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Background: ALK‐tyrosine kinase inhibitors (TKIs) have been proven effective for treating ALK‐positive non‐small cell lung cancer (NSCLC), although patients present with variable responses and disease progression courses. The detailed underlying molecular mechanisms require further investigation to yield a better prognosis. Methods: Targeted next‐generation sequencing (NGS) mutation profiling was performed on samples from 42 NSCLC patients confirmed positive for ALK rearrangements by fluorescence in situ hybridization or immunohistochemistry who experienced disease progression after crizotinib treatment. Results: ALK rearrangements were not confirmed in six patients (14%) with other potential oncogenic drivers identified by NGS, who therefore did not respond to crizotinib and had significantly shorter overall survival (OS) compared to NGS ALK ‐positive patients. Fifteen ALK activating mutations were detected in 8 out of 26 post‐treatment samples (31%), among which ALK L1196M and G1269A were the most common acquired mutations detected in half of the patients with ALK activating mutations. Dynamic monitoring of the genetic evolution in one patient revealed both spatial and temporal heterogeneity of resistant mechanisms during different ALK‐TKI treatment courses. Activation of ALK downstream or bypass pathways was detected in patients without ALK activating mutations, such as genetic alterations in PIK3CA, MET, and KRAS. Interestingly, we identified two patients with acquired mutations in the DNA mismatch repair gene POLE, which resulted in a dramatically increased tumor mutation burden, and might contribute to the poor response to crizotinib. Conclusions: Heterogeneous resistant mechanisms have been identified and correlate to diverse responses to crizotinib. Comprehensive and dynamic mutation profiling is required to better predict clinical outcomes. [ABSTRACT FROM AUTHOR]

Background: Dilated cardiomyopathy (DCM) is a major cause of heart failure and heart transplantation. Recently, some studies have reported that the autoimmune response in myocardial cells might be related to the pathogenesis of DCM. The CD247 gene has been previously found to be involved in autoimmune disease. Therefore, our study aimed to clarify the hypothesis that there is a certain linkage between polymorphisms of the CD247 gene and the triggering of DCM risk. Methods: In the present study, two single nucleotide polymorphisms (SNPs) of the CD247 gene, rs12141731 and rs858543, were genotyped by polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) in 355 DCM patients and 404 age- and sex-matched controls. Results: Pearson's chi-squared test for the CD247 gene revealed that SNP rs858543 (p = 0.001, OR = 0.72, 95% CI = (0.588–0.882), but not SNP rs12141731, was associated with DCM in the Chinese Han population. Haplotype analysis revealed that the CC haplotype was associated with increased DCM susceptibility, while CT was a protective haplotype. Cox multivariate survival analysis indicated that the rs858543 TT genotype (HR: 0.608, 95% CI = 0.402–0.921, p = 0.019) was an independent multivariate predictor for longer overall survival in DCM patients. CD247 mRNA expression levels were significantly decreased in DCM patients (p = 0.02). Conclusions: Our study suggested that a polymorphism in the CD247 gene may be a risk factor for DCM in the Chinese Han population. Trial registration: ChiCTR2000029701. [ABSTRACT FROM AUTHOR]

Zanthoxylum is a versatile economic tree species utilized for its spice, seasoning, oil, medicinal, and industrial raw material applications, and it has a lengthy history of cultivation and domestication in China. This has led to the development of numerous cultivars. However, the phenomenon of mixed cultivars and confusing names has significantly obstructed the effective utilization of Zanthoxylum resources and industrial development. Consequently, conducting genetic diversity studies and cultivar identification on Zanthoxylum are crucial. This research analyzed the genetic traits of 80 Zanthoxylum cultivars using simple sequence repeat (SSR) and inter-Primer Binding Site (iPBS) molecular markers, leading to the creation of a DNA fingerprint. This study identified 206 and 127 alleles with 32 SSR markers and 10 iPBS markers, respectively, yielding an average of 6.4 and 12.7 alleles (Na) per marker. The average polymorphism information content (PIC) for the SSR and iPBS markers was 0.710 and 0.281, respectively. The genetic similarity coefficients for the 80 Zanthoxylum accessions ranged from 0.0947 to 0.9868 and from 0.2206 to 1.0000, with mean values of 0.3864 and 0.5215, respectively, indicating substantial genetic diversity. Cluster analysis, corroborated by principal coordinate analysis (PCoA), categorized these accessions into three primary groups. Analysis of the genetic differentiation among the three Zanthoxylum (Z. bungeanum, Z. armatum, and Z. piperitum) populations using SSR markers revealed a mean genetic differentiation coefficient (Fst) of 0.335 and a gene flow (Nm) of 0.629, suggesting significant genetic divergence among the populations. Molecular variance analysis (AMOVA) indicated that 65% of the genetic variation occurred within individuals, while 35% occurred among populations. Bayesian model-based analysis of population genetic structure divided all materials into two groups. The combined PI and PIsibs value of the 32 SSR markers were 4.265 × 10− 27 and 1.282 × 10− 11, respectively, showing strong fingerprinting power. DNA fingerprints of the 80 cultivars were established using eight pairs of SSR primers, each assigned a unique numerical code. In summary, while both markers were effective at assessing the genetic diversity and relationships of Zanthoxylum species, SSR markers demonstrated superior polymorphism and cultivar discrimination compared to iPBS markers. These findings offer a scientific foundation for the conservation and sustainable use of Zanthoxylum species. [ABSTRACT FROM AUTHOR]

Wheat leaf rust, caused by Puccinia triticina, is one of the most common fungal diseases of wheat in China and occurs widely in various wheat-growing regions. To clarify the epidemic, spread rules, and population structure of P. triticina among different regions, 217 isolates of P. triticina collected from Hebei, Shandong, Sichuan, and Xinjiang in China were tested by 34 Thatcher near-isogenic lines and 21 pairs of EST-SSR primers. A total of 83 races were identified, and THTT, PHTT, THTS, and PHJT were the most predominant races in the four provinces in 2009. We found enriched virulence and genetic diversity in the four P. triticina populations and a significant correlation between genetic polymorphism and geographic regions. However, no significant correlation was found between virulence phenotypes and molecular genotypes. Moreover, a notable high level of gene flow (Nm = 2.82 > 1) among four P. triticina populations was detected. The genetic relationship among Hebei, Shandong, and Sichuan populations was close, possibly due to the spread of P. triticina from Sichuan to Shandong and then to Hebei. In contrast, the Xinjiang population was relatively independent. Genetic differentiation analysis showed some level of differentiation among or within populations of P. triticina in the four provinces, and the genetic variation within populations (74.97%) was higher than across populations (25.03%). Our study provides a basis for a better understanding of the regional migration, epidemic, and population structure of P. triticina in China. [ABSTRACT FROM AUTHOR]

Introduction: Alveolar echinococcosis (AE) is a life-threatening disease in humans caused by the larval stage of Echinococcus multilocularis. Domestic animals, dogs, foxes, and small mammals constitute the circular chain of AE. To evaluate the infection, distribution, and genetic polymorphism of AE in the Ili Prefecture (Nilka, Xinyuan and Zhaosu), we conducted this survey. Methods: In June and July 2018, 267 small mammals were captured using waterinfusion and mousetrap methods. Combined pathogenic and molecular biological methods were used to observe the histopathology of Echinococcus carried by rodents, amplify the mitochondrial nad1 gene of the pathogen, and investigate the genotype and haplotype diversity of Echinococcus in rodents in Ili Prefecture. Results: Morphological identification revealed that these captured small mammals belonged to three species, with Microtus gregalis being the dominant species (183/267). Pathological and molecular biological results confirmed that E. multilocularis was the pathogen of echinococcosis in small mammals, with an infection rate of 15.73% (42/267). Among the three areas sampled, the highest infection rate of rodents was 25.45% (14/55) in Nilka County. However, there was no significant difference in the infection rates between regions (χ² = 5.119, p > 0.05). Of the three captured rodent species, M. gregalis had the highest infection rate of 17.49% (32/183), but there was no significant difference in infection rates between the rodent species (χ² = 1.364, p > 0.05). Phylogenetic analyses showed that the nad1 gene sequences obtained in this study clustered in the same clade as isolates from China. These isolates contained 21 haplotypes (Hap_1-21); Hap_2 was the most common haplotype (9/42). Furthermore, haplotype diversity (0.925 ± 0.027) and nucleotide diversity (0.01139 ± 0.00119) were higher in the Ili Prefecture than in other regions, indicating that population differentiation was high. Tajima's D and Fu's Fs tests were negative (p > 0.10), indicating that the population had expanded. The low fixation index (Fst) ranged from 0.00000 to 0.16945, indicating that the degree of genetic differentiation was different among different populations. Discussion: In summary, Ili Prefecture is a high incidence area of AE, and Microtus spp. may play an important role in the transmission of AE in this area. The results of this study provide basic data for further study of the molecular epidemiology, genetic differences, and control of E. multilocularis in the Ili Prefecture, Xinjiang. [ABSTRACT FROM AUTHOR]

The most prevalent hip disease in neonates is developmental dysplasia of the hip (DDH). A timely and accurate diagnosis is required to provide the most effective treatment for pediatric patients with DDH. Heredity and gene variation have been the subject of increased attention and research worldwide as one of the factors contributing to the pathogenesis of DDH. Genome-wide association studies (GWAS), genome-wide linkage analyses (GWLA), and exome sequencing (ES) have identified variants in numerous genes and single-nucleotide polymorphisms (SNPs) as being associated with susceptibility to DDH in sporadic and DDH family patients. Furthermore, the DDH phenotype can be observed in animal models that exhibit susceptibility genes or loci, including variants in CX3CR1, KANSL1, and GDF5. The dentification of noncoding RNAs and de novo gene variants in patients with DDH-related syndrome has enhanced our understanding of the genes implicated in DDH. This article reviews the most recent molecular mechanisms and genetic factors that contribute to DDH. [ABSTRACT FROM AUTHOR]

Cancer is the leading cause of disease-related death among children. Vincristine (VCR), a key component of childhood cancer treatment protocols, is associated with the risk of peripheral neuropathy (PN), a condition that may be reversible upon drug discontinuation but can also leave lasting sequelae. Single nucleotide polymorphism (SNP) in genes involved in VCR pharmacokinetics and pharmacodynamics have been investigated in relation to an increased risk of PN. However, the results of these studies have been inconsistent. A retrospective cohort study was conducted to investigate the potential association of drug transporter genes from the ATP-binding cassette (ABC) family and the centrosomal protein 72 (CEP72) gene with the development of PN in 88 Caucasian children diagnosed with cancer and treated with VCR. Genotyping was performed using real-time PCR techniques for the following SNPs: ABCB1 rs1128503, ABCC1 rs246240, ABCC2 rs717620, and CEP72 rs924607. The results indicated that age at diagnosis (OR = 1.33; 95% CI = 1.07–1.75) and the ABCC1 rs246240 G allele (OR = 12.48; 95% CI = 2.26–100.42) were associated with vincristine-induced peripheral neuropathy (VIPN). No association was found between this toxicity and CEP72 rs924607. Our study provides insights that may contribute to optimizing childhood cancer therapy in the future by predicting the risk of VIPN [ABSTRACT FROM AUTHOR]

Chimonanthus praecox, a member of the Calycanthaceae family, is a unique, traditional, and famous flowering economic tree species in China. Despite the existence of several varieties, only a few cultivars have been formally named. Currently, expression sequence tag–simple sequence repeat (EST-SSR) markers are extensively used to identify different species and varieties; a large number of microsatellites can be identified from transcriptome databases. A total of 162,638 unigenes were assembled using RNA-seq; 82,778 unigenes were annotated using the Nr, Nt, Swiss-Prot, Pfam, GO, KOG, and KEGG databases. In total, 13,556 SSR loci were detected from 11,691 unigenes, with trinucleotide repeat motifs being the most abundant among the six repeat motifs. To develop the markers, 64,440 pairs of SSR primers with polymorphism potential were designed, and 75 pairs of primers were randomly selected for amplification. Among these markers, seven pairs produced amplified fragments of the expected size with high polymorphism. Using these markers, 12 C. praecox varieties were clustered into two monophyletic clades. Microsatellites in the transcriptome of C. praecox exhibit rich types, strong specificity, and great polymorphism potential. These EST-SSR markers serve as molecular technical methods for identifying different varieties of C. praecox and facilitate the exploration of a large number of candidate genes associated with important traits. [ABSTRACT FROM AUTHOR]

We previously showed that several polymorphisms in genes encoding pattern recognition receptors that cause amino acid substitutions alter pathogen recognition ability and disease susceptibility in pigs. In this study, we expanded our analysis to a wide range of immune-related genes and investigated polymorphism distribution and its influence on pneumonia in multiple commercial pig populations. Among the polymorphisms in 42 genes causing 634 amino acid substitutions extracted from the swine genome database, 80 in 24 genes were found to have a minor allele frequency of at least 10% in Japanese breeding stock pigs via targeted resequencing. Of these, 62 single nucleotide polymorphisms (SNPs) in 23 genes were successfully genotyped in 862 pigs belonging to four populations with data on pneumonia severity. Association analysis using a generalized linear mixed model revealed that 12 SNPs in nine genes were associated with pneumonia severity. In particular, SNPs in the cellular receptor for immunoglobulin G FCGR2B and the intracellular nucleic acid sensors IFI16 and LRRFIP1 were found to be associated with mycoplasmal pneumonia of swine or porcine pleuropneumonia in multiple populations and may therefore have wide applications in the improvement of disease resistance in pigs. Functional analyses at the cellular and animal levels are required to clarify the mechanisms underlying the effects of these SNPs on disease susceptibility. [ABSTRACT FROM AUTHOR]

Aim: Our study aimed to assess the association between UCP2 gene 3' untranslated region insertion/deletion (3'UTR I/D) and A55V (alanine/valine) polymorphisms and neural tube defects (NTDs) susceptibility. Materials and methods: According to pre-determined inclusion and exclusion criteria, the article search was conducted to search articles published before October 2023. Two authors independently screened the included articles and extracted their basic characteristics. After quality evaluation, the meta-analysis and trial sequential analysis (TSA) were conducted using RevMan 5.4, Stata/MP 17, and TSA 0.9.5.10 Beta. Subgroup analysis was conducted based on country and case group composition. Sensitivity analysis was conducted using a one-by-one exclusion method. Begg's and Egger's tests were used to evaluate publication bias. Results: A total of seven articles were included. Overall meta-analysis revealed significant heterogeneity among the included studies for 3'UTR I/D polymorphism of the UCP2 gene. Significant statistical data indicated that those with the DD genotype and D allele had higher chances of NTD compared to those with the II genotype and the I allele, respectively. The combined result of II vs. ID was not statistically significant. A55V variation showed no statistical significance in the risk of NTD, despite the absence of significant heterogeneity across the included studies. Most of the heterogeneity was resolved after subgrouping, and a higher risk of the ID genotype was found than the II genotype for Chinese people. Genotyping NTD patients or their mothers was not a factor affecting the heterogeneity. Sensitivity analysis and publication bias analysis suggested that positive findings supported our results. Conclusion: The UCP2 gene 3'UTR I/D polymorphism increased the likelihood of developing NTDs in the Chinese population, with the D allele being the risk factor, which contributed to the understanding of the genetic basis of NTDs. TSA indicated that more high-quality original studies were needed in the future for further validation. [ABSTRACT FROM AUTHOR]

Objective: To reveal the contributing effects of MTDH gene SNPs in the risk of invasive ductal breast cancer (IDC). Patients and methods: A case–control study was conducted, recruiting a total of 300 cases of IDC and 565 cancer-free controls from East China. Genotyping of three single-nucleotide polymorphisms (SNPs) in the MTDH gene was performed. Genomic DNA was extracted from peripheral blood samples of patients. The three SNPs (rs1311 T > C, rs16896059 G > A, rs2449512 A > G) in the MTDH gene were selected for detection using a TaqMan real-time polymerase chain reaction assay. The association between MTDH and the risk of IDC was analyzed employing an epidemiology case–control study and a multinomial logistic regression model. Results: Among the three evaluated SNPs, rs1311 T > C, rs16896059 G > A, and rs2449512 A > G demonstrated a significant association with an increased risk of IDC. Furthermore, stratified analysis revealed that individuals carrying the rs1311 CC genotype, rs16896059 GA/AA genotypes, and rs2449512 GG genotype were more susceptible to developing IDC in subgroups of patients younger than 53 years, without family history of IDC, pre-menopause status, clinical stage 2, high grade, with no distant metastasis or invasion, Her2-positive type, ER positive, PR positive, and Ki67 cells less than 10%. However, carriers of the rs16896059 GA/AA genotypes and rs2449512 GG genotype had an elevate the risk of IDC in patients with tumor size larger than 2 cm, post-menopause status, clinical stage 3, with invasion, lymph node infiltration, ER negative, PR negative, Her2 negative, and Ki67 cells exceeding 10%. Compared to the reference haplotype TGA, haplotypes TAA, TAG, and TGG were significantly associated with an increased IDC risk. Conclusion: In this study, we demonstrated a significant association between MTDH gene polymorphisms and an increased risk of IDC. Moreover, our findings suggested that MTDH gene polymorphisms could serve as a potential biomarker for IDC subtyping and therapeutic selection. [ABSTRACT FROM AUTHOR]

Genetics is a key factor that governs the susceptibility to oxidative stress. In the body, oxidative burden is regulated by the balance between the prooxidant genes that orchestrate processes that produce oxidant species, while the antioxidant genes aid those involved in scavenging these species. Together, the two components aid in maintaining the oxidative balance in the body. Genetic variations can influence the expression and activity of the encoded proteins which can then affect their efficiency in regulating redox processes, thereby increasing the risk of oxidative stress. This review studies single nucleotide polymorphisms (SNPs) that bear relevance to oxidative stress by exploring the variations in the prooxidant genes, such as XDH, CYBA, CYP1A1, PTGS2, NOS, and MAO and antioxidant genes including SOD, CAT, GPX, GSS, GLUL, GSR, GSTM1, GSTM5, GSTP1, TXN and HMOX1. Early identification of individuals at the increased risk of oxidative stress is possible from the assessment of sequence of these genes. Integrating genetic insights into oxidative stress management measures can pave the way for personalized medicine that tailors' healthcare approaches to individual genetic profiles. Effective genetic assessment along with routine quantification of biological markers can improve and monitor treatment strategies, enhancing mitigation approaches that maintain cellular health and promote longevity. [ABSTRACT FROM AUTHOR]

Sesame, Sesamum indicum L., is one of the oldest domesticated crops used for its oil and protein in many parts of the world. To build genomic resources for sesame that could be used to improve sesame productivity and responses to stresses, a USDA sesame germplasm collection of 501 accessions originating from 36 countries was used in this study. The panel was genotyped using genotyping-by-sequencing (GBS) technology to explore its genetic diversity and population structure and the relatedness among its accessions. A total of 24,735 high-quality single-nucleotide polymorphism (SNP) markers were identified over the 13 chromosomes. The marker density was 1900 SNP per chromosome, with an average polymorphism information content (PIC) value of 0.267. The marker polymorphisms and heterozygosity estimators indicated the usefulness of the identified SNPs to be used in future genetic studies and breeding activities. The population structure, principal components analysis (PCA), and unrooted neighbor-joining phylogenetic tree analyses classified two distinct subpopulations, indicating a wide genetic diversity within the USDA sesame collection. Analysis of molecular variance (AMOVA) revealed that 29.5% of the variation in this population was due to subpopulations, while 57.5% of the variation was due to variation among the accessions within the subpopulations. These results showed the degree of differentiation between the two subpopulations as well as within each subpopulation. The high fixation index (FST) between the distinguished subpopulations indicates a wide genetic diversity and high genetic differentiation among and within the identified subpopulations. The linkage disequilibrium (LD) pattern averaged 161 Kbp for the whole sesame genome, while the LD decay ranged from 168 Kbp at chromosome LG09 to 123 Kbp in chromosome LG05. These findings could explain the complications of linkage drag among the traits during selections. The selected accessions and genotyped SNPs provide tools to enhance genetic gain in sesame breeding programs through molecular approaches. [ABSTRACT FROM AUTHOR]

Simple Summary: This study aimed to reveal the single nucleotide polymorphisms (SNPs) of the bovine Stearoyl-CoA desaturase-1 (SCD1) to explore the correlation between genotypes and carcass, meat quality, adipogenic traits, fatty acid composition, and milk production traits in cattle. Four SNPs, g.21272246 A>G, g.21272306 T>C, g.21272422 C>T, and g.21272529 A>G, were found by Sanger sequencing; further statistical analysis showed that these four SNPs of the SCD1 gene were significantly associated with carcass traits and meat quality, including carcass weight, carcass fat coverage rate, rib eye area, marbling score, adipogenic traits, and fatty acid composition. Additionally, a modest effect on milk production traits, such as average milk yield and milk fat content, was observed in cows. Further haplotype analysis indicated that the combinations of H2H3 and H2H2 of SNPs had a higher value than others. Our results indicate that these four SNPs are potentially effective markers and could be used in marker-assisted breeding to improve meat and milk quality simultaneously in the future. Stearoyl-CoA desaturase-1 (SCD1) is a key enzyme in the biosynthesis of monounsaturated fatty acids and is considered a candidate gene for improving milk and meat quality traits. Sanger sequencing was employed to investigate the genetic polymorphism of the fifth exon and intron of bovine SCD1, revealing four SNPs, g.21272246 A>G, g.21272306 T>C, g.21272422 C>T, and g.21272529 A>G. Further variance analysis and multiple comparisons were conducted to examine the relationship between variation sites and economic traits in Chinese Simmental cattle, as well as milk production traits in Holstein cows. The findings revealed these four loci exhibited significant associations with carcass traits (carcass weight, carcass length, backfat thickness, and waist meat thickness), meat quality (pH value, rib eye area, and marbling score), adipogenic traits (fat score and carcass fat coverage rate), and fatty acid composition (linoleic acid and α-linolenic acid). Furthermore, these loci were additionally found to be significantly associated with average milk yield and milk fat content in cows. In addition, a haplotype analysis of combinations of SNPs showed that H2H3 has a significant association with adipogenic traits and H2H2 was associated with higher levels of linoleic acid and α-linolenic acid than the other combinations. These results suggest that the four SNPs are expected to be prospective genetic markers for the above economic traits. In addition, the function of SNPs in exon 5 of SCD1 on gene expression and protein structure needs to be explored in the future. [ABSTRACT FROM AUTHOR]

The incidence of thyroid cancer, one of the most common forms of endocrine cancer, is increasing rapidly worldwide in developed and developing countries. Various risk factors can increase susceptibility to thyroid cancer, but particular emphasis is put on the role of DNA repair genes, which have a significant impact on genome stability. Polymorphisms of these genes can increase the risk of developing thyroid cancer by affecting their function. In this article, we present a concise review on the most common polymorphisms of selected DNA repair genes that may influence the risk of thyroid cancer. We point out significant differences in the frequency of these polymorphisms between various populations and their potential relationship with susceptibility to the disease. A more complete understanding of these differences may lead to the development of effective prevention strategies and targeted therapies for thyroid cancer. Simultaneously, there is a need for further research on the role of polymorphisms of previously uninvestigated DNA repair genes in the context of thyroid cancer, which may contribute to filling the knowledge gaps on this subject. [ABSTRACT FROM AUTHOR]

Simple Summary: It is a fundamental question: what is the earliest commencement of autoimmune diseases? In recent years, one process deemed to be essential is central self-tolerance during the neonatal period, when the immune system selects and destroys autoimmune T-cells. This mechanism is genetically governed by the master gene AIRE. Genetic variations in this gene may cause a less efficient clearance of autoimmune T-cells, causing severe autoimmune diseases decades later. According to numerous research studies and our preliminary results, genetic polymorphisms in this master gene may be at the root of several autoimmune diseases. Although the interaction of genes and disease has been well studied in Asian populations, results are scarce in European populations. Our study is intended to analyse the association between genetic variations in this master gene and rheumatoid arthritis in subjects of Hungarian origin. We successfully identified an association between polymorphisms and the disease, reinforcing the notion that immunologic events during the neonatal period may contribute to autoimmune diseases. A further strength of our research is that in the future, because of its neonatal involvement, AIRE can be used as a risk biomarker in cases in which other regular markers cannot predict the disease risk. Background: Rheumatoid arthritis (RA) is chronically persistent synovitis and systemic inflammation. Although multiple contributors are detected, only one is pivotal in the neonatal period: the negative selection of autoimmune naïve T-cells by the autoimmune regulator (AIRE) transcriptional factor. Methods: Single-nucleotide polymorphisms (SNPs) in the DNA-binding site of AIRE may determine its function and expression. We intended to analyse site-specific allelic polymorphisms in two exon (rs878081 and rs1055311) and three intron (rs1003853, rs2075876, and rs1003854) loci with an RA risk. Our analytical case-control study analysed 270 RA patients and 322 control subjects in five different genetic models using quantitative real-time PCR (qPCR) with TaqMan® assays. Results: Statistically significant differences were found between the odds of allelic polymorphisms in the loci of rs878081, rs1003854, and rs1003853 among the controls and RA patients, and the disease activity seemed to be significantly associated with the genotypic subgroups of rs878081 and rs1055311. Our in silico analysis supported this, suggesting that allele-specific alterations in the binding affinity of transcriptional factor families might determine RA activity. Conclusion: Our findings highlight the involvement of neonatal self-tolerance in RA pathogenesis, providing novel insights into disease development and paving the way for an analysis of further site-specific genetic polymorphisms in AIRE to expand the intervention time for RA. [ABSTRACT FROM AUTHOR]

Recurrent miscarriage (RM) is a severe pregnancy complication that results in the loss of two or more spontaneous pregnancies. RM has several complex reasons. Advances in genetics, immunology, and cell biology have strongly connected non-coding RNAs (ncRNAs) to recurrent miscarriages. NcRNAs regulate placental trophoblast cell processes, which affect trophoblast development, migration, and invagination; they also have a role in breast and ovarian cancer. As a result, their abnormal expression may contribute to the progression of RM. Several investigations have found a connection between RM and genetic polymorphisms that regulate cell migration. Variations in the long non-coding RNA (lncRNA) SOX2OT gene have been associated with a variety of cancer-related illnesses, particularly colorectal cancer, breast cancer, and cancer of the digestive tract. According to a recent study, the long non-coding SOX2OT rs9839776 CT raises the risk of RM. In this review, we explain the existing evidence supporting a relationship between the LncRNA SOX2OT rs9839776 polymorphisms and recurrent miscarriages. [ABSTRACT FROM AUTHOR]

BACKGROUND: Manganese is both an essential element and a known toxicant, and it plays important roles in many mechanisms in relation to type 2 diabetes (T2D). However, epidemiological studies of this relationship are rare. OBJECTIVE: We investigated the association between plasma manganese and newly diagnosed T2D as well as whether the association could be modified by manganese superoxide dismutase (MnSOD) polymorphisms. METHODS: We conducted a case -- control study of 3,228 participants in China: 1,614 T2D patients and 1,614 controls. Concentrations of plasma magnesium were measured, and all participants were genotyped for the MnSOD Vall6Ala polymorphism (rs4880). RESULTS: A U-shaped association was observed between plasma manganese and T2D, with increased odds ratios (ORs) in relation to either low or high plasma manganese levels. Compared with the middle tertile, the multivariate-adjusted ORs [95% confidence intervals (CIs)] of T2D associated with the lowest tertile and the highest tertile of plasma manganese were 1.89 (1-53, 2.33) and 1.56 (1.23, 1-97), respectively. In spline analysis, the U-shaped association was consistently indicated, with the lowest odds of T2D at the plasma manganese concentration of 4.95 ug/L. Minor allele frequencies (C allele) of the MnSOD Vall6Ala polymorphism (rs4880) in the normal glucose tolerance (NGT) and the T2D groups were 13.57% and 14.50%, respectively. The MnSOD rs4880 polymorphism was not associated with T2D, and no interaction was found between plasma manganese and the MnSOD rs4880 polymorphism in relation to T2D. CONCLUSIONS: Our results suggested a U-shaped association between plasma manganese and T2D; both low and high levels of plasma manganese were associated with higher odds of newly diagnosed T2D. The U-shaped association was not modified by the MnSOD rs4880 polymorphism. Citation: Shan Z, Chen S, Sun T, Luo C, Guo Y, Yu X, Yang W, Hu FB, Liu L. 2016. U-shaped association between plasma manganese levels and type 2 diabetes. Environ Health Perspect 124:1876-1881; http://dx.doi.org/10.1289/EHP176 [ABSTRACT FROM AUTHOR]

Background: Previous genome-wide association studies investigating the relationship between the HLA-DRB1 and the risk of Parkinson’s disease (PD) have shown limited racial diversity and have not explored clinical heterogeneity extensively. Methods: The study consisted of three parts: a case–control study, a crosssectional study, and a longitudinal cohort study. The case–control study included 477 PD patients and 477 healthy controls to explore the relationship between rs660895 and PD susceptibility. The cross-sectional study utilized baseline data from 429 PD patients to examine the correlation between rs660895 and PD features. The longitudinal study included 388 PD patients who completed a 3-year follow-up to investigate the effects of rs660895 on PD progression. Results: In the case–control study, HLA-DRB1 rs660895-G allele was associated with a decreased risk of PD in allele model (adjusted OR=0.72, p  =  0.003) and dominant model (AG  +  GG vs. AA: adjusted OR  =  0.67, p  =  0.003). In the crosssectional analysis, there was no association between rs660895 and the onset age, motor phenotype, or initial motor symptoms. In the longitudinal analysis, PD patients with the G allele exhibited a slower progression of motor symptoms (MDS-UPDRS-III total score: β  = −5.42, p  <  0.001, interaction p time × genotype  <  0.001) and non-motor symptoms (NMSS score: β  = −4.78, p  =  0.030, interaction p time × genotype  <  0.001). Conclusion: Our findings support HLA-DRB1 rs660895-G allele is a protective genetic factor for PD risk in Chinese population. Furthermore, we also provide new evidence for the protective effect of rs660895-G allele in PD progression. [ABSTRACT FROM AUTHOR]

Objectives: Isoniazid is a key drug in the chemotherapy of tuberculosis (TB), however, interindividual variability in pharmacokinetic parameters and drug plasma levels may affect drug responses including drug induced hepatotoxicity. The current study investigated the relationships between isoniazid exposure and isoniazid metabolism-related genetic factors in the context of occurrence of drug induced hepatotoxicity and TB treatment outcomes. Methods: Demographic characteristics and clinical information were collected in a prospective TB cohort study in Latvia (N = 34). Time to sputum culture conversion (tSCC) was used as a treatment response marker. Blood plasma concentrations of isoniazid (INH) and its metabolites acetylisoniazid (AcINH) and isonicotinic acid (INA) were determined at three time points (pre-dose (0 h), 2 h and 6 h after drug intake) using liquid chromatography-tandem mass spectrometry. Genetic variations of three key INH-metabolizing enzymes (NAT2, CYP2E1, and GSTM1) were investigated by application PCR- and Next-generation sequencing-based methods. Depending on variables, group comparisons were performed by Student's t-test, one-way ANOVA, Mann-Whitney-Wilcoxon, and Kruskal-Wallis tests. Pearson correlation coefficient was calculated for the pairs of normally distributed variables; model with rank transformations were used for non-normally distributed variables. Time-to-event analysis was performed to analyze the tSCC data. The cumulative probability of tSCC was obtained using Kaplan-Meier estimators. Cox proportional hazards models were fitted to estimate hazard rate ratios of successful tSCC. Results: High TB treatment success rate (94.1%) was achieved despite the variability in INH exposure. Clinical and demographic factors were not associated with either tSCC, hepatotoxicity, or INH pharmacokinetics parameters. Correlations between plasma concentrations of INH and its metabolites were NAT2 phenotypedependent, while GSTM1 genetic variants did not showed any effects. CYP2E1*6 (T > A) allelic variant was associated with INH pharmacokinetic parameters. Decreased level of AcINH was associated with hepatotoxicity, while decreased values of INA/INH and AcINH/INH were associated with month two sputum culture positivity. Conclusion: Our findings suggest that CYP2E1, but not GSTM1, significantly affects the INH pharmacokinetics along with NAT2. AcINH plasma level could serve as a biomarker for INH-related hepatotoxicity, and the inclusion of INH metabolite screening in TB therapeutic drug monitoring could be beneficial in clinical studies for determination of optimal dosing strategies. [ABSTRACT FROM AUTHOR]

The most critical forms of coronavirus disease 2019 (COVID-19) are associated with excessive activation of the inflammasome. Despite the COVID-19 impact on public health, we still do not fully understand the mechanisms by which the inflammatory response influences disease prognosis. Accordingly, we aimed to elucidate the role of polymorphisms in the key genes of the formation and signaling of the inflammasome as biomarkers of COVID-19 severity. For this purpose, a large and well-defined cohort of 377 COVID-19 patients with mild (n = 72), moderate (n = 84), severe (n = 100), and critical (n = 121) infections were included. A total of 24 polymorphisms located in inflammasome-related genes (NLRP3, NLRC4, NLRP1, CARD8, CASP1, IL1B, IL18, NFKB1, ATG16L1, and MIF) were genotyped in all of the patients and in the 192 healthy controls (HCs) (who were without COVID-19 at the time of and before the study) by RT-qPCR. Our results showed that patients with mild, moderate, severe, and critical COVID-19 presented similar allelic and genotypic distribution in all the variants studied. No statistically significant differences in the haplotypic distribution of NLRP3, NLRC4, NLRP1, CARD8, CASP1, IL1B, and ATG16L1 were observed between COVID-19 patients, who were stratified by disease severity. Each stratified group of patients presented a similar genetic distribution to the HCs. In conclusion, our results suggest that the inflammasome polymorphisms studied are not associated with the worsening of COVID-19. [ABSTRACT FROM AUTHOR]

Introduction: Acute lymphoblastic leukemia (ALL) is the most frequent pediatric leukemia; it can be defined according to chromosomic and genomic data. Cytogenetic analyses and determination of chromosomal numbers (such as hypo- or hyperdiploidy) and/or specific chromosomal rearrangements are basic for ALL classification and treatment. Even though cure rates of childhood ALL are at ~95%, pharmacogenetic aspects are of raising importance. Material and Methods: We have analyzed the literature for ALL subtypes, corresponding therapy options, and pharmacogenetic implications. Results: Data for ALL subtypes such as B-ALL, T-ALL, Ph-like ALL, DS-ALL, ETP-ALL, BCR-ABL1-like ALL are presented here. The gene polymorphism which lead to metabolizability of 6-MP are ITPA variants (94C>A) and IVS2+21A>C, in conjunction with TPMT (238G>C, TPMT*3B 460G>A and *3C 719A>G and NUDT15 (415C>T). For methotrexate metabolism gene polymorphisms are found for gene MTHFR as C677T and A1298C. Conclusion: In the last decade in many hospital laboratories, pharmacogenetic aspects gain more and more importance. Application of many molecular biology methods provided progress in treatment and diagnosis of ALL patients. Combination therapy is proposed as an alternative to single drug treatments. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastoma is a highly aggressive and lethal brain tumor that has seen marginal improvement in patient outcomes despite decades of concerted efforts. This study investigated the impact of tumor molecular features, sex, and their interaction on the survival of patients with newly diagnosed glioblastoma. Our findings show that females are more often found to have silencing of the MGMT promoter, but that they also receive a greater survival benefit, which is more clinically and statistically significant, associated with MGMT promoter silencing that is not reflected in males. These findings may significantly impact both our understanding as well as the clinical management of the disease. Rather than the established practice of using temozolomide to treat MGMT promoter methylated patients as a whole, our findings suggest that females accrue a disproportionate survival benefit compared to males who, regardless of methylation status, may experience better survival outcomes from alternative treatment options. Introduction: Sex differences in glioblastoma (GBM) have been observed in incidence, genetic and epigenetic alterations, and immune response. These differences have extended to the methylation of the MGMT promoter, which critically impacts temozolomide resistance. However, the association between sex, MGMT methylation, and survival is poorly understood, which this study sought to evaluate. Methods: A retrospective cohort study was conducted and reported following STROBE guidelines, based on adults with newly diagnosed GBM who received their first surgical intervention at Cleveland Clinic (Ohio, USA) between 2012 and 2018. Kaplan–Meier and multivariable Cox proportional hazards models were used to analyze the association between sex and MGMT promoter methylation status on overall survival (OS). MGMT was defined as methylated if the mean of CpG 1-5 ≥ 12. Propensity score matching was performed on a subset of patients to evaluate the effect of individual CpG site methylation. Results: A total of 464 patients had documented MGMT methylation status with a mean age of 63.4 (range 19–93) years. A total of 170 (36.6%) were female, and 133 (28.7%) received gross total resection as a first intervention. A total of 42.5% were MGMT methylated, with females more often having MGMT methylation than males (52.1% vs. 37.4%, p = 0.004). In univariable analysis, OS was significantly longer for MGMT promoter methylated than un-methylated groups for females (2 yr: 36.8% vs. 11.1%; median: 18.7 vs. 9.5 months; p = 0.001) but not for males (2 yr: 24.3% vs. 12.2%; median: 12.4 vs. 11.3 months; p = 0.22, p for MGMT–sex interaction = 0.02). In multivariable analysis, MGMT un-methylated versus methylated promoter females (2.07; 95% CI, 1.45–2.95; p < 0.0001) and males (1.51; 95% CI, 1.14–2.00; p = 0.004) had worse OS. Within the MGMT promoter methylated group, males had significantly worse OS than females (1.42; 95% CI: 1.01–1.99; p = 0.04). Amongst patients with data on MGMT CpG promoter site methylation values (n = 304), the median (IQR) of CpG mean methylation was 3.0% (2.0, 30.5). Females had greater mean CpG methylation than males (11.0 vs. 3.0, p < 0.002) and higher per-site CpG methylation with a significant difference at CPG 1, 2, and 4 (p < 0.008). After propensity score matching, females maintained a significant survival benefit (18.7 vs. 10.0 months, p = 0.004) compared to males (13.0 vs. 13.6 months, p = 0.76), and the pattern of difference was significant (P for CpG–sex interaction = 0.03). Conclusions: In this study, females had higher mean and individual CpG site methylation and received a greater PFS and OS benefit by MGMT methylation that was not seen in males despite equal degrees of CpG methylation. [ABSTRACT FROM AUTHOR]

Background and Objectives: Drug resistant epilepsy (DRE) is a major hurdle in epilepsy, which hinders clinical care, patients' management and treatment outcomes. DRE may partially result from genetic variants that alter proteins responsible for drug targets and drug transporters in the brain. We aimed to examine the relationship between SCN1A, GABRA1 and ABCB1 polymorphism and drug response in epilepsy children in Vietnam. Materials and Methods: In total, 213 children diagnosed with epilepsy were recruited in this study (101 were drug responsive and 112 were drug resistant). Sanger sequencing had been performed in order to detect six single nucleotide polymorphisms (SNPs) belonging to SCN1A (rs2298771, rs3812718, rs10188577), GABRA1 (rs2279020) and ABCB1 (rs1128503, rs1045642) in study group. The link between SNPs and drug response status was examined by the Chi-squared test or the Fisher's exact test. Results: Among six investigated SNPs, two SNPs showed significant difference between the responsive and the resistant group. Among those, heterozygous genotype of SCN1A rs2298771 (AG) were at higher frequency in the resistant patients compared with responsive patients, playing as risk factor of refractory epilepsy. Conversely, the heterozygous genotype of SCN1A rs3812718 (CT) was significantly lower in the resistant compared with the responsive group. No significant association was found between the remaining four SNPs and drug response. Conclusions: Our study demonstrated a significant association between the SCN1A genetic polymorphism which increased risk of drug-resistant epilepsy in Vietnamese epileptic children. This important finding further supports the underlying molecular mechanisms of SCN1A genetic variants in the pathogenesis of drug-resistant epilepsy in children. [ABSTRACT FROM AUTHOR]

Hepatitis B virus (HBV) B infections remain a primary global health concern. The immunopathology of the infection, specifically the interactions between HBV and the host immune system, remains somewhat unknown. It has been discovered that innate immune reactions are vital in eliminating HBV. Toll-like receptors (TLRs) are an essential category of proteins that detect pathogen-associated molecular patterns (PAMPs). They begin pathways of intracellular signals to stimulate pro-inflammatory and anti-inflammatory cytokines, thus forming adaptive immune reactions. HBV TLRs include TLR2, TLR3, TLR4, TLR7 and TLR9. Each TLR has its particular molecule to recognize; various TLRs impact HBV and play distinct roles in the pathogenesis of the disease. TLR gene polymorphisms may have an advantageous or disadvantageous efficacy on HBV infection, and some single nucleotide polymorphisms (SNPs) can influence the progression or prognosis of infection. Additionally, it has been discovered that similar SNPs in TLR genes might have varied effects on distinct populations due to stress, diet, and external physical variables. In addition, activation of TLR-interceded signaling pathways could suppress HBV replication and increase HBV-particular T-cell and B-cell reactions. By identifying these associated polymorphisms, we can efficiently advance the immune efficacy of vaccines. Additionally, this will enhance our capability to forecast the danger of HBV infection or the threat of dependent liver disease development via several TLR SNPs, thus playing a role in the inhibition, monitoring, and even treatment guidance for HBV infection. This review will show TLR polymorphisms, their influence on TLR signaling, and their associations with HBV diseases. [ABSTRACT FROM AUTHOR]

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common entity (30%-40%) and can significantly limit the quality of life of patients, especially those that persist for more than 6 months after treatment (chronic neuropathy). Studies have shown a possible association between the presence of genetic polymorphisms in ABCB1 and the development of acute CIPN, although this relationship with chronic CIPN remains unexplored. This is an analytical observational case-control study defined by the presence (cases) or absence (controls) of CIPN at 6 months after the end of the neurotoxic drug. Our aim is to demonstrate whether these ABCB1 polymorphisms also influence the chronification of this toxicity, as well as the clinical factors that can help us to predict it. Methods: The study included 152 patients treated with tri-weekly oxaliplatin (O) or weekly paclitaxel (P); 86 cases and 66 controls. Clinical and analytical parameters were analysed including the study of ABCB1 genetic polymorphisms in a blood sample. Results: ABCB1 genetic polymorphisms C1236T (rs1128503) and C3435T (rs1045642) are associated with the development of chronic CIPN in patients treated with P. No differences were found in patients treated with O. Other predictive factors to be considered in the development of this toxicity are age >60 years, BMI ≥30, toxic habits and cardiovascular risk factors. Conclusion: CIPN is a common and understudied toxicity, despite being a limiting factor in the quality of life of many patients. As described in acute CIPN, our study demonstrates the relationship between chronic neuropathy and being a carrier of specific polymorphisms (C1236T and C3435T) of the ABCB1 gene in patients treated with P. In addition, there are modifiable factors (obesity, smoking, or alcohol) that may influence its development. Further prospective studies are needed to investigate genetic and clinical modifiable factors predisposing to CIPPN to develop prevention and treatment strategies. [ABSTRACT FROM AUTHOR]

Background: The interaction between environmental and genetic factors that influence eye growth, regulated by vision, contributes to the development and progression of myopia. This dynamic interaction significantly contributes to the multifaceted development and progression of myopia, a prevalent ocular condition. Our study delves into the associations between ZNF676 and CTC1 gene polymorphisms and their impact on the relative leukocyte telomere length (relative LTL) in myopia, as well as its degree. By unravelling these underpinnings in conjunction with environmental influences, we aim to enhance our understanding of the complex mechanisms that drive the onset and severity of myopia. Methods: This study included patients with myopia and ophthalmologically healthy subjects. DNA was extracted from peripheral venous blood by the salting out method. Genotyping of ZNF676 rs412658 and CTC1 rs3027234, as well as the measurement of relative LTL, were conducted using a real-time polymerase chain reaction method (RT-PCR). The data obtained were statistically analyzed using the "IBM SPSS Statistics 29.0" software program. Results: The results show that myopic patients who are homozygous for the rs3027234 rare allele genotype of the CTC1 gene have statistically significantly shorter relative LTL compared to patients with the CC and CT genotypes. Also, men with the CTC1 rs3027234 TT genotype have statistically significantly longer leukocyte telomeres than women with the same genotype. The respective median (IQR) of the relative LTL for women and men is 0.280 (0.463) vs. 0.696 (0.440), with a p-value of 0.027. The myopia group with the ZNF676 rs412658 CC genotype has statistically significantly shorter leukocyte telomeres than the control group with the same genotype (age ≤ 29), and the p-value is 0.011. Also, the myopia group with the ZNF676 rs412658 CT and CTC1 rs3027234 CT genotypes have statistically significantly longer leukocyte telomeres than the control group with the same genotypes (age > 29), with p-values that are, respectively, 0.016 and 0.012. The evaluation of the genotype distributions of the polymorphisms in the myopia patients showed that ZNF676 rs412658 CT genotype carriers have 4-fold decreased odds of high myopia occurrence (OR = 0.250; CI: 0.076–0.826; p = 0.023). Also, the evaluation of the allele distributions of the polymorphism under the additive genetic model in the myopia group showed that the ZNF676 rs412658 T allele was associated with similar odds of high myopia (OR = 0.269; 95% CI: 0.090–0.807; p = 0.019). The comprehensive p-value, assessing the relative LTL of subjects across the different levels of myopia, signifies a statistical difference in the relative LTL among individuals with varying degrees of myopia. There was a statistically significant difference in relative LTL between mild and moderate myopia degrees (0.819 (1.983) vs. 0.083 (0.930), p = 0.007). Conclusions: CTC1 rs3027234 TT may be considered a protective genotype for telomere shortening in men, while the overall telomere shortening might be linked to the worse myopia degree. The ZNF676 rs412658 T allele may protect against a high myopia occurrence. [ABSTRACT FROM AUTHOR]

This study aimed to comprehensively analyze the problem of overweight and obesity among psoriatic patients by investigating the influence of body mass composition, anhedonia and depression, environmental factors and FTO gene polymorphisms. Methods: The study enrolled 30 overweight or obese adult patients with chronic plaque psoriasis and 30 overweight or obese volunteers (northern Poland region, Caucasian population). Mood disorders, body mass composition by using bioelectrical impedance analysis (BIA) and FTO gene polymorphisms (rs9939609, rs1558902) by tetra-primer amplification refractory mutation system PCR (T-ARMS-PCR) were assessed. Results: Results revealed significantly higher visceral adipose tissue levels in psoriatic patients (5.23 ± 2.29 [L] vs. 3.41 ± 1.86 [L]), p = 0.001), especially among men, along with elevated rates of moderate and severe depression (26.67% vs. 6.67% and 13.33% vs. 3.33%, p = 0.048 respectively). Additionally, FTO gene polymorphisms correlated with waist–hip ratio differences in both groups. Conclusions: The study highlights the importance of evaluating body composition beyond body mass index, recognizing its influence on psoriasis and associated conditions like depression. The FTO gene may serve as a potential genetic link between psoriasis and obesity, warranting further research for validation. Adiposity emerges as a key and modifiable risk factor, underscoring the clinical implications of body composition complexities in psoriasis management. [ABSTRACT FROM AUTHOR]

Background: The majority of congenital heart diseases (CHDs) are thought to result from the interactions of genetics and the environment factors. This study aimed to assess the association of maternal non-occupational phthalates exposure, metabolic gene polymorphisms and their interactions with risk of CHDs in offspring. Methods: A multicenter case-control study of 245 mothers with CHDs infants and 268 control mothers of health infant was conducted from six hospitals. Maternal urinary concentrations of eight phthalate metabolites were measured by ultra-high performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS). Twenty single nucleotide polymorphisms (SNPs) in cytochrome P450 family 2 subfamily C member 9 (CYP2C9) and 19 (CYP2C19), uridine diphosphate (UDP) glucuronosyl transferase family 1 member A7 (UGT1A7), family 2 member B7 (UGT2B7) and B15(UGT2B15) genes were genotyped. The multivariate logistic regressions were used to estimate the association between maternal phthalates exposure or gene polymorphisms and risk of CHDs. Generalized multifactor dimensionality reduction (GMDR) was used to analyze the gene–gene and gene–phthalates exposure interactions. Results: There was no significant difference in phthalate metabolites concentrations between the cases and controls. No significant positive associations were observed between maternal exposure to phthalates and CHDs. The SNPs of UGT1A7 gene at rs4124874 (under three models, log-additive: aOR = 1.74, 95% CI:1.28–2.37; dominant: aOR = 1.86, 95% CI:1.25–2.78; recessive: aOR = 2.50, 95% CI: 1.26–4.94) and rs887829 (under the recessive model: aOR = 13.66, 95% CI: 1.54–121) were significantly associated with an increased risk of CHDs. Furthermore, the associations between rs4124874 (under log-additive and dominant models) of UGT1A7 were statistically significant after the false discovery rate correction. No significant gene-gene or gene-phthalate metabolites interactions were observed. Conclusions: The polymorphisms of maternal UGT1A7 gene at rs4124874 and rs887829 were significantly associated with an increased risk of CHDs. More large-scale studies or prospective study designs are needed to confirm or refute our findings in the future. [ABSTRACT FROM AUTHOR]

Introduction: Autoimmune diseases result from the loss of immune tolerance, and they exhibit complex pathogenic mechanisms that remain challenging to effectively treat. It has been reported that the altered expression levels of co-stimulatory/inhibitory molecules will affect the level of T/B cell activation and lead to the loss of immune tolerance. Methods: In this study, we evaluated the gene polymorphisms of the ligand genes corresponding co-stimulatory system that were expressed on antigen-presenting cells (CD80, CD86, ICOSLG, and PDL1) from 60 systemic lupus erythematosus (SLE) patients and 60 healthy controls. Results: The results showed that rs16829984 and rs57271503 of the CD80 gene and rs4143815 of the PDL1 gene were associated with SLE, in which the G-allele of rs16829984 (p=0.022), the A-allele of rs57271503 (p=0.029), and the GG and GC genotype of rs4143815 (p=0.039) may be risk polymorphisms for SLE. Discussion: These SNPs are in the promoter and 3'UTR of the genes, so they may affect the transcription and translation activity of the genes, thereby regulating immune function and contributing to the development of SLE. [ABSTRACT FROM AUTHOR]

Selenium has been proven to influence several biological functions, showing to be an essential micronutrient. The functional studies demonstrated the benefits of a balanced selenium diet and how its deficiency is associated with diverse diseases, especially cancer and viral diseases. Selenium is an antioxidant, protecting the cells from damage, enhancing the immune system response, preventing cardiovascular diseases, and decreasing inflammation. Selenium can be found in its inorganic and organic forms, and its main form in the cells is the selenocysteine incorporated into selenoproteins. Twenty-five selenoproteins are currently known in the human genome: glutathione peroxidases, iodothyronine deiodinases, thioredoxin reductases, selenophosphate synthetase, and other selenoproteins. These proteins lead to the transport of selenium in the tissues, protect against oxidative damage, contribute to the stress of the endoplasmic reticulum, and control inflammation. Due to these functions, there has been growing interest in the influence of polymorphisms in selenoproteins in the last two decades. Selenoproteins' gene polymorphisms may influence protein structure and selenium concentration in plasma and its absorption and even impact the development and progression of certain diseases. This review aims to elucidate the role of selenoproteins and understand how their gene polymorphisms can influence the balance of physiological conditions. In this polymorphism review, we focused on the PubMed database, with only articles published in English between 2003 and 2023. The keywords used were "selenoprotein" and "polymorphism". Articles that did not approach the theme subject were excluded. Selenium and selenoproteins still have a long way to go in molecular studies, and several works demonstrated the importance of their polymorphisms as a risk biomarker for some diseases, especially cardiovascular and thyroid diseases, diabetes, and cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Single-Nucleotide-Polymorphisms in long non-coding RNAs are correlated with esophageal carcinogenesis, yet research remains restricted in Asian ethnicities. Herein, FFPE specimens were obtained from surgically treated esophageal cancer patients for genotyping deriving from European ancestry. HULC rs7763881 polymorphism was not associated with cancer predisposition. LINC00951 rs11752942 was underrepresented in Ca19.9 elevated subgroup. HOTAIR rs920778 was more frequent in both worse differentiation grade and positive Signet Ring Cell and Ca19.9 subgroups. POLR2E rs3787016 was identified less frequently in Adenocarcinoma, Signet Ring Cell, and Diffuse histological subtypes, as well as in Perineural, Lymphovascular, and Perivascular Invasion positive, while it was found more often in CEA positive subgroup of the whole cancer cohort. Taken together, these lncRNAs polymorphisms are promising not only as future therapeutic agents but also as novel markers for predictive analysis of esophageal cancer risk and oncological outcomes including survival. Long non-coding RNAs' HOTAIR rs920778, LINC00951 rs11752942, POLR2E rs3787016, and HULC rs7763881 are progressively reported having a close genetic affinity with esophageal carcinogenesis in the East. Nonetheless, their correlation with variables already endorsed as significant prognostic factors in terms of staging, guiding treatment and predicting recurrence, metastasis, and survival have yet to be explored. Herein, we investigated their prognostic value by correlating them with clinicopathological and laboratory prognostic markers in esophageal cancer in the West. Formalin-fixed paraffin-embedded tissue specimens from 95 consecutive patients operated on for esophageal cancer between 2014 and 2018 were compared with 121 healthy community controls. HULC was not detected differently in any of the cancer prognostic subgroups. LINC00951 was underrepresented in Ca19.9 elevated subgroup. HOTAIR was more frequent in both worse differentiation grade and positive Signet-Ring-Cell and Ca19.9 subgroups. POLR2E was identified less frequently in Adenocarcinoma, Signet-Ring-Cell, and Diffuse histologies, as well as in Perineural, Lymphovascular, and Perivascular Invasion positive, while it was overrepresented in CEA positive subgroup. These lncRNAs polymorphisms may hold great potential not only as future therapeutic agents but also as novel markers for predictive analysis of esophageal cancer risk, clinical outcome, and survival. Clinical implications of these findings need to be validated with prospective larger sample-size studies. [ABSTRACT FROM AUTHOR]

Simple Summary: Although papillary thyroid carcinoma (PTC) has a relatively indolent behavior, the clinical course in patients with recurrent or metastatic disease is still unfavorable. Polymorphisms in long non-coding RNA and microRNA genes may play a significant role in PTC. Thus, we evaluated the association of HOTAIR rs920778, MIR155HG rs1893650, TERC rs10936599, miR-155 rs767649, miR-196a2 rs11614913 and miR-146a rs2910164 polymorphisms with the PTC risk and prognosis, in 102 PTC patients and 106 controls. Our results showed that the HOTAIR rs920778 polymorphism is associated with an increased PTC risk, as well as with lymph node metastasis, recurrence, and progression-free survival. Multivariate Cox regression revealed that ATA risk and HOTAIR rs920778 polymorphism are independent prognostic factors in PTC. In addition, we observed a novel association of the MIR155HG rs1893650 polymorphism with the reduced PTC risk. Polymorphisms in HOTAIR and MIR155HG genes could potentially be new biomarkers for risk assessment and prognosis in PTC patients. Polymorphisms in long non-coding RNA and microRNA genes may play a significant role in the susceptibility and progression of papillary thyroid carcinoma (PTC). The current study investigates the polymorphisms HOTAIR rs920778, MIR155HG rs1893650, TERC rs10936599, miR-155 rs767649, miR-196a2 rs11614913 and miR-146a rs2910164 in 102 PTC patients and 106 age- and sex-matched controls of the Caucasian Serbian population, using real-time PCR. We observed differences in genotype distributions of the HOTAIR rs920778 (p = 0.016) and MIR155HG rs1893650 (p = 0.0002) polymorphisms between PTC patients and controls. HOTAIR rs920778 was associated with increased PTC susceptibility (adjusted OR = 1.497, p = 0.021), with the TT variant genotype increasing the risk compared to the CC genotype (OR = 2.466, p = 0.012) and C allele carriers (CC + CT) (OR = 1.585, p = 0.006). The HOTAIR rs920778 TT genotype was associated with lymph node metastasis (p = 0.022), tumor recurrence (p = 0.016), and progression-free survival (p = 0.010) compared to C allele carriers. Multivariate Cox regression revealed that ATA risk (HR = 14.210, p = 0.000004) and HOTAIR rs920778 (HR = 2.811, p = 0.010) emerged as independent prognostic factors in PTC. A novel polymorphism, MIR155HG rs1893650, was negatively correlated with susceptibility to PTC, with TC heterozygotes exerting a protective effect (OR = 0.268, p = 0.0001). These results suggest that the polymorphisms HOTAIR rs920778 and MIR155HG rs1893650 could be potential prognostic and risk biomarkers in papillary thyroid carcinomas. [ABSTRACT FROM AUTHOR]

Background: Coronary artery disease is caused by changes in the coronary arteries due to the atherosclerotic process and thrombotic changes. A very important role in the development of the atherosclerotic process in the coronary vessels is played by the inflammatory process and the immune response. Due to the important role of lipids and the coagulation process in the atherosclerotic process, research has also focused on genes affecting lipid metabolism and the coagulation system. Lipoprotein lipase (LPL) is an enzyme that metabolises lipids, hydrolysing triglycerides to produce free fatty acids and glycerol. Protein C (PC) is an essential component of coagulation and fibrinolysis. It is activated on the endothelial surface by the membrane-bound thrombin-thrombomodulin complex. Platelet-derived growth factor (PDGF) has a number of important functions in processes related to fibroblast and smooth muscle cell function. Due to their influence on lipid metabolism and coagulation processes, LPL, PROCR (endothelial cell protein C receptor) and PDGF may affect the atherosclerotic process and, thus, the risk of coronary heart disease. The aim of the study was to examine the associations between the LPL rs264, PROCR rs867186 and PDGF rs974819 gene polymorphisms and the risk of unstable angina and selected clinical parameters. Methods: The study included 232 patients with unstable angina and 144 healthy subjects as the control group. Genotyping was performed using real-time PCR. Results: There were no statistically significant differences in the distribution of the polymorphisms tested between the patients with unstable angina and the control subjects. The results showed associations between the PROCR rs867186 and PDGF rs974819 polymorphisms and some clinical parameters in patients with unstable angina. In patients with the PDGF rs974819 CC genotype, there were increased values for cholesterol and LDL serum levels in comparison with patients with the PDGF rs974819 CT and TT genotypes. In patients with the PROCR rs867186 AA genotype, HDL serum levels were lower than in patients with the GA genotype. Conclusions: The results of our study did not show that the LPL rs264, PROCR rs867186 and PDGF rs974819 gene polymorphisms were significant risk factors for unstable angina in our population. The results of the study suggest that PDGF rs974819 and PROCR rs867186 may be associated with some parameters of lipid metabolism. [ABSTRACT FROM AUTHOR]

Pemphigus foliaceus (PF) is an autoimmune skin blistering disease characterized by antidesmoglein-1 IgG production, with an endemic form (EPF) in Brazil. Genetic and epigenetic factors have been associated with EPF, but its etiology is still not fully understood. To evaluate the genetic association of histone (de)acetylation-related genes with EPF susceptibility, we evaluated 785 polymorphisms from 144 genes, for 227 EPF patients and 194 controls. Carriers of HDAC4_rs4852054*A were more susceptible (OR = 1.79, p = 0.0038), whereas those with GSE1_rs13339618*A (OR = 0.57, p = 0.0011) and homozygotes for PHF21A_rs4756055*A (OR = 0.39, p = 0.0006) were less susceptible to EPF. These variants were not associated with sporadic PF (SPF) in German samples of 75 SPF patients and 150 controls, possibly reflecting differences in SPF and EPF pathophysiology. We further evaluated the expression of histone (de)acetylation-related genes in CD4+ T lymphocytes, using RNAseq. In these cells, we found a higher expression of KAT2B, PHF20, and ZEB2 and lower expression of KAT14 and JAD1 in patients with active EPF without treatment compared to controls from endemic regions. The encoded proteins cause epigenetic modifications related to immune cell differentiation and cell death, possibly affecting the immune response in patients with PF. [ABSTRACT FROM AUTHOR]

Neurally mediated syncope (NMS) is associated with a sudden loss of consciousness. However, the diagnostic tools and measures for prognosis management are limited. To overcome these limitations, the differences in the binding energies of Giα-protein-coupled receptors to the Glu9 and Glu12 residues on the α2B-AR gene were elucidated through the analysis of α2B-AR gene polymorphism. The suppression of the activity of adenylate cyclase (AC), which is involved in vasoconstriction, may be related to the onset of NMS. The head-up tilt (HUT) test results indicated differences in systolic blood pressure (SBP) and AC activity between patients with vasodepressor (VT)-NMS and healthy volunteers. Patients with VT-NMS had increased AC activity and decreased SBP. Conversely, in healthy volunteers, no changes in AC activity or SBP were found. These findings suggest that a high SBP and elevated AC activity at rest are likely to cause syncope. A high incidence of cardiovascular events is found in patients with negative HUT test results, highlighting the importance of investigating the cause of syncope in cases where the HUT test results are negative. Overall, our results may provide a means of assessing the risk of NMS development within healthy populations and underscore the importance of subsequent treatments for NMS. [ABSTRACT FROM AUTHOR]

Vascular endothelial growth factor (VEGF) is a heparin-specific growth factor specific for vascular endothelial cells and induces angiogenesis via binding to vascular endothelial growth factor receptor (VEGFR). Chronic kidney disease (CKD), accompanied by microvascular disease, is recognized as an irreversible reduction of renal function. The effects of VEGF on CKD risk were evaluated in this study. 121 CKD patients and 50 healthy volunteers were evaluated in the current study. Data mining using the China Biological Medicine (CBM) and NCBI/PubMed databases, was performed and applicable investigations were pursued. Pooled mean differences (MD) and pooled odds ratios (OR), with corresponding confidence intervals (CIs), were calculated by meta-analysis. The levels of Scr, BUN and VEGF in the CKD group were significantly higher, when compared with the control group (P < 0.01). For the metaanalysis, thirteen articles and our current study were evaluated. VEGF levels was found to be associated with CKD risk (P < 0.00001). In the sub-group meta-analysis, we found that the pooled MD of VEGF levels was related to the early CKD group, although the difference was not notable. However, the meta-analysis itself indicated that the pooled MD of VEGF levels were in accordance with severe CKD group (P < 0.00001). Furthermore, VEGF +936C/T T allele was not associated with CKD risk (P = 0.69). VEGF levels are apparently associated with CKD risk, especially in more severe CKD. Gene polymorphism analysis indicates that the VEGF +936C/T T allele is not associated with CKD risk. [ABSTRACT FROM AUTHOR]

Since SLCO1B1 encodes the uptake transporter OATP1B1, which can influence the pharmacokinetic and pharmacodynamic profiles of edoxaban, polymorphisms in SLCO1B1 may affect the edoxaban response. This study aimed to investigate the association between SLCO1B1 gene polymorphisms and the bleeding risk in patients receiving edoxaban. We genotyped 10 single-nucleotide polymorphisms (SNPs) from the SLCO1B1 gene in patients receiving edoxaban. We also analyzed rs3842 of ABCB1 as a confounder. The odds ratio (OR) and adjusted OR (AOR) were calculated from univariate and multivariable analysis, respectively. The area under the receiver operating characteristic curve (AUROC) was constructed for the discrimination of the model. A total of 159 patients receiving edoxaban were analyzed. Overdose and rs4149056 showed significant association with bleeding complications by around 11- and 5.5-fold, respectively. Additionally, patients with the rs4149057 variant allele (C) had a 3.9-fold increased bleeding risk compared with wild-type homozygote carriers (TT), whereas rs2306283 variant homozygote (GG) carriers had a 0.27-fold reduced bleeding risk compared with wild-type allele (A) carriers. Patients with the variant-type homozygote (CC) of ABCB1 rs3842 had a higher bleeding risk than T allele carriers (AOR = 5.3 and 5.9). The final models for multivariable analyses were acceptable based on the AUROC values (> 0.70). These findings may help predict bleeding risk in patients taking edoxaban and help personalize treatment. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) is a prominent global health issue, as it ranks as the fifth most prevalent type of cancer and the fourth most significant cause of cancer-related mortality worldwide. Although H. pylori is known to play a role in the development of GC, genetic factors also play a role in its onset and progression. Recent studies have shown that genetic polymorphisms are strongly associated with the development of GC and that certain single nucleotide polymorphisms (SNPs) can be used as biomarkers for early diagnosis and prevention. Epigenetic disturbances, such as DNA methylation, are involved in the development of GC, and mutations in the DNA methyltransferase (DNMT) gene have been found to increase the risk of GC. However, previous findings on the association between DNMTs SNPs and GC risk have been inconsistent. In this study, an updated meta-analysis of three well-studied and controversial DNMTs polymorphic loci, DNMT1 rs16999593, DNMT3A rs1550117 and DNMT3B rs1569686, was performed to provide more reliable results. It was found that DNMT1 rs16999593 was not associated with GC, DNMT3A rs1550117 may have a positive association with GC risk, and DNMT3B rs1569686 may be a protective factor for GC. These findings may provide valuable information for early diagnosis and prevention of GC, but further studies are needed to confirm these results. [ABSTRACT FROM AUTHOR]

Faba bean is considered one of the most prominent grain legumes, with high protein content for human food consumption and livestock feed. The present study evaluated the nature of gene action and determined the genetic diversity among different populations of three crosses for resistance to foliar diseases at the molecular level. Analysis of variance exposed significant differences among the generations for all measured traits. Both dominance and additive gene effects were essential, but dominance genes, for the most part, exhibited greater effects than additive ones. This indicates an essential role for dominant genes alongside the additives one in inheriting such traits. The third cross (Marina × Giza 40) gave desired significant and positive (additive × additive) values for the number of pods/plant, seeds/plant, and seed yield/plant, in addition to desirable negative values for chocolate spot and rust characteristics. Furthermore, assessing the lines under study using seven SCoT primers disclosed three bands with recorded molecular weights of 260, 207, and 178 bp, generated by SCoT-1, SCoT-4, and SCoT-7 primers, respectively. These bands exist in the resistant parent (Marina), which could be attributed to the high-disease-resistance phenotypes, and they are absent in the sensitive parent (Giza 40) and other putative sensitive lines. Based on the molecular profiles and the genetic similarity between parents and the selected lines, the highest similarity value (0.91) was detected between Marina genotype and BC1, revealing a high foliar disease resistance. Meanwhile, Giza 40 (susceptible to foliar diseases) exhibited the maximum value (0.93) with F2. Additionally, cluster analysis based on genetic relationships was performed, and a high level of correlation between the results of PCR-based SCoT analysis and the foliar disease reactions was observed in the field. Consequently, this study concluded that SCoT markers created reliable banding profiles for evaluating genetic polymorphism among faba bean lines, which could be a foundation for developing an efficient breeding program. [ABSTRACT FROM AUTHOR]

Background: Osteoarthritis (OA) is caused by a complex set of pathophysiological factors. The genetic factors involved in the occurrence and progress of the disease have been widely discussed by scholars. It was found that growth differentiation factor 5 (GDF5) gene polymorphisms may be linked to OA susceptibility, which has been controversial and needs to be further confirmed by an updated meta-analysis. Objectives: We examined the association between GDF5 rs143383 single nucleotide polymorphism (SNP) and OA susceptibility. Methods: All relevant articles that met the criteria are retrieved and included, and the search deadline is June 2022. The allele frequencies and different genotype frequencies of GDF5 rs143383 loci in each study were extracted and statistically analyzed by R4.1.3 software, and the different genetic models were analyzed based on their odds ratio (OR) and 95% confidence interval (CI). Results: The meta-analysis explained that GDF5 rs143383 SNP was crucial correlated with OA in all patients with OA of knee, hip and hand. The codominant gene model in the whole crowd (OR = 1.17, 95% CI 1.07–1.27, P < 0.01) enlightened that OA was vitally associated with GDF5 gene polymorphism. At the same time, we did a subgroup analysis based on ethnicity. The codominant gene model (OR = 1.31, 95% CI 1.12–1.53, P < 0.01) in Asian population, the codominant homozygote model (OR = 1.28, 95% CI 1.14–1.43), codominant heterozygote gene model (OR = 1.12, 95% CI 1.01–1.23, P = 0.02), and dominant gene model (OR = 1.19, 95% CI 1.09–1.31, P < 0.01) in Caucasian are analyzed by subgroup analysis. It means that there is a momentous relationship between the GDF5rs143383 gene polymorphism and OA, especially among Caucasians. In addition, we also discussed different types of OA separately and discover that the GDF5rs143383 gene polymorphism was relevant for knee osteoarthritis (KOA) and hand osteoarthritis, and it was more significant in the Caucasian population. But due to the high heterogeneity in hip osteoarthritis, it could not be accurately concluded. Furthermore, we also analyzed the osteoarthritis of different genders and found that the GDF5 rs143383 SNP was associated with both men and women and was still significant in the Caucasian population. Conclusion: We found a close association between osteoarthritis and GDF5rs143383SNP in this study. From the analysis of each group, we got the same conclusion in KOA and hand OA, but which need further verification in hip OA. Considering gender, we found a close relationship between GDF5 rs143383 SNP and OA of the knee, hip and hand, both for men and women. This conclusion is more obvious in Caucasian people. [ABSTRACT FROM AUTHOR]

Background: Proline-glutamate (PE)/proline-PE (PPE) proteins play an important role in the development of mycobacterial pathogenicity by modulating the host immune system. In the present investigation, the structural changes in PE-polymorphic GC-rich sequences (PGRS) family protein Wag22 (Rv1759c), PE_PGRS31 (Rv1768), PE_PGRS32 (Rv1803), and PE_PGRS33 gene (Rv1818c) were compared and analyzed in exponential state and under in vitro model of latency in same clinical isolates of Mycobacterium tuberculosis (MTB). Methods: MTB strains were isolated from clinically and laboratory-confirmed cases of tuberculosis (TB). The TB isolates were subjected to the Xpert MTB/rifampin test and then, further susceptibility testing using proportional methods was performed on them. The isolates were characterized using both 16S–23S RNA and hsp65 genes spacer polymerase chain reaction-restriction fragment length polymorphism. Selected isolates studied at two experimental set–up at exponential phase OD 600 = 0.05 (5 cfu/mL × 106 cfu/mL) and under zero oxygen and nutrition for 26 months to selected isolates studied at two experimental setup in exponential phase OD600 = 0.05 (5 cfu/mL × 106 cfu/mL) and under zero oxygen and nutrition after 26 months. Whole-genome sequencing was performed on studied isolates and the protein structures were analyzed using a bioinformatics web server. Results: No deletion, insertion, or substation occurred in susceptible, mono-drug and multidrug resistant-TB isolates were observed at PE-PGRS family protein Wag22 (Rv1759c) and PE_PGRS31 (Rv1768) at exponential phase. Although, a large deletion (at Rv1759c; Rv1768) was observed in extensively drug-resistant (XDR) and totally drug-resistant (TDR) TB isolates at the exponential phase. All studied TDR-TB isolates had a common deletion position from amino acid 1 (methionine) to amino acid 83 (glycine) and from amino acid 725 (proline) to amino acid 914 (threonine) at PE-PGRS family protein Wag22 (Rv1759c). At PE_PGRS32 (Rv1803), deletion occurred from amino acid 1 (methionine) to amino acid 212 (glycine) in latent TDR-TB bacilli. No changes in Rv1803 were observed in other studied isolates. In contrast, 66.6% of studied isolates had either insertion, deletion, substitution, or combination of changes at PE_PGRS33 (Rv1818c). However, the majority of changes at Rv1818c occurred in drug-resistant isolates. We also documented the region of deletion and insertion at PE_PGRS33 (Rv1818c) is different in active and latent TDR-TB isolates. Conclusions: Changes in these PE-PGRS family protein was associated with drug susceptibility patterns of individual isolates. Our result showed a total frameshift mutation of protein that had a different length in comparison to the original protein. These changes might disturb the interactions between XDR and TDR-TB isolates and immune responses, which needs further investigation. [ABSTRACT FROM AUTHOR]

Physical performance has been the focus of studies examining genetic influences in martial arts. There has been little quantitative analysis of the interaction between psychological traits and gene variants in athletes. This study aimed to determine whether the rs4680 polymorphism of the COMT gene (catechol-O-methyltransferase) was linked to other sports phenotypes such as temperament, mental toughness, and stress tolerance. In our study, we concentrated on the case-control analysis of athletes in the aspect of their personality traits in association with the COMT gene polymorphism. Participants comprised 258 combat sports athletes and 278 healthy male individuals as a control group. Psychometric properties were assessed with the Revised Temperament and Character Inventory (TCI-R). COMT polymorphism testing was performed using real-time PCR. We found a statistically significant effect of a complex factor COMT rs4680 genotype with combat athletes/controls and novelty seeking (F2,530 = 5.958, p = 0.0028, η² = 0.022), self-management (F2,530 = 6.772, p = 0.0012, η² = 0.025), and with self-transcendence skills (F2,530 = 9.387, p = 0.00009, η² = 0.034). The results are important for encouraging further studies on the genetic makeup of athletes in conjunction with personality traits. Due to the multigene and multifactorial nature of determinants of sports predispositions, we propose to take into account also other features, especially when studying genes related to cerebral neurotransmission. It is a holistic departure, and it clearly illustrates the relationship between the given characteristics of an athlete. [ABSTRACT FROM AUTHOR]

Background: This study explores the association between growth arrest-specific 5 (GAS5) rs145204276, nuclear paraspeckle assembly transcript 1 (NEAT1) rs512715, and Maternally Expressed 3 (MEG3) rs4081134 polymorphisms and their impact on susceptibility to papillary thyroid carcinoma (PTC), considering differential expression of long noncoding RNAs (lncRNAs) in PTC. Methods: A case-control study involving 125 papillary thyroid carcinoma (PTC) patients and 125 controls was conducted. Genotyping of polymorphisms was performed using tetra-primer amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) and PCR-restriction fragment length polymorphism (PCR-RFLP) methods. Results: No significant association was found between the two groups regarding genotypes and allelic frequencies of GAS-5 145204276 and MEG3 rs4081134 polymorphisms. Genetic models also showed the same results. Regarding NEAT1 rs512715, The PTC group had more GC genotypes and over-dominant models of NEAT1 rs512715 than controls, while controls showed a higher frequency of recessive models. Conclusion: GAS5 rs145204276 and MEG3 rs4081134 polymorphisms showed no significant association with papillary thyroid carcinoma (PTC) risk. In contrast, NEAT1 rs512715 exhibited a significant impact on PTC development. [ABSTRACT FROM AUTHOR]

Background: Methotrexate (MTX), utilized as a graft-versus-host disease (GvHD) prophylactic agent in allogeneic hematopoietic stem cell transplantation (allo-HSCT), has been proven to effectively decrease the occurrence of the peri-engraftment syndrome (Peri-ES) and acute GvHD (aGvHD). Changes in the pharmacodynamics of MTX are closely associated with gene polymorphisms in genes encoding drug-metabolizing enzymes and transporters. Nevertheless, the current studies mainly concentrate on leukemia or autoimmune diseases, and limited studies on allo-HSCT were reported. Methods: Here, we retrospectively assessed the relationship between MTX-related transporter and metabolizing enzyme gene polymorphisms, clinical characteristics, and outcomes in 57 pediatric patients who received haploid HSCT (haplo-HSCT) with malignant tumors at a single center. Results: We discovered all gene polymorphisms were in the Hardy–Weinberg equilibrium in our cohort. We discovered a significant correlation between platelet recovery time and ABCB1 (1236C>T) (p = 0.042). Compared with patients with SLCO1B1 (1865+4846T>C) TT, patients with SLCO1B1 (1865+4846T>C) TC/CC had an increased incidence of Peri-ES (p = 0.030). Based on the multivariate Cox analysis, we discovered that SLCO1B1 (1865+4846T>C) TT genotype was an independent protective factor for Peri-ES morbidity (hazard ratio (HR) = 0.464, p = 0.031), and the dose of mononuclear cells reinfused was significantly correlated with II–IV aGvHD (HR = 2.604, p = 0.039). Conclusion: In summary, our findings prove that the host’s genotypes might modify the risk of developing Peri-ES, contribute to a better understanding of the inter-individual difference in efficacy, and facilitate the development of individualized approaches to GvHD prophylaxis. [ABSTRACT FROM AUTHOR]

Background: Taxane-induced peripheral neuropathy (TIPN) is an important cause of premature treatment cessation and dose-limitation in cancer therapy. It also reduces quality of life and survivorship in affected patients. Genetic polymorphisms in the CYP3A family have been investigated but the findings have been inconsistent and contradictory. Methods: A systematic review identified 12 pharmacogenetic studies investigating genetic variation in CYP3A4*22 and CYP3A5*3 and TIPN. In our candidate gene study, 288 eligible participants (211 taxane participants receiving docetaxel or paclitaxel, and 77 control participants receiving oxaliplatin) were successfully genotyped for CYP3A4*22 and CYP3A5*3. Genotyping data was transformed into a combined CYP3A metaboliser phenotype: Poor metabolisers, intermediate metabolisers and extensive metabolisers. Individual genotypes and combined CYP3A metaboliser phenotypes were assessed in relation to neurotoxicity, including by meta-analysis where possible. Results: In the systematic review, no significant association was found between CYP3A5*3 and TIPN in seven studies, with one study reporting a protective association. For CYP3A4*22, one study has reported an association with TIPN, while four other studies failed to show an association. Evaluation of our patient cohort showed that paclitaxel was found to be more neurotoxic than docetaxel (p < 0.001). Diabetes was also significantly associated with the development of TIPN. The candidate gene analysis showed no significant association between either SNP (CYP3A5*3 and CYP3A4*22) and the development of TIPN overall, or severe TIPN. Meta-analysis showed no association between these two variants and TIPN. Transformed into combined CYP3A metaboliser phenotypes, 30 taxane recipients were poor metabolisers, 159 were intermediate metabolisers, and 22 were extensive metabolisers. No significant association was observed between metaboliser status and case-control status. Summary: We have shown that the risk of peripheral neuropathy during taxane chemotherapy is greater in patients who have diabetes. CYP3A genotype or phenotype was not identified as a risk factor in either the candidate gene analysis or the systematic review/meta-analysis, although we cannot exclude the possibility of a minor contribution, which would require a larger sample size. [ABSTRACT FROM AUTHOR]

Background: Gastric cancer (GC) is one of the most common malignancies, affected by several genetic loci in the clinical phenotype. This study aimed to determine the association between PTGER4 and PRKAA1 gene polymorphisms and the risk of GC. Methods: A total of 509 GC patients and 507 age and sex-matched healthy controls were recruited to explore the association between PTGER4 and PRKAA1 genetic polymorphisms and GC susceptibility. Logistic regression analysis was used to study the correlation between these SNPs and GC, with odd ratio (OR) and 95% confidence interval (CI) as indicators. Multifactor dimensionality reduction was utilized to analyze the genetic relationships among SNPs. was conducted to predict gene expression, the impact of SNPs on gene expression, and the signaling pathways involved in PTGER4 and PRKAA1. Results: Overall, rs10036575 in PTGER4 (OR = 0.82, p = 0.029), rs10074991 (OR = 0.82, p = 0.024) and rs13361707 (OR = 0.82, p = 0.030) in PRKAA1 were associated with susceptibility to GC. Stratification analysis revealed that the effects of these SNPs in PTGER4 and PRKAA1 on GC susceptibility were dependent on smoking and were associated with a reduced risk of adenocarcinoma (p < 0.05). Bioinformatics analysis showed an association between SNPs and corresponding gene expression (p < 0.05), and PRKAA1 may affect GC by mediating RhoA. Conclusion: This study suggests that PTGER4 and PRKAA1 SNPs might affect the susceptibility of GC, providing a new biological perspective for GC risk assessment, pathogenesis exploration, and personalized treatment. [ABSTRACT FROM AUTHOR]

Non Alcoholic Fatty Liver Disease (NAFLD) is an emerging epidemic worldwide. It comprehends simple steatosis to escalating steatosis with associated fibrosis, cirrhosis, and Hepatocellular Carcinoma (HCC). NAFLD patients are at increased risk of liver-related as well as cardiovascular mortality. It seems to have a robust interconnection with visceral adiposity, Insulin Resistance (IR), inflammation, and environmental factors. Although the pathogenesis of NAFLD is presumed to be linked to lifestyle patterns, nutritional factors, and genetics, the predictor of advancement of this disease spectrum caused by genetics stands imprecise. In the past decade, multiple genome-wide associations and large candidate gene studies have recognised the contribution of several genetic polymorphisms in regulating hepatic lipid metabolism, thus influencing NAFLD establishment and progression. Recent understanding of the genetic underpinning of NAFLD explains the involvement of several common naturally occurring variants in PNPLA3, TM6SF2, MBOAT7, GCKR, LYPLAL1 and PPP1R3B genes in the evolution of the disease. The genetic landscape may play a role to appraise the risk stratification and ascertaining the potential therapeutic target in NAFLD patients. The perspective of this review was to emphasise the genetic basis of the NAFLD spectrum, which modulates the severity and progression of the disease. [ABSTRACT FROM AUTHOR]

Knowledge about the genetic diversity of the available common bean germplasm can help breeders properly direct the choice of genetic material in the breeding process. The aim of the present work was to estimate the usefulness of 10 RAPD and 10 SCoT markers in genetic diversity detection among 33 common bean genotypes. Both molecular marker systems were able to generate high levels of polymorphism in the genetic material, which was supported by the relatively high polymorphic information content (PIC) values observed for the used markers. The Diversity Detection Index (DDI) and Marker Index (MI) were used to compare the effectiveness of RAPD and SCoT markers. For both techniques, high values of MI and DDI were calculated, representing their effectivity. The SCoT markers showed higher values of the parameters used (MI = 7.474, DI = 2.265) than the RAPD markers (MI = 5.323, DDI = 1.612), indicating their higher efficiency in the detection of molecular variability. Three constructed dendrograms and PCoA plots were created using RAPD and SCoT, and both methods combined confirmed sufficient separation of the bean genotypes from each other. At the same time, a higher efficiency of SCoT markers compared to RAPD markers in the detection of the genetic diversity of beans was also proven. The results may be of future interest in the choice of genetically distant material for breeding purposes. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a systemic disease characterized by non-infectious inflammation of the joints and surrounding tissues, which can cause severe health problems, affect the patient's daily life, and even cause death. RA can be clinically diagnosed by the occurrence of blood serological markers, rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (anti-CCP). However, about 20% of RA patients exhibit negative results for both markers, which makes RA diagnosis difficult and, therefore, may delay the effective treatment. Previous studies found some evidence that human leukocyte antigen (HLA)-related genes might be the susceptibility genes for RA and their polymorphisms might contribute to varieties of susceptibility and disease severity. This study aimed for the genetic polymorphisms of the RA patient genome and their effects on the RA patient's serological makers, RF and anti-CCP. A total of 4580 patients' electronic medical records from 1992 to 2020 were retrieved from the China Medical University Hospital database. The most representative single-nucleotide polymorphisms (SNPs) were identified through a genome-wide association study (GWAS) followed by enzyme-linked immunosorbent assay (ELISA) validation using the blood from 30 additional RA patients. The results showed significant changes at the position of chromosome 6 with rs9270481 being the most significant locus, which indicated the location of the HLA-DRB1 gene. Further, patients with the CC genotype at this locus were more likely to exhibit negative results for RF and anti-CCP than those with the TT genotype. The C allele was also more likely to be associated with negative results for RF and anti-CCP. The results demonstrated that a genetic polymorphism at rs9270481 affected the expression of RF and anti-CCP in RA patients, which might indicate the necessity to develop a personalized treatment plan for each individual patient based on the genetic profile. [ABSTRACT FROM AUTHOR]