencies of mutant allele A carriers and the A allele of Bax -248G > A polymorphism showed about 2-fold significant increase of endometriosis risk (p = 0.04; p = 0.01, respectively). The frequencies of the mutant genotype AA and A allele carriers of Bcl-2 -938C > A polymorphism were approximately 4 and 2.5-fold higher in endometriosis compared to the control women, which were highly significant (p > 0.001). Moreover, the allele A frequency of Bcl-2 -938C > A was associated with a 2-fold higher risk of endometriosis (p > 0.001). Furthermore, the combination effects of these 2 single nucleotide polymorphisms showed that women with Bax -248G > A GGand Bcl-2 -938C > A AA variant alleles were associated with about 5 times higher risk of endometriosis (p > 0.001). Notably, a significant difference was observed in mutant allele distribution between minimal/mild (stage I and II) and moderate/severe (stage III and IV) women with endometriosis disease. Conclusion: The results of our study provide evidence that Bcl-2 -938C > A and Bax -248G > A single nucleotide polymorphisms might be associated with the risk of endometriosis.