UNASSIGNED: The toxin-antitoxin (TA) system plays a vital role in the virulence and pathogenicity of Mycobacterium tuberculosis (M. tuberculosis). However, the regulatory mechanisms and the impact of gene mutations on M. tuberculosis transmission remain poorly understood.
UNASSIGNED: To investigate the influence of gene mutations in the toxin-antitoxin system on M. tuberculosis transmission dynamics.
UNASSIGNED: We performed whole-genome sequencing on the analyzed strains of M. tuberculosis. The genes associated with the toxin-antitoxin system were obtained from the National Center for Biotechnology Information (NCBI) Gene database. Mutations correlating with enhanced transmission within the genes were identified by using random forest, gradient boosting decision tree, and generalized linear mixed models.
UNASSIGNED: A total of 13,518 M. tuberculosis isolates were analyzed, with 42.29% (n = 5,717) found to be part of genomic clusters. Lineage 4 accounted for the majority of isolates (n = 6488, 48%), followed by lineage 2 (n = 5133, 37.97%). 23 single nucleotide polymorphisms (SNPs) showed a positive correlation with clustering, including vapB1 G34A, vapB24 A76C, vapB2 T171C, mazF2 C85T, mazE2 G104A, vapB31 T112C, relB T226A, vapB11 C54T, mazE5 T344C, vapB14 A29G, parE1 (C103T, C88T), and parD1 C134T. Six SNPs, including vapB6 A29C, vapB31 T112C, parD1 C134T, vapB37 G205C, Rv2653c A80C, and vapB22 C167T, were associated with transmission clades across different countries. Notably, our findings highlighted the positive association of vapB6 A29C, vapB31 T112C, parD1 C134T, vapB37 G205C, vapB19 C188T, and Rv2653c A80C with transmission clades across diverse regions. Furthermore, our analysis identified 32 SNPs that exhibited significant associations with clade size.
UNASSIGNED: Our study presents potential associations between mutations in genes related to the toxin-antitoxin system and the transmission dynamics of M. tuberculosis. However, it is important to acknowledge the presence of confounding factors and limitations in our study. Further research is required to establish causation and assess the functional significance of these mutations. These findings provide a foundation for future investigations and the formulation of strategies aimed at controlling TB transmission.

BACKGROUND: Chemokines and cytokines are components of the tumor microenvironment and also influence tumorigenesis and its composition. However, whether they genetically proxy tumorigenesis is unclear. For causal inferences, eQTL and pQTL were used to determine the role of chemokines and cytokines in pan-cancer. The impact on the tumor immune microenvironment was also explored.
METHODS: This study leveraged summary statistics from respective genome-wide association studies (GWAS) of 109 cytokines and chemokines in 18 types of solid tumors. Single nucleotide polymorphisms (SNPs) robustly associated with the cytokines and chemokines, located in or close to their coding gene (cis), were used as instrumental variables. A two-sample MR design was employed, followed by comprehensive sensitivity analyses to validate the robustness of results. The impact on immune infiltration was investigated using the TIMER and TISIDB websites. Survival analysis was conducted using the K-M plotter and TIMER 2.0 websites. The TISCH and GEO databases were used to carry out scRNA cell analysis.Analyzing relevant proteins using the STRING database and conducting enrichment pathways for GO analysis of the identified proteins.
RESULTS: The results of the inverse-variance weighted (IVW) method using cis-protein QTL (cis-pQTL) instruments showed the causal effects of TNF in reducing the risk of squamous cell lung cancer (LUSC) and HGF in reducing the risk of head and neck cancer (HNSC).The results were consistent with the eQTL. HGF was associated with better overall survival (OS) in HNSC, regardless of the types of cells enriched. However, high expression of the ligand MET for HGF leads to a decrease in overall survival in LUSC. TNF was related to poor OS in LUSC with no significant impact. However, in CD8 + T cell-enriched, eosinophil-enriched, macrophage-enriched, and NK cell-deficient types of LUSC, high expression of TNF leads to a poor prognosis, and there is statistical significance. The results showed a significant positive correlation between TNF and most immune cell infiltration, immunomodulator and chemokine in LUSC. HGF is positively correlated with the majority of immune cells except CD56 + cells, as well as some immune regulatory factors and chemotactic factors. According to single-cell sequencing results, HGF is mainly secreted by fibroblasts and myofibroblasts in HNSC, while in LUSC, it is primarily secreted by macrophages and CD8 + T cells secrete TNF. The GO/KEGG analysis suggests that proteins related to HGF are mainly involved in regulating peptidyl-tyrosine phosphorylation and positive regulation of the MAPK cascade. Proteins related to TNF are primarily associated with the regulation of I-kappaB kinase/NF-kappaB signaling and cytokine-mediated signaling pathway.
CONCLUSIONS: HGF is primarily secreted by fibroblasts in HNSC and may have a protective effect on the occurrence and prognosis of HNSC. These effects are independent of immune cell influence, and this role may not necessarily be mediated through the HGF/MET pathway. On the other hand, TNF in LUSC is mainly secreted by immune cells like CD8 + T cell, and it may have a protective effect on the occurrence of LUSC. However, it\'s impact on the prognosis of LUSC through the immune microenvironment may have a different effect.
Chemokines and cytokines are not only components of the tumor microenvironment but also affect tumorigenesis and the composition of the tumor microenvironment. However, whether they genetically proxy tumorigenesis is unclear. For causal inferences, eQTL and pQTL were used to define the role of chemokines and cytokines in pan-cancer. The impact on the tumor immune microenvironment was also explored. This study leveraged the summary statistic from respective genome wide association study (GWAS) of 109 cytokines and chemokines to 18 types of solid tumor. Single nucleotide polymorphisms (SNPs) robustly associated with the cytokines and chemokines, located in or close to their coding gene (cis), were used as instrumental variables. A two-sample MR design was employed, followed by comprehensive sensitivity analyses to validate the robustness of results. The results showed HGF is primarily secreted by fibroblasts in HNSC, and it may have a protective effect on the occurrence and prognosis of HNSC. These effects are independent of immune cell influence, and this role may not be mediated through the HGF/MET pathway. On the other hand, TNF in LUSC is mainly secreted by immune cells like CD8 + T cell, and it may have a protective effect on the occurrence of LUSC. However, it’s impact on the prognosis of LUSC through the immune microenvironment may have a different effect.

Carcinogenesis is closely related to the expression, maintenance, and stability of DNA. These processes are regulated by one-carbon metabolism (1CM), which involves several vitamins of the complex B (folate, B2, B6, and B12), whereas alcohol disrupts the cycle due to the inhibition of folate activity. The relationship between nutrients related to 1CM (all aforementioned vitamins and alcohol) in breast cancer has been reviewed. The interplay of genes related to 1CM was also analyzed. Single nucleotide polymorphisms located in those genes were selected by considering the minor allele frequency in the Caucasian population and the linkage disequilibrium. These genes were used to perform several in silico functional analyses (considering corrected p-values < 0.05 as statistically significant) using various tools (FUMA, ShinyGO, and REVIGO) and databases such as the Kyoto Encyclopedia of Genes and Genomes (KEGG) and GeneOntology (GO). The results of this study showed that intake of 1CM-related B-complex vitamins is key to preventing breast cancer development and survival. Also, the genes involved in 1CM are overexpressed in mammary breast tissue and participate in a wide variety of biological phenomena related to cancer. Moreover, these genes are involved in alterations that give rise to several types of neoplasms, including breast cancer. Thus, this study supports the role of one-carbon metabolism B-complex vitamins and genes in breast cancer; the interaction between both should be addressed in future studies.

UNASSIGNED: The study was conducted to identify the sequence variation of Toll-like receptor 4 (TLR4) in exon 2 of South African Dorper sheep.
UNASSIGNED: Blood samples were collected from fifty (n = 50) South African Dorper sheep aged between 3 and 4 years. The Deoxyribonucleic acid (DNA) was extracted, amplified, and sequenced for the TLR4 gene. DNA sequencing was used to identify the sequence variations of the TLR4 gene in South African Dorper sheep.
UNASSIGNED: The results showed that one synonymous single nucleotide polymorphism (SNP) of the TLR4 gene in exon 2 position T2249C was identified. Two genotypes (TT and TC) were discovered from the identified SNP. The dominant genotype was TT (0.60) over TC (0.40), with the dominant allele T (0.80) over C (0.20). The results also indicated that the used population was in the Hady-Weinberg Equilibrium. Polymorphism genetic analysis findings suggest that the identified sequence variation of TLR4 in exon 2 of South African Dorper sheep was moderate polymorphism.
UNASSIGNED: TLR4 gene at exon 2 of South African Dorper sheep had the SNP (T>C) at position 2249 bp with two genotypes (TT and TC).

Intracranial aneurysms (IAs) are present in ~2% of the general population, and genetic factors cannot be excluded for the risk of their development. The gene factors that result in the changes in the vascular extracellular matrix (ECM) may also be a key reason for IAs being hereditary. The VCAN gene [also known as chondroitin sulfate proteoglycan 2 (CSPG2)] plays various roles in maintaining ECM functions. The present systematic review and meta-analysis aimed to investigate all eligible articles involving IAs on the association with germ line SNPs of DNA repair genes (up to January, 2024). The total number of patients was 2,308 [987 cases (poor outcomes) and 1,321 controls (good outcomes)]. The results revealed that rs2287926 G/G genotype and G allele and rs251124 T/T genotype and minor allele T increased the risk of developing IAs. However, further studies are required to examine these gene polymorphisms as screening markers for IAs.

Schizophrenia (SZ) is a multifactorial and neurodegenerative disorder that results from the interaction between genetic and environmental factors. Notably, hundreds of single nucleotide polymorphisms (SNPs) are associated with the susceptibility to SZ. Vitamin D (VD) plays an essential role in regulating several genes important for maintaining brain function and health. To the best of the authors\' knowledge, no studies have yet been conducted on the association between the VD pathway and patients with SZ. Therefore, the present study aimed to assess the potential association between eight SNPs in genes related to the VD pathway, including CYP2R1, CYP27B1, CYP24A1 and VDR among patients with SZ. A case-control study was conducted, involving a total of 400 blood samples drawn from 200 patients and 200 healthy controls. Genomic DNA was extracted and variants were genotyped using the tetra-amplification refractory mutation system-polymerase chain reaction method. The present study revealed statistically significant differences between patients with SZ and controls regarding the genotypes and allele distributions of three SNPs [CYP2R1 (rs10741657), CYP27B1 (rs10877012) and CYP24A1 (rs6013897) (P<0.0001)]. The AA genotype of rs10741657 was identified to be associated with SZ (P<0.0001) and the frequency of the A allele was higher in patients with SZ (P<0.0001) compared with the control group. Similarly, the TT genotype of rs10877012 was revealed to be associated with SZ (P<0.0001) and the T allele was more frequent in patients with SZ (P<0.0001) than in the control group. Moreover, the AA genotype of rs6013897 was revealed to be associated with SZ (P<0.0001), although no significant difference was detected between the two groups regarding the A allele (P=0.055). VDR (rs2228570, rs1544410, rs731236 and rs7975232) and CYP27B1 (rs4646536) gene polymorphisms did not exhibit a significant association with SZ. While the studied SNPs revealed promising discriminatory capacity between patients with SZ and controls, the rs10741657 SNP exhibited the most optimal area under the curve value at 0.615. A logistic model was applied considering only the significant SNPs and VD levels, which revealed that rs6013897 (T/A) and VD may have protective effects (0.267, P<0.001; 0.888, P<0.001, respectively). Moreover, a low serum VD level was highly prevalent in patients with SZ compared with the controls. Based on this finding, an association between serum 25(OH)D and SZ could be demonstrated. The present study revealed that CYP2R1 (rs10741657), CYP27B1 (rs10877012) and CYP24A1 (rs6013897) gene SNPs may be associated with SZ susceptibility.

Diabetic Kidney Disease (DKD) remains the leading cause of Chronic and End Stage Kidney Disease (ESKD) worldwide, with an increasing epidemiological burden. However, still, the disease awareness remains low, early diagnosis is difficult, and therapeutic management is ineffective. These might be attributed to the fact that DKD is a highly heterogeneous disease, with disparities and variability in clinical presentation and progression patterns. Besides environmental risk factors, genetic studies have emerged as a novel and promising tool in the field of DKD. Three decades ago, family studies first reported that inherited genetic factors might confer significant risk to DKD development and progression. During the past decade, genome-wide association studies (GWASs) screening the whole genome in large and multi-ethnic population-based cohorts identified genetic risk variants associated with traits defining DKD in both type 1 and 2 diabetes. Herein, we aim to summarize the existing data regarding the progress in the field of genomics in DKD, present how the revolution of GWAS expanded our understanding of pathophysiologic disease mechanisms and finally, suggest potential future directions.

OBJECTIVE: To confirm if the CYP17A1 gene regulates the ratio of T/E leading to MetS-BPH.
METHODS: 824 men, aged 47-88 years, were recruited into this study through consecutive routine physical examination programs and long-term outpatient screening. Several parameters, including SNPs of CYP17A1 gene, total testosterone, estradiol, and the ratio of total testosterone to estradiol (T/E) were obtained for each participant. Based on the diagnosis of BPH, MetS, and MetS-BPH, the participants were divided into BPH and non-BPH groups, MetS and non-MetS groups, and MetS-BPH and non-MetS-BPH groups. Values of the obtained parameters were evaluated using one-way analysis of variance, Student\'s t-test, Chi-squared test, and logistic regression analysis.
RESULTS: SNPs of the CYP17A1 gene, including the rs743572 genotypes (GG, GA, and AA), rs3781287 genotypes (GG, GT, TT), and rs4919686 genotypes (CC, CA, and AA), were present in every group. Only the GG genotype of rs743572 was independently associated with BPH (OR = 5.868, 95% CI: 3.363-7.974, P < 0.001), MetS (OR = 7.228, 95% CI: 3.925-11.331, P < 0.001), and MetS-BPH (OR = 3.417, 95% CI: 1.783-5.266, P < 0.001) after adjusting for age. In the population of genotype GG of rs743572, the decrease in T/E ratio was an independent risk factor for BPH (OR = 839.756, 95% CI: 36.978-1334.263, P = 0.001), MetS (OR = 376.988, 95% CI: 12.980-488.976, P < 0.003), and MetS-BPH (OR = 388.236, 95% CI: 24.869-495.363, P = 0.003).
CONCLUSIONS: The GG genotype of rs743572 in CYP17A1 gene regulating the decrease of T/E ratio can be an independent risk factor for MetS-BPH populations.
BACKGROUND: ChiCTR2200057632 \"retrospectively registered\".
UNASSIGNED: March 15, 2022 \"retrospectively registered\".

UNASSIGNED: Acute Lymphoblastic Leukemia (ALL) is a multifactorial disease that results from the interaction between multiple genetic factors. ALL is characterized by uncontrolled production of hematopoietic precursor cells of the lymphoid progenitors within the bone marrow. The development of hematological malignancies has been associated with malignant-like cells that express low levels of immunogenic surface molecules, thus, facilitating their escape from cellular antineoplastic immune responses. This risk may be partly influenced by variations in polymorphic genes that control immune function and regulation. Toll-like receptors (TLRs) are well known pattern recognition receptors playing key role in innate immune response. Abnormal expression and dysregulation of TLRs will provide an opportunity for cancer cells to escape from the immune system and enhance their proliferation and angiogenesis. Toll-like receptor 2 (TLR2) play an essential role in innate immunity. Single nucleotide polymorphisms (SNPs) are present in a number of TLR genes and have been associated with various disorders.
UNASSIGNED: In this study, 265 subjects have been divided into two groups included 150 patients with ALL and115 healthy volunteers. All subjects were genotyped using TaqMan PCR techniques. In total, Five SNPs were statistically evaluated in the TLR2 (rs1898830 A/G, rs3804099 T/C, rs3804100 T/C, rs1339 T/C, and rs1337 C/G), which may influence the susceptibility of ALL. Minor allele frequency and genotype distribution were compared across the study groups, and the relative risk and differences between patients and controls were estimated. Moreover, the mRNA expression level was evaluated in patients with ALL and the matched healthy individuals by Real-Time Quantitative Reverse Transcription PCR (qRT-PCR).
UNASSIGNED: TLR2 rs1898830 A/G; rs3804099 T/C; rs3804100 T/C; rs1339 T/C, were significantly decrease the risk in our population, overall and for certain subtypes and ALL samples exhibited significant increase in the mRNA levels of TLR2.
UNASSIGNED: This study shows that TLR2 could be an independent prognostic factor of ALL risks in the Saudi population. Suggesting that genetic variation in genes associated with an immune response may be important in the etiology of ALL. In addition, the results herein revealed that TLR2 overexpression is associated with ALL and has diverse biological significance in the context of the complex relationship between inflammation and cancer development. Therefore, these data could open further studies to explore the possible clinical relevance of TLRs as pathological markers for Leukemia and enhance the strategies regarding hematological malignancies prevention based on their gene expression.

UNASSIGNED: Basal cell carcinoma (BCC) is the most common skin cancer, lacking reliable biomarkers or therapeutic targets for effective treatment. Genome-wide association studies (GWAS) can aid in identifying drug targets, repurposing existing drugs, predicting clinical trial side effects, and reclassifying patients in clinical utility. Hence, the present study investigates the association between plasma proteins and skin cancer to identify effective biomarkers and therapeutic targets for BCC.
UNASSIGNED: Proteome-wide mendelian randomization was performed using inverse-variance-weight and Wald Ratio methods, leveraging 1 Mb cis protein quantitative trait loci (cis-pQTLs) in the UK Biobank Pharma Proteomics Project (UKB-PPP) and the deCODE Health Study, to determine the causal relationship between plasma proteins and skin cancer and its subtypes in the FinnGen R10 study and the SAIGE database of Lee lab. Significant association with skin cancer and its subtypes was defined as a false discovery rate (FDR) < 0.05. pQTL to GWAS colocalization analysis was executed using a Bayesian model to evaluate five exclusive hypotheses. Strong colocalization evidence was defined as a posterior probability for shared causal variants (PP.H4) of ≥0.85. Mendelian randomization-Phenome-wide association studies (MR-PheWAS) were used to evaluate potential biomarkers and therapeutic targets for skin cancer and its subtypes within a phenome-wide human disease category.
UNASSIGNED: PTGES2, RNASET2, SF3B4, STX8, ENO2, and HS3ST3B1 (besides RNASET2, five other plasma proteins were previously unknown in expression quantitative trait loci (eQTL) and methylation quantitative trait loci (mQTL)) were significantly associated with BCC after FDR correction in the UKB-PPP and deCODE studies. Reverse MR showed no association between BCC and these proteins. PTGES2 and RNASET2 exhibited strong evidence of colocalization with BCC based on a posterior probability PP.H4 >0.92. Furthermore, MR-PheWAS analysis showed that BCC was the most significant phenotype associated with PTGES2 and RNASET2 among 2,408 phenotypes in the FinnGen R10 study. Therefore, PTGES2 and RNASET2 are highlighted as effective biomarkers and therapeutic targets for BCC within the phenome-wide human disease category.
UNASSIGNED: The study identifies PTGES2 and RNASET2 plasma proteins as novel, reliable biomarkers and therapeutic targets for BCC, suggesting more effective clinical application strategies for patients.