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CNS & Neurological Disorders Drug... Jun 2024The association between carbamazepine (CBZ) metabolism and resistance in epilepsy and the genetic polymorphisms of CYP3A5 (rs776746 and rs15524) and CYP3A4 (rs2242480,...
BACKGROUND AND OBJECTIVE
The association between carbamazepine (CBZ) metabolism and resistance in epilepsy and the genetic polymorphisms of CYP3A5 (rs776746 and rs15524) and CYP3A4 (rs2242480, rs2740574, rs35599367, rs12721627, and rs28371759) has been the subject of previous investigations with controversial results. We conducted a systematic review to assess the potential link between these polymorphisms and CBZ metabolism and resistance.
METHODS
Identifying relevant studies, was carried out bay searching PubMed, Scopus, PharmGKB, EPIGAD, and PHARMAADME databases up until June 2023. The studies included in our analysis investigated the connection between CYP3A5 (rs776746 and rs15524) and CYP3A4 (rs2242480, rs2740574, rs35599367, rs12721627, and rs28371759) polymorphisms and CBZ metabolism and resistance.
RESULTS
This review included a total of 23 studies and more than 2177 epilepsy patients. As a result the CYP3A4 (rs12721627 and rs28371759) polymorphisms are associated with reduced catalytic activity, where the CYP3A4 (rs2740574) polymorphism is linked to lower levels of CBZ-diol and decreased activity. It's been found also that the CYP3A5 (rs776746) polymorphism influences the dose-adjusted plasma levels of CBZ.
CONCLUSION
Although these findings highlight the impact of genetic variations in the CYP3A4 and CYP3A5 genes on CBZ pharmacokinetics and pharmacodynamics, further studies across diverse populations are essential to enhance personalized epilepsy therapy in clinical settings.
PubMed: 38859787
DOI: 10.2174/0118715273298953240529100325 -
Clinical Pharmacology and Therapeutics Jun 2024In this study, we investigated the combined influence of pregnancy and genetic polymorphisms on efavirenz pharmacokinetics in cervicovaginal fluid (CVF) of women...
In this study, we investigated the combined influence of pregnancy and genetic polymorphisms on efavirenz pharmacokinetics in cervicovaginal fluid (CVF) of women receiving antiretroviral therapy. Women receiving efavirenz-containing antiretroviral therapy were recruited from two hospitals in Nigeria during 2017-2020. Sparse CVF and plasma samples were obtained during pregnancy to assess the possible association between drug concentration and CYP2B6 polymorphisms (stage I). Participants were stratified into three CYP2B6 516G>T (rs3745274) genotype groups and re-enrolled for intensive pharmacokinetic sampling (stage II). Overall, 159 women (142 pregnant and 12 postpartum) contributed samples in stage I (88 CVF, 81 plasma and 73 paired). CYP2B6 516G>T (rs3745274) remained independently associated with log efavirenz CVF concentration during pregnancy after adjusting for plasma concentration, with β (Log efavirenz concentration, 95%CI) of 0.204 (0.027, 0.382), P = 0.025). Median (IQR) efavirenz C in CVF during pregnancy (n = 12) vs. postpartum (n = 12) was 243 ng/mL (168-402) vs. 447 ng/mL (159-974), C was 1,031 ng/mL (595-1,771) vs. 1,618 ng/mL (675-2,695), and AUC was 16,465 ng.h/mL (9,356-30,417) vs. 30,715 ng.h/mL (10,980-43,714). CVF-to-plasma AUC ratio was 0.36 during pregnancy and 0.46 postpartum. Upon stratification, efavirenz clearance during pregnancy was 57.9% higher than postpartum in patients with the CYP2B6 516GT genotype; the AUC and C were 33.8% and 8.6% lower, respectively. Efavirenz C in CVF exceeded the protein binding-adjusted IC (PBIC) of 126 ng/mL during pregnancy and postpartum. Efavirenz is well distributed into the CVF; both pregnancy and CYP2B6 polymorphisms affect the extent of exposure.
PubMed: 38859656
DOI: 10.1002/cpt.3343 -
Reviews in the Neurosciences Jun 2024Migraine is a multidimensional disease affecting a large portion of the human population presenting with a variety of symptoms. In the era of personalized medicine,... (Review)
Review
Migraine is a multidimensional disease affecting a large portion of the human population presenting with a variety of symptoms. In the era of personalized medicine, successful migraine treatment presents a challenge, as several studies have shown the impact of a patient's genetic profile on therapy response. However, with the emergence of contemporary treatment options, there is promise for improved outcomes. A literature search was conducted in PubMed and Scopus, in order to obtain studies investigating the impact of genetic factors on migraine therapy outcome. Overall, 23 studies were included in the current review, exhibiting diversity in the treatments used and the genetic variants investigated. Divergent genes were assessed for each category of migraine treatment. Several genetic factors were identified to contribute to the heterogeneous response to treatment. SNPs related to pharmacodynamic receptors, pharmacogenetics and migraine susceptibility loci were the most investigated variants, revealing some interesting significant results. To date, various associations have been recorded correlating the impact of genetic factors on migraine treatment responses. More extensive research needs to take place with the aim of shedding light on the labyrinthine effects of genetic variations on migraine treatment, and, consequently, these findings can promptly affect migraine treatment and improve migraine patients' life quality in the vision of precise medicine.
PubMed: 38856190
DOI: 10.1515/revneuro-2024-0045 -
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 -
Gene Jun 2024To investigate the allelic and genotypic frequencies of the two genetic variations, NC_000006.12: g.160275887C > T (rs662301) and NC_000006.12:g.160231826 T > C...
PURPOSE
To investigate the allelic and genotypic frequencies of the two genetic variations, NC_000006.12: g.160275887C > T (rs662301) and NC_000006.12:g.160231826 T > C (rs315978), in the SLC22A2 gene among the Saudi population. The primary goal is to elucidate potential associations with these genetic variations and the response to metformin therapy over 6 months to enhance our knowledge of the genetic basis of Type 2 Diabetes Mellitus (T2DM) and its clinical management in the Saudi population.
MATERIALS/METHODS
76 newly diagnosed T2DM patients, aged 30 to 60, of both sexes and Saudi origin, were treated with metformin monotherapy. Blood samples were collected before and after 6 months of therapy,80 healthy individuals were included as controls. Genomic DNA was extracted. Genotyping of the SLC22A2 genetic variations was performed using TaqMan® SNP Genotyping Assays. Binary logistic regression was utilized to evaluate how certain clinical parameters influence T2DM concerning the presence of SLC22A2 gene variants.
RESULTS
Among these patients, 73.3 % were responders, and 26.7 % were non-responders. For these variants, no statistically significant differences in genotype or allele frequencies were observed between responders and non-responders (p = 0.375 and p = 0.384 for rs662301; p = 0.473 and p = 0.481 for rs315978, respectively). For the SLC22A2 variant rs662301, the C/C genotype was significantly associated with increased T2DM risk with age and elevated HbA1c levels. Similarly, rs315978 revealed higher T2DM susceptibility and HbA1c elevation in C/C genotype carriers, specifically with advancing age compared to individuals with C/T and T/T genotypes.
CONCLUSION
The study offers insights into the genetic landscape of T2DM in Saudi Arabia. Despite the absence of significant associations with treatment response, the study suggests potential age-specific associations, this highlights the complexity of the disease. This research underscores the necessity for expanded research, considering diverse populations and genetic factors, to develop personalized treatment approaches. This study serves as a foundation for future investigations into the Saudi population, recognizing the need for a larger sample size.
PubMed: 38852696
DOI: 10.1016/j.gene.2024.148648 -
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 -
Clinica Chimica Acta; International... Jun 2024Determination of DPYD and UGT1A1 polymorphisms prior to 5-fluorouracil and irinotecan therapy is crucial for avoiding severe adverse drug effects. Hence, there is a...
BACKGROUND
Determination of DPYD and UGT1A1 polymorphisms prior to 5-fluorouracil and irinotecan therapy is crucial for avoiding severe adverse drug effects. Hence, there is a pressing need for accurate and reliable genotyping methods for the most common DPYD and UGT1A1 polymorphisms. In this study, we introduce a novel polymerase chain reaction (PCR) melting curve analysis method for discriminating DPYD c.1236G > A, c.1679 T > G, c.2846A > T, IVS14 + 1G > A and UGT1A1*1, *28, *6 (G71R) genotypes.
METHODS
Following protocol optimization, this technique was employed to genotype 28 patients, recruited between March 2023 and October 2023, at the First Affiliated Hospital of Xiamen University. These patients included 20 with UGT1A1 *1/*1, 8 with UGT1A1 *1/*28, 4 with UGT1A1 *28/*28, 22 with UGT1A1*6 G/G, 6 with UGT1A1*6 G/A, 4 with UGT1A1*6 A/A, 27 with DPYD(c.1236) G/G, 3 with DPYD(c.1236) G/A, 2 with DPYD(c.1236) A/A, 27 with DPYD(c.1679) T/T, 2 with DPYD(c.1679) T/G, 3 with DPYD(c.1679) G/G, 28 with DPYD(c.2846A/T) A/A, 2 with DPYD(c.2846A/T) A/T, 2 with DPYD(c.2846A/T) T/T, 28 with DPYD(c.IVS14 + 1) G/G, 2 with DPYD(c.IVS14 + 1) G/G, and 2 with DPYD(c.IVS14 + 1) G/G, as well as 3 plasmid standards. Method accuracy was assessed by comparing results with those from Sanger sequencing or Multiplex quantitative PCR(qPCR). Intra- and inter-run precision of melting temperatures (Tms) were calculated to evaluate reliability, and sensitivity was assessed through limit of detection examination.
RESULTS
The new method accurately identified all genotypes and exhibited higher accuracy than Multiplex qPCR. Intra- and inter-run coefficients of variation for Tms were both ≤1.97 %, with standard deviations ≤0.95 °C. The limit of detection was 0.09 ng/μL of input genomic DNA.
CONCLUSION
Our developed PCR melting curve analysis offers accurate, reliable, rapid, simple, and cost-effective detection of DPYD and UGT1A1 polymorphisms. Its application can be easily extended to clinical laboratories equipped with a fluorescent PCR platform.
PubMed: 38848897
DOI: 10.1016/j.cca.2024.119761 -
Naunyn-Schmiedeberg's Archives of... Jun 2024Cancer remains a global health challenge, prompting a search for effective treatments with fewer side effects. Thymol, a natural monoterpenoid phenol derived primarily... (Review)
Review
Cancer remains a global health challenge, prompting a search for effective treatments with fewer side effects. Thymol, a natural monoterpenoid phenol derived primarily from thyme (Thymus vulgaris) and other plants in the Lamiaceae family, is known for its diverse biological activities. It emerges as a promising candidate in cancer prevention and therapy. This study aims to consolidate current research on thymol's anticancer effects, elucidating its mechanisms and potential to enhance standard chemotherapy, and to identify gaps for future research. A comprehensive review was conducted using databases like PubMed/MedLine, Google Scholar, and ScienceDirect, focusing on studies from the last 6 years. All cancer types were included, assessing thymol's impact in both cell-based (in vitro) and animal (in vivo) studies. Thymol has been shown to induce programmed cell death (apoptosis), halt the cell division cycle (cell cycle arrest), and inhibit cancer spread (metastasis) through modulation of critical signaling pathways, including phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), extracellular signal-regulated kinase (ERK), mechanistic target of rapamycin (mTOR), and Wnt/β-catenin. It also enhances the efficacy of 5-fluorouracil (5-FU) in colorectal cancer treatments. Thymol's broad-spectrum anticancer activities and non-toxic profile to normal cells underscore its potential as an adjunct in cancer therapy. Further clinical trials are essential to fully understand its therapeutic benefits and integration into existing treatment protocols.
PubMed: 38847831
DOI: 10.1007/s00210-024-03196-3