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Food Science & Nutrition Jun 2024Metabolic Syndrome (MetS) is a constellation of risk factors including abdominal obesity, high triglycerides, low HDL cholesterol (HDL-C), elevated blood pressure, and...
Metabolic Syndrome (MetS) is a constellation of risk factors including abdominal obesity, high triglycerides, low HDL cholesterol (HDL-C), elevated blood pressure, and elevated fasting glucose. In Spain, according to WHO criteria, the MetS prevalence is shown to be 32% in men and 29% in women. The role of dietary habits is one of the main therapeutic strategies for the management of MetS but the most effective dietary pattern has not been established yet. This study aimed to analyze the effect of on body composition, serum lipids, and MetS components of a high-MUFA and high-fiber diet (HMFD). A case-control study was performed considering 40 cohabiting women. Participants were randomly assigned to HMFD group or high mono-unsaturated diet (HMD) group to receive one of the two proposed dietary interventions. All data (serum lipids, blood pressure, height, weight, body composition, and waist circumference) were collected fasting at baseline, 55, 98, and 132 days. The HMFD group showed higher decrease in waist circumference than in the HMD group. LDL-C dropped in both groups. Triglycerides in the HMFD group dropped during the intervention, but once the intervention was over, they returned to baseline values. The mean systolic blood pressure was lower in HMFD group. A HMFD from a weekly consumption of processed meat (Torrezno de Soria) deeply fried in extra virgin olive oil in combination with vegetables logged in a Mediterranean diet can improve MetS risk factors in healthy overweight women.
PubMed: 38873480
DOI: 10.1002/fsn3.4042 -
Saudi Pharmaceutical Journal : SPJ :... Jul 2024Hecogenin (HEC) is a steroidal saponin found in many plant species and serves as a precursor for steroidal drugs. The diuretic effects of HEC and its derivative,...
Hecogenin (HEC) is a steroidal saponin found in many plant species and serves as a precursor for steroidal drugs. The diuretic effects of HEC and its derivative, hecogenin acetate (HA), remain largely unexplored. The present study aimed to explore the potential diuretic effects of HEC and HA compared to furosemide (FUR) and spironolactone (SPIR). Additionally, the study aimed to explore the underlying mechanism particularly focusing on aldosterone synthase gene expression. Fifty-four Sprague-Dawley rats were allocated into nine groups (Group 1-9). Group 1 (control) received the vehicle, Groups 2 received FUR 10 mg/kg, Group 3, 4, and 5 were given HEC, while Groups 6, 7 and 8 received HA i.p at doses of 5, 10, and 25 mg/kg, respectively. Group 9 received SPIR i.p at the dose of 25 mg/kg. Urine volume, diuretic index and diuretic activity were monitored at 1, 2, 3, 4, 5, 6, and 24 h post-administration. Treatment was given daily for seven days. After that, rats were sacrificed and blood was collected for serum electrolytes determination. Adrenal glands were dissected out for gene expression studies. The results revealed that HEC and HA at the administered doses significantly and dose-dependently increased urine and electrolyte excretion. These results were primarily observed at 25 mg/kg of each compound. Gene expression studies demonstrated a dose-dependent reduction in aldosterone synthase gene expression, suggesting aldosterone synthesis inhibition as a potential mechanism for their diuretic activity. Notably, HA exhibited more pronounced diuretic effects surpassing those of HEC. This enhanced diuretic activity of HA can be attributed to its stronger impact on aldosterone synthase inhibition. These findings offer valuable insights into the diuretic effects of both HEC and HA along with their underlying molecular mechanisms.
PubMed: 38873334
DOI: 10.1016/j.jsps.2024.102105 -
Translational Psychiatry Jun 2024Excessive and persistent aggressiveness is the most common behavioral problem that leads to psychiatric referrals among children. While half of the variance in childhood...
Excessive and persistent aggressiveness is the most common behavioral problem that leads to psychiatric referrals among children. While half of the variance in childhood aggression is attributed to genetic factors, the biological mechanism and the interplay between genes and environment that results in aggression remains elusive. The purpose of this systematic review is to provide an overview of studies examining the genetics of childhood aggression irrespective of psychiatric diagnosis. PubMed, PsycINFO, and MEDLINE databases were searched using predefined search terms for aggression, genes and the specific age group. From the 652 initially yielded studies, eighty-seven studies were systematically extracted for full-text review and for further quality assessment analyses. Findings show that (i) investigation of candidate genes, especially of MAOA (17 studies), DRD4 (13 studies), and COMT (12 studies) continue to dominate the field, although studies using other research designs and methods including genome-wide association and epigenetic studies are increasing, (ii) the published articles tend to be moderate in sizes, with variable methods of assessing aggressive behavior and inconsistent categorizations of tandem repeat variants, resulting in inconclusive findings of genetic main effects, gene-gene, and gene-environment interactions, (iii) the majority of studies are conducted on European, male-only or male-female mixed, participants. To our knowledge, this is the first study to systematically review the effects of genes on youth aggression. To understand the genetic underpinnings of childhood aggression, more research is required with larger, more diverse sample sets, consistent and reliable assessments and standardized definition of the aggression phenotypes. The search for the biological mechanisms underlying child aggression will also benefit from more varied research methods, including epigenetic studies, transcriptomic studies, gene system and genome-wide studies, longitudinal studies that track changes in risk/ameliorating factors and aggression-related outcomes, and studies examining causal mechanisms.
Topics: Child; Female; Humans; Male; Aggression; Catechol O-Methyltransferase; Gene-Environment Interaction; Genome-Wide Association Study; Monoamine Oxidase; Receptors, Dopamine D4
PubMed: 38862490
DOI: 10.1038/s41398-024-02870-7 -
Clinical and Translational Science Jun 2024Specific selective serotonin reuptake inhibitors (SSRIs) metabolism is strongly influenced by two pharmacogenes, CYP2D6 and CYP2C19. However, the effectiveness of... (Randomized Controlled Trial)
Randomized Controlled Trial
Specific selective serotonin reuptake inhibitors (SSRIs) metabolism is strongly influenced by two pharmacogenes, CYP2D6 and CYP2C19. However, the effectiveness of prospectively using pharmacogenetic variants to select or dose SSRIs for depression is uncertain in routine clinical practice. The objective of this prospective, multicenter, pragmatic randomized controlled trial is to determine the effectiveness of genotype-guided selection and dosing of antidepressants on control of depression in participants who are 8 years or older with ≥3 months of depressive symptoms who require new or revised therapy. Those randomized to the intervention arm undergo pharmacogenetic testing at baseline and receive a pharmacy consult and/or automated clinical decision support intervention based on an actionable phenotype, while those randomized to the control arm have pharmacogenetic testing at the end of 6-months. In both groups, depression and drug tolerability outcomes are assessed at baseline, 1 month, 3 months (primary), and 6 months. The primary end point is defined by change in Patient-Reported Outcomes Measurement Information System (PROMIS) Depression score assessed at 3 months versus baseline. Secondary end points include change inpatient health questionnaire (PHQ-8) measure of depression severity, remission rates defined by PROMIS score < 16, medication adherence, and medication side effects. The primary analysis will compare the PROMIS score difference between trial arms among those with an actionable CYP2D6 or CYP2C19 genetic result or a CYP2D6 drug-drug interaction. The trial has completed accrual of 1461 participants, of which 562 were found to have an actionable phenotype to date, and follow-up will be complete in April of 2024.
Topics: Humans; Cytochrome P-450 CYP2D6; Selective Serotonin Reuptake Inhibitors; Pharmacogenomic Testing; Cytochrome P-450 CYP2C19; Depression; Prospective Studies; Female; Male; Pharmacogenomic Variants; Adult; Pragmatic Clinical Trials as Topic; Antidepressive Agents
PubMed: 38860639
DOI: 10.1111/cts.13822 -
Translational Andrology and Urology May 2024The association between psoriasis and erectile dysfunction (ED) is currently inconsistent in epidemiological and observational studies and the causal relationship...
BACKGROUND
The association between psoriasis and erectile dysfunction (ED) is currently inconsistent in epidemiological and observational studies and the causal relationship between them has not been established. The aim of our study is to explore the potential genetic association between ED and psoriasis.
METHODS
We explored the putative causality between psoriasis and ED by bidirectional Mendelian randomization (MR). The single nucleotide polymorphisms (SNPs) associated with psoriasis were retrieved from a large-scale public genome-wide association study (GWAS). The summary statistics of ED were obtained from individuals of European ancestry with 6,175 cases 217,630 controls. Inverse-variant weighted (IVW), weighted median (WM), MR-Egger, MR-Steiger, and MR pleiotropy residual sum and outlier (MR-PRESSO) test were employed in MR analyses to investigate the bidirectional causal relationship between psoriasis and ED. Several sensitivity analyses were employed to confirm the findings of the MR analysis.
RESULTS
Our MR analysis indicated that genetically predicted psoriasis showed no association with a higher risk of ED [odds ratio (OR) 2.878, 95% confidence interval (CI): 0.175-47.289, P=0.46]. As for the other direction, no causal association was disclosed between ED and psoriasis (OR 0.999, 95% CI: 0.997-1.002, P=0.62). These findings remained consistent in sensitivity analyses.
CONCLUSIONS
The study revealed a negative genetic association between psoriasis and ED. Certain acquired factors may contribute to a strong clinical connection between the two, highlighting the need for comprehensive management of these risk factors.
PubMed: 38855583
DOI: 10.21037/tau-24-10 -
Clinical and Translational Science Jun 2024Computational methods analyze genomic data to identify genetic variants linked to drug responses, thereby guiding personalized medicine. This study analyzed 942...
Computational methods analyze genomic data to identify genetic variants linked to drug responses, thereby guiding personalized medicine. This study analyzed 942 whole-genome sequences from the Electricity Generating Authority of Thailand (EGAT) cohort to establish a population-specific pharmacogenomic database (TPGxD-1) in the Thai population. Sentieon (version 201808.08) implemented the GATK best workflow practice for variant calling. We then annotated variant call format (VCF) files using Golden Helix VarSeq 2.5.0 and employed Stargazer v2.0.2 for star allele analysis. The analysis of 63 very important pharmacogenes (VIPGx) reveals 85,566 variants, including 13,532 novel discoveries. Notably, we identified 464 known PGx variants and 275 clinically relevant novel variants. The phenotypic prediction of 15 VIPGx demonstrated a varied metabolic profile for the Thai population. Genes like CYP2C9 (9%), CYP3A5 (45.2%), CYP2B6 (9.4%), NUDT15 (15%), CYP2D6 (47%) and CYP2C19 (43%) showed a high number of intermediate metabolizers; CYP3A5 (41%), and CYP2C19 (9.9%) showed more poor metabolizers. CYP1A2 (52.7%) and CYP2B6 (7.6%) were found to have a higher number of ultra-metabolizers. The functional prediction of the remaining 10 VIPGx genes reveals a high frequency of decreased functional alleles in SULT1A1 (12%), NAT2 (84%), and G6PD (12%). SLCO1B1 reports 20% poor functional alleles, while PTGIS (42%), SLCO1B1 (4%), and TPMT (5.96%) showed increased functional alleles. This study discovered new variants and alleles in the 63 VIPGx genes among the Thai population, offering insights into advancing clinical pharmacogenomics (PGx). However, further validation is needed using other computational and genotyping methods.
Topics: Humans; Thailand; Whole Genome Sequencing; Phenotype; Pharmacogenetics; Databases, Genetic; Pharmacogenomic Variants; Male; Female; Alleles; Southeast Asian People
PubMed: 38853370
DOI: 10.1111/cts.13830 -
Farmacia Hospitalaria : Organo Oficial... Jun 2024Pharmacogenetics evaluates how genetic variations influence drug responses. Nowadays, genetic tests have advanced, becoming more affordable, and its integration is... (Review)
Review
INTRODUCTION
Pharmacogenetics evaluates how genetic variations influence drug responses. Nowadays, genetic tests have advanced, becoming more affordable, and its integration is supported by stronger clinical evidence. Guidelines such as those from CPIC (Clinical Pharmacogenetics Implementation Consortium) and resources like PharmGKB facilitate genotype-based prescribing; and organizations like the FDA promote genetic testing before initiating certain medications. Preventive pharmacogenetic panels seem promising, but further research on biomarkers and diverse populations is needed. The aim of this review is to analyze recent evidence on the genotype-drug response relationship to examine how the genetic profile of patients influences the clinical response to treatments, and analyze the areas of research that need further study to advance towards a genetic-based precision medicine.
MATERIALS AND METHODS
A systematic search was conducted on PubMed to identify articles investigating the genotype-drug response relationship. The search strategy included terms such as "pharmacogenetics", "personalized treatment", "precision medicine", "dose adjustment", "individualized dosing", "clinical routine" and "clinical practice." Clinical trials, observational studies, and meta-analyses published in English or Spanish between 2013 and 2023 were included. The initial search resulted in a total of 136 articles for analysis.
RESULTS
49 articles were included for the final analysis following review by two investigators. A relationship between genetic polymorphisms and drug response or toxicity was found for drugs such as opioids, GLP-1 agonists, tacrolimus, oral anticoagulants, antineoplastics, atypical antipsychotics, efavirenz, clopidogrel, lamotrigine, anti-TNF-α agents, voriconazole, antidepressants, or statins. However, for drugs like metformin, quetiapine, irinotecan, bisoprolol, and anti-VEGF agents, no statistically significant association between genotype and response was found.
CONCLUSION
The studies analyzed in this review suggest a strong correlation between genetic variability and individual drug responses, supporting the use of pharmacogenetics for treatment optimization. However, for certain drugs like metformin or quetiapine, the influence of genotype on their response remains unclear. More studies with larger sample sizes, greater ethnic diversity, and consideration of non-genetic factors are needed. The lack of standardization in analysis methods and accessibility to genetic testing are significant challenges in this field. As a conclusion, pharmacogenetics shows immense potential in personalized medicine, but further research is required.
PubMed: 38851909
DOI: 10.1016/j.farma.2024.03.010 -
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