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Psychiatry Research Aug 2024Given that anxiety disorders (AD) are associated with reduced vagally-mediated heart rate variability (HRV), genetic variants related to HRV may provide insight into...
Given that anxiety disorders (AD) are associated with reduced vagally-mediated heart rate variability (HRV), genetic variants related to HRV may provide insight into anxiety etiology. This study used polygenic risk scores (PRS) to explore the genetic overlap between AD and HRV, and investigated whether HRV-related polymorphisms influence anxiety risk. Resting vagally-mediated HRV was measured using a wearable device in 188 European individuals (AD=101, healthy controls=87). AD PRS was tested for association with resting HRV, and HRV PRS for association with AD. We also investigated 15 significant hits from an HRV genome-wide association study (GWAS) for association with resting HRV and AD and if this association is mediated through resting HRV. The AD PRS and HRV PRS showed nominally significant associations with resting HRV and anxiety disorders, respectively. HRV GWAS variants associated with resting HRV were rs12980262 (NDUFA11), rs2680344 (HCN4), rs4262 and rs180238 (GNG11), and rs10842383 (LINC00477). Mediation analyses revealed that NDUFA11 rs12980262 A-carriers and GNG11 rs180238 and rs4262 C-carriers had higher anxiety risk through lower HRV. This study supports an anxiety-HRV genetic relationship, with HRV-related genetic variants translating to AD. This study encourages exploration of HRV genetics to understand mechanisms and identify novel treatment targets for anxiety.
Topics: Humans; Male; Female; Adult; Anxiety Disorders; Heart Rate; Multifactorial Inheritance; Genome-Wide Association Study; Polymorphism, Single Nucleotide; Middle Aged; Young Adult; Biomarkers; Genetic Predisposition to Disease
PubMed: 38850888
DOI: 10.1016/j.psychres.2024.115982 -
Archivum Immunologiae Et Therapiae... Jan 2024The aim of the present study was to determine the associations between the genetic variability and the expression and the risk of development of post-transplant...
The aim of the present study was to determine the associations between the genetic variability and the expression and the risk of development of post-transplant complications after allogeneic hematopoietic stem cell transplantation (HSCT). HSCT recipients and their donors were genotyped for two polymorphisms (rs1065075, rs3828903). Moreover, the expression of a soluble form of MICB was determined in the recipients' serum samples after transplantation using the Luminex assay. Our results revealed a favorable role of the rs1065075 allele. Recipients with donors carrying this genetic variant were less prone to developing chronic graft-versus-host disease (cGvHD) when compared to recipients without any symptoms of this disease (41.41% 65.38%, = 0.046). Moreover, the rs1065075 allele was associated with a lower incidence of cytomegalovirus (CMV) reactivation, both as a donor ( = 0.015) and as a recipient allele ( = 0.039). The rs1065075 variant was also found to be associated with decreased serum soluble MICB (sMICB) levels, whereas serum sMICB levels were significantly higher in recipients diagnosed with CMV infection ( = 0.0386) and cGvHD ( = 0.0008) compared to recipients without those complications. A protective role of the allele was also observed for the rs3828903 polymorphism, as it was more frequently detected among donors of recipients without cGvHD (89.90% 69.23%; = 0.013). genetic variants, as well as serum levels of sMICB, may serve as prognostic factors for the risk of developing cGvHD and CMV infection after allogeneic HSCT.
Topics: Humans; Graft vs Host Disease; Cytomegalovirus Infections; Hematopoietic Stem Cell Transplantation; Male; Female; Transplantation, Homologous; Adult; Middle Aged; Genetic Predisposition to Disease; Chronic Disease; Minor Histocompatibility Antigens; Histocompatibility Antigens Class I; Polymorphism, Single Nucleotide; Alleles; Genotype; Young Adult; Cytomegalovirus; Adolescent; Risk; Risk Factors
PubMed: 38847554
DOI: 10.2478/aite-2024-0012 -
Cancer Drug Resistance (Alhambra,... 2024Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell non-Hodgkin lymphoma (NHL). Despite the availability of clinical and molecular algorithms applied for...
Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell non-Hodgkin lymphoma (NHL). Despite the availability of clinical and molecular algorithms applied for the prediction of prognosis, in up to 30%-40% of patients, intrinsic or acquired drug resistance occurs. Constitutional genetics may help to predict R-CHOP resistance. This study aimed to validate previously identified single nucleotide polymorphisms (SNPs) in the literature as potential predictors of R-CHOP resistance in DLBCL patients, SNPs. Twenty SNPs, involved in R-CHOP pharmacokinetics/pharmacodynamics or other pathobiological processes, were investigated in 185 stage I-IV DLBCL patients included in a multi-institution pharmacogenetic study to validate their previously identified correlations with resistance to R-CHOP. Correlations between rs2010963 ( gene) and sex ( = 0.046), and rs1625895 ( gene) and stage ( = 0.003) were shown. After multivariate analyses, a concordant effect (i.e., increased risk of disease progression and death) was observed for rs1883112 ( gene) and rs1800871 ( gene). When patients were grouped according to the revised International Prognostic Index (R-IPI), both these SNPs further discriminated progression-free survival (PFS) and overall survival (OS) of the R-IPI-1-2 subgroup. Overall, patients harboring the rare allele showed shorter PFS and OS compared with wild-type patients. Two out of the 20 study SNPs were validated. Thus, these results support the role of previously identified rs1883112 and rs1800871 in predicting DLBCL resistance to R-CHOP and highlight their ability to further discriminate the prognosis of R-IPI-1-2 patients. These data point to the need to also focus on host genetics for a more comprehensive assessment of DLBCL patient outcomes in future prospective trials.
PubMed: 38835350
DOI: 10.20517/cdr.2024.10 -
Therapie May 2024The French National Health Data System (SNDS) comprises healthcare data that cover 99% of the population (over 67 million individuals) in France. The aim of this study...
AIM OF THE STUDY
The French National Health Data System (SNDS) comprises healthcare data that cover 99% of the population (over 67 million individuals) in France. The aim of this study was to present an overview of published pharmacoepidemiological studies using the SNDS in its maturation phase.
METHODS
We conducted a systematic literature review of original research articles in the Pubmed and EMBASE databases from January 2012 until August 2018.
RESULTS
A total of 316 full-text articles were included, with an annual increase over the study period. Only 16 records were excluded after screening because they did not involve the SNDS but other French healthcare databases. The study design was clearly reported in only 66% of studies of which 57% were retrospective cohorts and 22% cross-sectional studies. The reported study objectives were drug utilization (65%), safety (22%) and effectiveness (9%). Almost all ATC groups were studied but the most frequent ones concerned the nervous system in 149 studies (49%), cardiovascular system drugs in 104 studies (34%) and anti-infectives for systemic use in 50 studies (16%).
CONCLUSION
The SNDS is of growing interest for studies on drug use and safety, which could be conducted more in specific populations, including children, pregnant women and the elderly, as these populations are often not included in clinical trials.
PubMed: 38834394
DOI: 10.1016/j.therap.2024.05.003 -
Pharmacological Research Jul 2024About 80 % of brain disorders have a genetic basis. The pathogenesis of most neurodegenerative diseases is associated with a myriad of genetic defects, epigenetic... (Review)
Review
About 80 % of brain disorders have a genetic basis. The pathogenesis of most neurodegenerative diseases is associated with a myriad of genetic defects, epigenetic alterations (DNA methylation, histone/chromatin remodeling, miRNA dysregulation), and environmental factors. The emergence of new sequencing technologies and tools to study the epigenome has led to identifying predictive biomarkers for earlier diagnosis, opening up the possibility of prophylactical interventions. As a result, advances in pharmacogenetics and pharmacoepigenomics now allow for personalized treatments based on the profile of each patient and the specific genetic and epigenetic mechanisms involved. This Review highlights the complexity of neurodegenerative diseases and the variability in patient responses to pharmacotherapy, emphasizing the influence of genetic polymorphisms on the pharmacokinetics and pharmacodynamics of drugs used to treat those conditions. We specifically discuss the potential modulatory effect of several genetic polymorphisms associated with an increased risk of developing different neurodegenerative diseases. We explore genetic and genomic technologies and the potential of analyzing individual-specific drug metabolism to predict and influence drug response and associated clinical outcomes. We also provide insights into the mechanism of action of the drugs under investigation and their potential impact on disease-modifying pathways. Finally, the Review underscores the great potential of this field to enhance the effectiveness and safety of drug treatments through personalized medicine.
Topics: Humans; Precision Medicine; Neurodegenerative Diseases; Pharmacogenetics; Epigenesis, Genetic; Animals; Epigenomics
PubMed: 38834164
DOI: 10.1016/j.phrs.2024.107247 -
Zhongguo Ying Yong Sheng Li Xue Za Zhi... Dec 2023In the United States, cancer is one of the major causes of death. In 2010 alone, over 1.5 million fresh instances were recorded and over 0.5 billion died. After the... (Review)
Review
In the United States, cancer is one of the major causes of death. In 2010 alone, over 1.5 million fresh instances were recorded and over 0.5 billion died. After the completion of human genome sequence, significant progress in characterizing human epigenomes, proteomes and metabolomes has been made; a stronger knowledge of pharmacogenomics has been established and the capacity for individual personalization of health care has grown considerably. Personalized medicine has recently been primarily used to systematically select or optimize the prevention and therapeutic care of the patient through genetic or other data about the particular patient. Molecular profiling in healthy samples and cancer patients can allow for more personalized medications than is currently available. Patient protein, genetic and metabolic information may be used for adapting medical attention to the needs of that individual. The development of complementary diagnostics is a key attribute of this medicinal model. Molecular tests measuring the level of proteins, genes or specific mutations are used to provide a specific treatment for a particular individual by stratify the status of a disease, selecting the right drugs and tailoring dosages to the particular needs of the patient. These methods are also available for assessing risk factors for a patient for a number of conditions and for tailoring individual preventive therapies. Recent advances of personalized cancer medicine, challenges and futures perspectives are discussed.
Topics: Precision Medicine; Humans; Neoplasms; Rare Diseases; Pharmacogenetics
PubMed: 38830754
DOI: 10.62958/j.cjap.2023.008 -
Circulation Jun 2024
Topics: Humans; Cardiomyopathy, Hypertrophic; Pharmacogenetics; Aminobutyrates; Benzylamines; Uracil; Urea
PubMed: 38829931
DOI: 10.1161/CIRCULATIONAHA.123.066916 -
The Pharmacogenomics Journal Jun 2024The aim was to determine if opioid neuroimmunopharmacology pathway gene polymorphisms alter serum morphine, morphine-3-glucuronide and morphine-6-glucuronide...
The aim was to determine if opioid neuroimmunopharmacology pathway gene polymorphisms alter serum morphine, morphine-3-glucuronide and morphine-6-glucuronide concentration-response relationships in 506 cancer patients receiving controlled-release oral morphine. Morphine-3-glucuronide concentrations (standardised to 11 h post-dose) were higher in patients without pain control (median (interquartile range) 1.2 (0.7-2.3) versus 1.0 (0.5-1.9) μM, P = 0.006), whereas morphine concentrations were higher in patients with cognitive dysfunction (40 (20-81) versus 29 (14-60) nM, P = 0.02). TLR2 rs3804100 variant carriers had reduced odds (adjusted odds ratio (95% confidence interval) 0.42 (0.22-0.82), P = 0.01) of opioid adverse events. IL2 rs2069762 G/G (0.20 (0.06-0.52)), BDNF rs6265 A/A (0.15 (0.02-0.63)) and IL6R rs8192284 carrier (0.55 (0.34-0.90)) genotypes had decreased, and IL6 rs10499563 C/C increased (3.3 (1.2-9.3)), odds of sickness response (P ≤ 0.02). The study has limitations in heterogeneity in doses, sampling times and diagnoses but still suggests that pharmacokinetics and immune genetics co-contribute to morphine pain control and adverse effects in cancer patients.
Topics: Humans; Morphine; Male; Female; Cancer Pain; Middle Aged; Analgesics, Opioid; Delayed-Action Preparations; Aged; Pharmacogenetics; Polymorphism, Single Nucleotide; Morphine Derivatives; Adult; Pharmacogenomic Variants; Toll-Like Receptor 2
PubMed: 38824169
DOI: 10.1038/s41397-024-00339-w -
The Journal of International Medical... May 2024Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) is currently used in clinical microbiology laboratories. This study aimed to...
OBJECTIVE
Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) is currently used in clinical microbiology laboratories. This study aimed to determine whether dual-polarity time-of-flight mass spectrometry (DP-TOF MS) could be applied to clinical nucleotide detection.
METHODS
This prospective study included 40 healthy individuals and 110 patients diagnosed with cardiovascular diseases. We used DP-TOF MS and Sanger sequencing to evaluate 17 loci across 11 genes associated with cardiovascular drug responses. In addition, we used DP-TOF MS to test 998 retrospectively collected clinical DNA samples with known results.
RESULTS
A, T, and G nucleotide detection by DP-TOF MS and Sanger sequencing revealed 100% concordance, whereas the C nucleotide concordance was 99.86%. Genotyping based on the results of the two methods showed 99.96% concordance. Regarding clinical applications, DP-TOF MS yielded a 99.91% concordance rate for known loci. The minimum detection limit for DNA was 0.4 ng; the inter-assay and intra-assay precision rates were both 100%. Anti-interference analysis showed that aerosol contamination greater than 10 copies/µL in the laboratory environment could influence the results of DP-TOF MS.
CONCLUSIONS
The DP-TOF MS platform displayed good detection performance, as demonstrated by its 99.96% concordance rate with Sanger sequencing. Thus, it may be applied to clinical nucleotide detection.
Topics: Humans; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Female; Male; Prospective Studies; Cardiovascular Diseases; Middle Aged; Adult; Aged; Sequence Analysis, DNA; DNA; Retrospective Studies; Case-Control Studies; Polymorphism, Single Nucleotide
PubMed: 38819085
DOI: 10.1177/03000605241255568 -
Clinical and Translational Science Jun 2024Pharmacogenetic (PGx)-informed medication prescription is a cutting-edge genomic application in contemporary medicine, offering the potential to overcome the... (Review)
Review
Pharmacogenetic (PGx)-informed medication prescription is a cutting-edge genomic application in contemporary medicine, offering the potential to overcome the conventional "trial-and-error" approach in drug prescription. The ability to use an individual's genetic profile to predict drug responses allows for personalized drug and dosage selection, thereby enhancing the safety and efficacy of treatments. However, despite significant scientific and clinical advancements in PGx, its integration into routine healthcare practices remains limited. To address this gap, the Qatar Genome Program (QGP) has embarked on an ambitious initiative known as QPGx-CARES (Qatar Pharmacogenetics Clinical Applications and Research Enhancement Strategies), which aims to set a roadmap for optimizing PGx research and clinical implementation on a national scale. The goal of QPGx-CARES initiative is to integrate PGx testing into clinical settings with the aim of improving patient health outcomes. In 2022, QGP initiated several implementation projects in various clinical settings. These projects aimed to evaluate the clinical utility of PGx testing, gather valuable insights into the effective dissemination of PGx data to healthcare professionals and patients, and identify the gaps and the challenges for wider adoption. QPGx-CARES strategy aimed to integrate evidence-based PGx findings into clinical practice, focusing on implementing PGx testing for cardiovascular medications, supported by robust scientific evidence. The current initiative sets a precedent for the nationwide implementation of precision medicine across diverse clinical domains.
Topics: Humans; Qatar; Pharmacogenetics; Precision Medicine; Pharmacogenomic Testing
PubMed: 38818903
DOI: 10.1111/cts.13800