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International Journal of... Apr 2024Pharmacogenetic research has led to significant progress in understanding how genetic factors influence drug response in tuberculosis (TB) treatment. One ongoing...
BACKGROUND
Pharmacogenetic research has led to significant progress in understanding how genetic factors influence drug response in tuberculosis (TB) treatment. One ongoing challenge is the variable occurrence of adverse drug reactions in some TB patients. Previous studies have indicated that genetic variations in the N-acetyltransferase 2 (NAT2) and solute carrier organic anion transporter family member 1B1 (SLCO1B1) genes can impact the blood concentrations of the first-line anti-TB drugs isoniazid (INH) and rifampicin (RIF), respectively. This study aimed to investigate the influence of pharmacogenetic markers in the NAT2 and SLCO1B1 genes on TB treatment outcomes using whole-exome sequencing (WES) analysis.
METHODS
DNA samples were collected from 30 healthy Iranian adults aged 18-40 years. The allelic frequencies of single-nucleotide polymorphisms (SNPs) in the NAT2 and SLCO1B1 genes were determined through WES.
RESULTS
Seven frequent SNPs were identified in the NAT2 gene (rs1041983, rs1801280, rs1799929, rs1799930, rs1208, rs1799931, rs2552), along with 16 frequent SNPs in the SLCO1B1 gene (rs2306283, rs11045818, rs11045819, rs4149056, rs4149057, rs2291075, rs201722521, rs11045852, rs11045854, rs756393362, rs11045859, rs74064211, rs201556175, rs34671512, rs71581985, rs4149085).
CONCLUSION
Genetic variations in NAT2 and SLCO1B1 can affect the metabolism of INH and RIF, respectively. A better understanding of the pharmacogenetic profile in the study population may facilitate the design of more personalized and effective TB treatment strategies. Further research is needed to directly correlate these genetic markers with clinical outcomes in TB patients.
Topics: Humans; Arylamine N-Acetyltransferase; Liver-Specific Organic Anion Transporter 1; Adult; Antitubercular Agents; Male; Young Adult; Mycobacterium tuberculosis; Polymorphism, Single Nucleotide; Rifampin; Adolescent; Female; Isoniazid; Iran; Tuberculosis; Gene Frequency; Exome Sequencing; Pharmacogenomic Testing; Pharmacogenetics
PubMed: 38916393
DOI: 10.4103/ijmy.ijmy_106_24 -
Reumatismo Jun 2024To evaluate the association of the rs11125908 polymorphism in the COMMD1 gene in the Cuban population with rheumatoid arthritis (RA).
OBJECTIVE
To evaluate the association of the rs11125908 polymorphism in the COMMD1 gene in the Cuban population with rheumatoid arthritis (RA).
METHODS
In this case-control study, 161 RA patients and 150 control subjects were genotyped for rs11125908 by the allele-specific polymerase chain reaction method. DNA sequencing was used to verify the assignation of the polymorphism. The odds ratios (OR) and their 95% confidence interval were calculated by logistic regression to determine the associations between genotypes and RA using the SNPStats software.
RESULTS
An association of the single nucleotide polymorphism with the disease was found in the overdominant model (p=0.025; OR=1.91) for the AG genotype. Our analyses revealed an association between rs11125908 and the subgroup of patients with swollen joints < median under the codominant model for AG (p=0.034; OR=2.30) and GG genotype (p=0.034; OR=0.82) and with the overdominant model (p=0.01; OR=2.38). The subgroup of patients with an age of onset lower than the mean and AG genotype showed an association in the overdominant model (p=0.027; OR=2.27). Disease activity score 28 with erythrocyte sedimentation rate and disease duration variables were not associated with the rs11125908 polymorphism.
CONCLUSIONS
rs11125908 was associated with RA and with the number of swollen joints and age of onset subgroup analyses. We provide concepts for treatments for RA, based on pharmacological management of COMMD1 expression.
Topics: Humans; Arthritis, Rheumatoid; Polymorphism, Single Nucleotide; Male; Female; Case-Control Studies; Middle Aged; Cuba; Adult; Adaptor Proteins, Signal Transducing; Genotype; Genetic Predisposition to Disease; Aged
PubMed: 38916163
DOI: 10.4081/reumatismo.2024.1691 -
The World Journal of Biological... Jun 2024For psychotic disorders (i.e. schizophrenia), pharmacotherapy plays a key role in controlling acute and long-term symptoms. To find the optimal individual dose and... (Review)
Review
BACKGROUND
For psychotic disorders (i.e. schizophrenia), pharmacotherapy plays a key role in controlling acute and long-term symptoms. To find the optimal individual dose and dosage strategy, specialized tools are used. Three tools have been proven useful to personalize drug treatments: therapeutic drug monitoring (TDM) of drug levels, pharmacogenetic testing (PG), and molecular neuroimaging.
METHODS
In these Guidelines, we provide an in-depth review of pharmacokinetics, pharmacodynamics, and pharmacogenetics for 50 antipsychotics. Over 30 international experts in psychiatry selected studies that have measured drug concentrations in the blood (TDM), gene polymorphisms of enzymes involved in drug metabolism, or receptor/transporter occupancies in the brain (positron emission tomography (PET)).
RESULTS
Study results strongly support the use of TDM and the cytochrome P450 (CYP) genotyping and/or phenotyping to guide drug therapies. Evidence-based target ranges are available for titrating drug doses that are often supported by PET findings.
CONCLUSION
All three tools discussed in these Guidelines are essential for drug treatment. TDM goes well beyond typical indications such as unclear compliance and polypharmacy. Despite its enormous potential to optimize treatment effects, minimize side effects and ultimately reduce the global burden of diseases, personalized drug treatment has not yet become the standard of care in psychiatry.
PubMed: 38913780
DOI: 10.1080/15622975.2024.2366235 -
Clinical Toxicology (Philadelphia, Pa.) Jun 2024Although valproic acid is generally well tolerated, hepatotoxicity is a common side effect in patients receiving long-term treatment. However, the mechanisms underlying...
INTRODUCTION
Although valproic acid is generally well tolerated, hepatotoxicity is a common side effect in patients receiving long-term treatment. However, the mechanisms underlying valproic acid-associated hepatotoxicity remain elusive.
METHODS
To investigate the mechanisms and explore the potential risk factors for valproic acid-associated hepatotoxicity, 165 age-matched pediatric patients were recruited for laboratory tests and glutamate-glutamine cycle analysis.
RESULTS
The concentration of glutamate in patients with hepatotoxicity was significantly greater than that in control patients, while the concentration of glutamine in patients with hepatotoxicity was significantly lower than that in control patients ( ˂ 0.05). In addition, the frequencies of the heterozygous with one mutant allele and homozygous with two mutant alleles genotypes in were significantly higher in the hepatotoxicity group than those in the control group (47.1 percent versus 32.5 percent, = 0.010; 17.6 percent versus 5.2 percent, = 0.001, respectively). Moreover, heterozygous carriers with one mutant allele and homozygous carriers with two mutant alleles genotypes of exhibited significant differences in the concentrations of glutamine and glutamate concentrations ( ˂ 0.001 and = 0.001, respectively) and liver function indicators (activities of aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transferase, ˂ 0.001, respectively). Furthermore, logistic regression analysis indicated that ( = 0.002, odds ratio: 3.027, 95 percent confidence interval, 1.521 - 6.023) and glutamate ( = 0.001, odds ratio: 2.235, 95 percent confidence interval, 1.369 - 3.146) were associated with a greater risk for hepatotoxicity, while glutamine concentrations were negatively associated with hepatotoxicity ( = 0.001, odds ratio: 0.711, 95 percent confidence interval, 0.629 - 0.804).
DISCUSSION
Understanding pharmacogenomic risks for valproic acid induced hepatotoxicity might help direct patient specific care. Limitations of our study include the exclusive use of children from one location and concomitant medication use in many patients.
CONCLUSION
Perturbation of the glutamate-glutamine cycle is associated with valproic acid-associated hepatotoxicity. Moreover, , glutamate and glutamine concentrations are potential risk factors for valproic acid-associated hepatotoxicity.
PubMed: 38913595
DOI: 10.1080/15563650.2024.2366920 -
American Journal of Health-system... Jun 2024In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been...
In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time.
PubMed: 38912618
DOI: 10.1093/ajhp/zxae171 -
Journal of Cancer 2024In this study, we aimed to elucidate the role of mitochondrial calcium uptake 1/2 (MiCU1/2) in breast cancer (BRCA) by employing a comprehensive multi-omics approach....
In this study, we aimed to elucidate the role of mitochondrial calcium uptake 1/2 (MiCU1/2) in breast cancer (BRCA) by employing a comprehensive multi-omics approach. Unlike previous research, we utilized a novel web application tailored for whole tumor tissue, single-cell, and spatial transcriptomics analysis to investigate the association between MiCU1/2 and the tumor immune microenvironment (TIME). Our gene set enrichment analysis (GSEA) provided insights into the primary biological effects of MiCU1/2, while our CRISPR-based drug screening repository identified potential effective drugs. Our study revealed that high MiCU1/2 expression serves as an independent diagnostic biomarker, correlating with advanced clinical status and indicating poorer recurrence-free survival (RFS) rates in BRCA patients. Additionally, spatial transcriptome analysis highlighted the heightened expression of MiCU1/2 in tumors and its relevance in surrounding immune cells. Furthermore, using the CIBERSORT algorithm, we discovered a positive correlation between MiCU1/2 levels and macrophage infiltration, underscoring their potential impact on immune infiltration. We also identified expression patterns of immune-related genes associated with responses against various immune cell types, including CXCL, MIF, GDF, SPP1, and IL16. Finally, our pharmacogenomic screening identified potential small molecule drugs capable of effectively targeting breast cancer cells with elevated MiCU1/2 expression. Overall, our study establishes MiCU1/2 as a promising novel biomarker for BRCA diagnosis and prognostic prediction, as well as a potential therapeutic target, highlighting the importance of exploring these pathways to advance patient care and outcomes in BRCA treatment.
PubMed: 38911376
DOI: 10.7150/jca.95979 -
Journal of Cancer 2024As we delve into the intricate world of mitochondrial inner membrane proteins, particularly Optic Atrophy types 1 and 3 (OPA1/3), we uncover their pivotal role in...
As we delve into the intricate world of mitochondrial inner membrane proteins, particularly Optic Atrophy types 1 and 3 (OPA1/3), we uncover their pivotal role in maintaining mitochondrial dynamic equilibrium and fusion, crucial for cellular energy production and synthesis. Despite extensive scrutiny, the significance of OPA1/3 in breast cancer (BRCA) and its interplay with the immune microenvironment remain elusive. We meticulously sourced BRCA data from renowned repositories such as The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Gene Expression Omnibus (GEO), and the Human Protein Atlas (HPA), leveraging cutting-edge techniques including single-cell RNA-sequencing (scRNA-seq), spatial transcriptomics, and pharmacogenomics. Through multifaceted data analysis, we endeavored to unravel the intricate role and potential value of OPA1/3 in BRCA tumorigenesis and progression. Our investigation reveals a conspicuous upregulation of OPA1/3 expression in BRCA, correlating with dismal prognoses. Kaplan-Meier plot analysis underscores that heightened OPA1/3 levels are associated with poor survival rates. Both clinical specimens and biobank biopsies corroborate the elevated expression of OPA1/3 in breast cancer patients. Moreover, scRNA-seq unveils a strong correlation between OPA1/3 and macrophage infiltration in the BRCA immune milieu, alongside its association with the cellular communication network involving CXCL, TGFb, VEGF, and IL16. In light of these findings, OPA1/3 emerges as a promising contender for therapeutic targeting and as a potential diagnostic, prognostic, and survival biomarker in BRCA. The implications of our study underscore the pressing need to explore these novel biomarkers to enhance patient outcomes.
PubMed: 38911373
DOI: 10.7150/jca.96100 -
Frontiers in Pharmacology 2024
PubMed: 38910892
DOI: 10.3389/fphar.2024.1439276 -
Biological Trace Element Research Jun 2024Humans are exposed to various chemical elements that have been associated with the development and progression of diseases such as coronary artery disease (CAD). Unlike...
Humans are exposed to various chemical elements that have been associated with the development and progression of diseases such as coronary artery disease (CAD). Unlike previous research, we employed a multi-element approach to investigate CAD patients and those with comorbid conditions such as diabetes (CAD-DM2), high blood pressure (CAD-HBP), or high blood lipids (CAD-HBL). Plasma concentrations of 21 elements, including lithium (Li), boron (B), aluminum (Al), calcium (Ca), titanium (Ti), vanadium (V), chromium (Cr), manganese (Mn), iron (Fe), cobalt (Co), nickel (Ni), copper (Cu), zinc (Zn), arsenic (As), selenium (Se), strontium (Sr), cadmium (Cd), tin (Sn), stibium (Sb), barium (Ba), and lead (Pb), were measured in CAD patients (n = 201) and healthy subjects (n = 110) using inductively coupled plasma-mass spectrometry (ICP-MS). Principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) models were utilized to analyze the ionomic profiles. Spearman correlation analysis was employed to identify the interaction patterns among individual elements. We found that levels of Ba, Li, Ni, Zn and Pb were elevated in the CAD group compared to the healthy group, while Sb, Ca, Cu, Ti, Fe, and Se were lower. Furthermore, the CAD-DM2 group exhibited higher levels of Ni and Cd, while the CAD-HBP group showed lower levels of Co and Mn. In the CAD-HBL group, Ti was increased, whereas Ba, Cr, Cu, Co, Mn, and Ni were reduced. In conclusion, ionomic profiles can be utilized to differentiate CAD patients from healthy individuals, potentially providing insights for future treatment or dietary interventions.
PubMed: 38910164
DOI: 10.1007/s12011-024-04227-z -
European Neuropsychopharmacology : the... Jun 2024
PubMed: 38909437
DOI: 10.1016/j.euroneuro.2024.05.003