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Heliyon Apr 2024Coronary artery disease (CAD) is the most common reason for mortality and disability-adjusted life years (DALYs) lost globally. This study aimed to suggest a new gene...
BACKGROUND
Coronary artery disease (CAD) is the most common reason for mortality and disability-adjusted life years (DALYs) lost globally. This study aimed to suggest a new gene list for the treatment of CAD by a systematic review of bioinformatics analyses of pharmacogenomics impacts of potential genes and variants.
METHODS
PubMed search was filtered by the title including Coronary Artery Disease during 2020-2023. To find the genes with pharmacogenetic impact on the CAD, additional filtrations were considered according to the variant annotations. Protein-Protein Interactions (PPIs), Gene-miRNA Interactions (GMIs), Protein-Drug Interactions (PDIs), and variant annotation assessments (VAAs) performed by STRING-MODEL (ver. 12), Cytoscape (ver. 3.10), miRTargetLink.2., NetworkAnalyst (ver 0.3.0), and PharmGKB.
RESULTS
Results revealed 5618 publications, 1290 papers were qualified, and finally, 650 papers were included. 4608 protein-coding genes were extracted, among them, 1432 unique genes were distinguished and 530 evidence-based repeated genes remained. 71 genes showed a pharmacogenetics-related variant annotation in at least (entirely 6331 annotations). Variant annotation assessment (VAA) showed 532 potential variants for the final report, and finally, the concluding PGs list represented 175 variants. Based on the function and MAF, 57 nonsynonymous variants of 29 Pharmacogenomics-related genes were associated with CAD.
CONCLUSION
Conclusively, evaluating circulating miR33a in individuals' plasma with CAD, and genotyping of rs2230806, rs2230808, rs2487032, rs12003906, rs2472507, rs2515629, and rs4149297 (ABCA1 variants) lead to precisely prescribing of well-known drugs. Also, the findings of this review can be used in both whole-genome sequencing (WGS) and whole-exome sequencing (WES) analysis in the prognosis and diagnosis of CAD.
PubMed: 38601677
DOI: 10.1016/j.heliyon.2024.e28983 -
Biochemistry and Biophysics Reports Jul 2024The urea transporter UT-B1, encoded by the gene, has been hypothesized to be a significant protein whose deficiency and dysfunction contribute to the pathogenesis of...
The urea transporter UT-B1, encoded by the gene, has been hypothesized to be a significant protein whose deficiency and dysfunction contribute to the pathogenesis of bladder cancer and many other diseases. Several studies reported the association of genetic alterations in the (UT-B1) gene with bladder carcinogenesis, suggesting a need for thorough characterization of the UT-B1 protein's coding and non-coding variants. This study used various computational techniques to investigate the commonly occurring germ-line missense and non-coding SNPs (ncSNPs) of the gene (UT-B1) for their structural, functional, and molecular implications for disease susceptibility and dysfunctionality. missense variants, primarily identified from the ENSEMBL genome browser, were screened through twelve functionality prediction tools leading to two variants D280Y (predicted detrimental by maximum tools) and D280N (high global MAF) for rs1058396. Subsequently, the ConSurf and NetSurf tools revealed the D280 residue to be in a variable site and exposed on the protein surface. According to I-Mutant2.0 and MUpro, both variants are predicted to cause a significant effect on protein stability. Analysis of molecular docking anticipated these two variants to decrease the binding affinity of UT-B1 protein for the examined ligands to a significant extent. Molecular dynamics also disclosed the possible destabilization of the UT-B1 protein due to single nucleotide polymorphism compared to wild-type protein which may result in impaired protein function. Furthermore, several non-coding SNPs were estimated to affect transcription factor binding and regulation of gene expression. Additionally, two ncSNPs were found to affect miRNA-based post-transcriptional regulation by creating new seed regions for miRNA binding. This comprehensive study of gene variants may serve as a springboard for future large-scale investigations examining polymorphisms.
PubMed: 38596408
DOI: 10.1016/j.bbrep.2024.101703 -
Heliyon Apr 2024Chronic Rhinosinusitis is a common disease in children. The main function of CFTR is to maintain the thickness of the mucous layer on the surface of the nasal mucosa....
BACKGROUND
Chronic Rhinosinusitis is a common disease in children. The main function of CFTR is to maintain the thickness of the mucous layer on the surface of the nasal mucosa. disease-causing variant can cause CFTR protein dysfunction and induce or aggravate chronic infection. However, the carrying status of the variants in the Chinese population is not clear.
OBJECTIVE
To study the frequency and variants of in Chinese children with CRS and to analyze the variants and the clinical characteristics and susceptibility to CRS.
METHODS
Whole Exome Sequencing was performed to analyze the genes in a total of 106 CRS children from the Chinese mainland area. The variants, frequency and clinical data were summarized and analyzed.
RESULTS
A total of 31 variants were detected, of which the carrying rate of 7 sites was significantly higher than that of the population database. 88 patients carried more than 2 variants. 37 people carried variants (MAF < 0.05), of which 91.89% had a history of recurrent upper respiratory infections, 16 had nasal polyps, 5 had bronchiectasis, and 1 was diagnosed with CF-related disorders.
CONCLUSION
The carrying rate of variants in Chinese CRS children increased, and the highest rates of variants (MAF < 0.05) are p.I556V, p. E217G, c.1210-12[T]. Carrying multiple variants, especially p.E217G, p.I807 M, p.V920L and c.1210-12[T] may lead to increased susceptibility to CRS. There are CF-related disorders in patients with CRS.
PubMed: 38590877
DOI: 10.1016/j.heliyon.2024.e27681 -
Neurology(R) Neuroimmunology &... May 2024Histiocytic disorders are pathologic expansions of myeloid cells in multiple organs, including the CNS. They share activation of the MAP kinase pathway due to either... (Observational Study)
Observational Study
OBJECTIVES
Histiocytic disorders are pathologic expansions of myeloid cells in multiple organs, including the CNS. They share activation of the MAP kinase pathway due to either variant or other variants in the RAS-RAF-MEK-ERK pathway. The rarity and heterogeneity of the disease only enable therapy through pathophysiologic considerations.
METHODS
We present 2 histiocytosis cases without sequence variants that affect the CNS, one with Erdheim-Chester disease and the other with an unspecified histiocytosis, and their diagnostic and therapeutic challenges.
RESULTS
In both cases, comprehensive analysis of the RAS-RAF-MEK-ERK signaling pathway secured the diagnosis. Treatment with the MEK inhibitor cobimetinib brought the disease to a complete halt. However, side effects such as thrombosis and serous macular edema made it necessary to reduce cobimetinib dosage. Low-dose cobimetinib maintenance medication was successful in preventing recurrence of histiocytic disease.
DISCUSSION
CNS involvement of histiocytic disorders can lead to detrimental neurologic symptoms. MEK inhibitors are effective treatment options for some of these patients. Since side effects are common, according to our cases we propose a low-dose treatment of 20 mg per day to balance treatment effects with side effects.
CLASSIFICATION OF EVIDENCE
This case report provides Class IV evidence. This is a single observational study without controls.
Topics: Humans; Proto-Oncogene Proteins B-raf; Mutation; Histiocytosis; Protein Kinase Inhibitors; Mitogen-Activated Protein Kinase Kinases; Azetidines; Piperidines
PubMed: 38588479
DOI: 10.1212/NXI.0000000000200233 -
BioRxiv : the Preprint Server For... Apr 2024Despite recent advances in therapeutic treatments, multiple myeloma (MM) remains an incurable malignancy. Epigenetic factors contribute to the initiation, progression,...
Despite recent advances in therapeutic treatments, multiple myeloma (MM) remains an incurable malignancy. Epigenetic factors contribute to the initiation, progression, relapse, and clonal heterogeneity in MM, but our knowledge on epigenetic mechanisms underlying MM development is far from complete. The SAGA complex serves as a coactivator in transcription and catalyzes acetylation and deubiquitylation. Analyses of datasets in the Cancer Dependency Map Project revealed many SAGA components are selective dependencies in MM. To define SAGA-specific functions, we focused on ADA2B, the only subunit in the lysine acetyltransferase (KAT) module that specifically functions in SAGA. Integration of RNA-seq, ATAC-seq, and CUT&RUN results identified pathways directly regulated by ADA2B include MTORC1 signaling, MYC, E2F, and MM-specific MAF oncogenic programs. We discovered that ADA2B is recruited to MAF and MYC gene targets, and that MAF shares a majority of its targets with MYC in MM cells. Furthermore, we found the SANT domain of ADA2B is required for interaction with both GCN5 and PCAF acetyltransferases, incorporation into SAGA, and ADA2B protein stability. Our findings uncover previously unknown SAGA KAT module-dependent mechanisms controlling MM cell growth, revealing a vulnerability that might be exploited for future development of MM therapy.
PubMed: 38585845
DOI: 10.1101/2024.03.26.586811 -
BioRxiv : the Preprint Server For... Mar 2024Human adaptive immunity is orchestrated by effector and regulatory T (Treg) cells. Natural Tregs arise in the thymus where they are shaped to recognize self-antigens,...
Human adaptive immunity is orchestrated by effector and regulatory T (Treg) cells. Natural Tregs arise in the thymus where they are shaped to recognize self-antigens, while type 1 Tregs or Tr1 cells are induced from conventional peripheral CD4 T cells in response to peripheral antigens, such as alloantigens and allergens. Tr1 cells have been developed as a potential therapy for inducing antigen-specific tolerance, because they can be rapidly differentiated in response to a target antigen. However, the epigenetic landscape and the identity of transcription factors (TFs) that regulate differentiation, phenotype, and functions of human antigen-specific Tr1 cells is largely unknown, hindering Tr1 research and broader clinical development. Here, we reveal the unique epigenetic signature of antigen-specific Tr1 cells, and TFs that regulate their differentiation, phenotype and function. We showed that induced antigen-specific Tr1 cells are distinct both clonally and transcriptionally from natural Tregs and other conventional CD4 T cells on a single-cell level. An integrative analysis of Tr1 cell epigenome and transcriptome identified a TF signature unique to antigen-specific Tr1 cells, and predicted that IRF4, BATF, and MAF act as their transcriptional regulators. Using functional genomics, we showed that each of these TFs play a non-redundant role in regulating Tr1 cell differentiation, suppressive function, and expression of co-inhibitory and cytotoxic proteins. By using the Tr1-specific TF signature as a molecular fingerprint, we tracked Tr1 cells in peripheral blood of recipients of allogeneic hematopoietic stem cell transplantation treated with adoptive Tr1 cell therapy. Furthermore, the same signature identified Tr1 cells in resident CD4 T cells in solid tumors. Altogether, these results reveal the epigenetic signature and the key transcriptional regulators of human Tr1 cells. These data will guide mechanistic studies of human Tr1 cell biology and the development and optimization of adoptive Tr1 cell therapies.
PubMed: 38559096
DOI: 10.1101/2024.03.07.582969 -
The Chinese Journal of Dental Research Mar 2024To explore the genetic background and clinical phenotypes of multiple idiopathic cervical root resorption (MICRR) in a Chinese family.
OBJECTIVE
To explore the genetic background and clinical phenotypes of multiple idiopathic cervical root resorption (MICRR) in a Chinese family.
METHODS
The proband and his three family members were clinically examined and had radiographs taken with a radiovisiography (RVG) system and CBCT to define the diagnosis of MICRR. Genomic DNA (gDNA) was extracted from peripheral blood samples of the patient, his father, mother and younger sister for whole exome sequencing (WES). The pathogenicity of rare variants with minor allele frequency (MAF) less than 0.005 were analysed following possible inheritance patterns, predicted results from 12 software programs, the American College of Medical Genetics (ACMG) 2015 criteria, and information from ClinVar, OMIM and HGMD databases as well as gene function.
RESULTS
The proband presented the typical MICRR phenotypes such as thin cervical pulp wall and apple core-like lesions in radiographs. Following the recessive inheritance pattern, WES analysis identified SHROOM2, SYTL5, MAGED1 and FLNA with a higher chance of causing MICRR. Four genes with compound heterozygous variants and another 27 genes with de novo variants either in autosomal-dominant or autosomal-recessive pattern were also found to have the potential pathogenicity.
CONCLUSION
A total of 35 novel potential pathogenic genes were found to be associated with MICRR from a Chinese family through WES. The new genetic background of MICRR may be helpful for clinical and molecular diagnosis.
Topics: Female; Humans; Carrier Proteins; Genes, Regulator; Membrane Proteins; Root Resorption; Tooth Resorption; Male; East Asian People
PubMed: 38546524
DOI: 10.3290/j.cjdr.b5128703 -
MedRxiv : the Preprint Server For... Mar 2024To evaluate whether there is an enrichment of rare variants in familial hemophagocytic lymphohistiocytosis (HLH) genes and systemic juvenile idiopathic arthritis (sJIA)...
OBJECTIVE
To evaluate whether there is an enrichment of rare variants in familial hemophagocytic lymphohistiocytosis (HLH) genes and systemic juvenile idiopathic arthritis (sJIA) with or without macrophage activation syndrome (MAS).
METHODS
Targeted sequencing of HLH genes (, , , , , ) was performed in sJIA subjects from an established cohort. Sequence data from control subjects were obtained (dbGaP:phs000280.v8.p2). Rare variant association testing (RVT) was performed with sequence kernel association test (SKAT) package. Significance was defined as p<0.05 after 100,000 permutations.
RESULTS
Sequencing data from 524 sJIA cases were jointly called and harmonized with exome-derived target data from 3000 controls. Quality control operations produced a set of 481 cases and 2924 ancestrally-matched control subjects. RVT of sJIA cases and controls revealed a significant association with rare protein-altering variants (minor allele frequency [MAF]<0.01) of (p=0.020), and ultra-rare variants (MAF<0.001) of (p=0.007) and (p=0.045). A subanalysis of 32 cases with known MAS and 90 without revealed significant association of rare variants (p=0.0047). Additionally, sJIA patients more often carried ≥2 HLH variants than did controls (p=0.007), driven largely by digenic combinations involving .
CONCLUSION
We identified an enrichment of rare HLH variants in sJIA patients compared with healthy controls, driven by and . Biallelic variation in HLH genes was associated with sJIA, driven by . Only displayed enrichment in patients with MAS. This suggests that HLH variants may contribute to the pathophysiology of sJIA, even without MAS.
PubMed: 38529491
DOI: 10.1101/2024.03.13.24304215 -
Cellular and Molecular Life Sciences :... Mar 2024Monocyte-derived macrophages play a key pathogenic role in inflammatory diseases. In the case of rheumatoid arthritis (RA), the presence of specific synovial...
Monocyte-derived macrophages play a key pathogenic role in inflammatory diseases. In the case of rheumatoid arthritis (RA), the presence of specific synovial tissue-infiltrating macrophage subsets is associated with either active disease or inflammation resolution. JAK inhibitors (JAKi) are the first targeted synthetic disease-modifying antirheumatic drugs (tsDMARD) approved for treatment of RA with comparable efficacy to biologics. However, the effects of JAKi on macrophage specification and differentiation are currently unknown. We have analyzed the transcriptional and functional effects of JAKi on human peripheral blood monocyte subsets from RA patients and on the differentiation of monocyte-derived macrophages promoted by granulocyte-macrophage colony-stimulating factor (GM-CSF), a factor that drives the development and pathogenesis of RA. We now report that JAKi Upadacitinib restores the balance of peripheral blood monocyte subsets in RA patients and skewed macrophages towards the acquisition of an anti-inflammatory transcriptional and functional profile in a dose-dependent manner. Upadacitinib-treated macrophages showed a strong positive enrichment of the genes that define synovial macrophages associated to homeostasis/inflammation resolution. Specifically, Upadacitinib-treated macrophages exhibited significantly elevated expression of MAFB and MAFB-regulated genes, elevated inhibitory phosphorylation of GSK3β, and higher phagocytic activity and showed an anti-inflammatory cytokine profile upon activation by pathogenic stimuli. These outcomes were also shared by macrophages exposed to other JAKi (baricitinib, tofacitinib), but not in the presence of the TYK2 inhibitor deucravacitinib. As a whole, our results indicate that JAKi promote macrophage re-programming towards the acquisition of a more anti-inflammatory/pro-resolution profile, an effect that correlates with the ability of JAKi to enhance MAFB expression.
Topics: Humans; Janus Kinase Inhibitors; Macrophages; Arthritis, Rheumatoid; Inflammation; Anti-Inflammatory Agents; MafB Transcription Factor
PubMed: 38528207
DOI: 10.1007/s00018-024-05196-1 -
Cell Reports Apr 2024Transcription factor MAFB regulates various homeostatic functions of macrophages. This study explores the role of MAFB in brown adipose tissue (BAT) thermogenesis using...
Transcription factor MAFB regulates various homeostatic functions of macrophages. This study explores the role of MAFB in brown adipose tissue (BAT) thermogenesis using macrophage-specific Mafb-deficient (Mafb::LysM-Cre) mice. We find that Mafb deficiency in macrophages reduces thermogenesis, energy expenditure, and sympathetic neuron (SN) density in BAT under cold conditions. This phenotype features a proinflammatory environment that is characterized by macrophage/granulocyte accumulation, increases in interleukin-6 (IL-6) production, and IL-6 trans-signaling, which lead to decreases in nerve growth factor (NGF) expression and reduction in SN density in BAT. We confirm MAFB regulation of IL-6 expression using luciferase readout driven by IL-6 promoter in RAW-264.7 macrophage cell lines. Immunohistochemistry shows clustered organization of NGF-producing cells in BAT, which are primarily TRPV1 vascular smooth muscle cells, as additionally shown using single-cell RNA sequencing and RT-qPCR of the stromal vascular fraction. Treating Mafb::LysM-Cre mice with anti-IL-6 receptor antibody rescues SN density, body temperature, and energy expenditure.
Topics: Animals; MafB Transcription Factor; Adipose Tissue, Brown; Mice; Macrophages; Cold Temperature; Neurons; Thermogenesis; Interleukin-6; RAW 264.7 Cells; Nerve Growth Factor; Energy Metabolism; Male; Mice, Inbred C57BL
PubMed: 38522069
DOI: 10.1016/j.celrep.2024.113978