Front Pharmacol. 2023 Nov 15;14:1290785. doi: 10.3389/fphar.2023.1290785. eCollection 2023.

ABSTRACT

Introduction: Bleeding is one of the most undesirable complications of direct oral anticoagulants (DOACs). While the ryanodine receptor (RYR2) has been related to cardiac diseases, research on bleeding complications is lacking. This study aimed to elucidate the association between RYR2 and bleeding risk to develop the risk scoring system in patients treated with DOACs. Methods: This study was a retrospective analysis of prospectively collected samples. We selected ten SNPs within the RYR2 gene, and two models were constructed (Model I: demographic factors only, Model II: demographic and genetic factors) in multivariable analysis. Independent risk factors for bleeding were used to develop a risk scoring system. Results: A total of 447 patients were included, and 49 experienced either major bleeding or clinically relevant non-major bleeding. In Model I, patients using rivaroxaban and experiencing anemia exhibited an increased bleeding risk after adjusting for covariates. Upon incorporating genetic factors into Model I, a significant association with bleeding was also observed in cases of overdosing on DOACs and in patients with a creatinine clearance (CrCl) < 30 mL/min, in addition to rivaroxaban and anemia (Model II). Among genetic factors, RYR2 rs12594 GG, rs17682073 AA, rs3766871 GG, and rs6678625 T alleles were associated with bleeding complications. The area under the receiver operating characteristic curve (AUROC) of Model I was 0.670, whereas that of Model II increased to 0.803, demonstrating better performance with the inclusion of genetic factors. Using the significant variables in Model II, a risk scoring system was constructed. The predicted bleeding risks for scores of 0, 1-2, 3-4, 5-6, 7-8, and 9-10 points were 0%, 1.2%, 4.6%, 15.7%, 41.7%, and 73.3%, respectively. Conclusion: This study revealed an association between RYR2 and bleeding complications among patients taking DOACs and established a risk scoring system to support individualized DOAC treatment for these patients.

PMID:38034995 | PMC:PMC10684747 | DOI:10.3389/fphar.2023.1290785

PLoS One. 2023 Nov 30;18(11):e0263710. doi: 10.1371/journal.pone.0263710. eCollection 2023.

ABSTRACT

α1C-tubulin (TUBA1C) is a member of the α-tubulin family and has served as a potential biomarker in a variety of cancers in many studies. In this study, the gene expression profile of TUBA1C in The Cancer Genome Atlas (TCGA) was extracted for analysis, and the prognostic value of TUBA1C in breast cancer was comprehensively evaluated. The Wilcoxon signed-rank test, Kruskal-Wallis test, and logistic regression analysis were performed to confirm the correlations between TUBA1C expression and the clinical characteristics of breast cancer patients. The effect of TUBA1C expression on the survival of breast cancer patients was assessed by Kaplan-Meier curve, Cox regression analysis, and the Kaplan-Meier plotter (an online database). The TCGA data set was used for the Gene Set Enrichment Analysis (GSEA). The results confirmed that high TUBA1C expression in breast cancer was closely correlated with survival time, survival status, and tumor size. In addition, elevated TUBA1C expression can predict poor overall survival (OS), recurrence-free survival (RFS), and distant metastasis-free survival (DMFS). Univariate and multivariate analyses (Cox regression analyses) confirmed that TUBA1C was an independent prognostic factor for the OS of breast cancer patients. The GSEA identified that the high TUBA1C expression phenotype was differentially enriched in cell cycle, basal transcription factor, P53 signaling pathway, pathways in cancer, TOLL-like receptor signaling pathway, and NOD-like receptor signaling pathway. In summary, high messenger RNA (mRNA) expression of TUBA1C is an independent risk factor for poor prognosis of breast cancer.

PMID:38032902 | DOI:10.1371/journal.pone.0263710

Expert Rev Neurother. 2023 Nov 30:1-16. doi: 10.1080/14737175.2023.2288107. Online ahead of print.

ABSTRACT

INTRODUCTION: There is a very wide spectrum of epilepsies and developmental and epileptic encephalopathies that affect children, from self-limited forms, not necessarily requiring treatment, to severe drug-resistant ones.

AREAS COVERED: In this perspective, the authors discuss the main factors to consider before drug prescription in children, considering the most recent clinical research, including age, seizure type, epilepsy syndrome, etiology, efficacy and safety profile, comorbidities, gender, available formulations, costs and drug coverage, and regulatory issues. The literature search was conducted through a PubMed search on antiseizure medications for patients aged 0-18, with respect to each of the aforementioned factors, and by checking the reference lists of relevant papers.

EXPERT OPINION: The most expanding field of research and innovation for clinical practice is precision medicine, which addresses the holistic treatment of genetic epilepsies and developmental and epileptic encephalopathies. It achieves this by addressing their detrimental effects on synapses, neurotransmission, and cellular signaling pathways with the double aim to treat seizures and to rescue neurodevelopmental trajectories, but also the issue of adverse events and drug resistance through pharmacogenomics.

PMID:38032395 | DOI:10.1080/14737175.2023.2288107

Br J Clin Pharmacol. 2023 Nov 29. doi: 10.1111/bcp.15978. Online ahead of print.

ABSTRACT

AIMS: We propose using glomerular filtration rate (GFR) as the physiological basis for distinguishing components of renal clearance.

METHODS: Gentamicin, amikacin and vancomycin are thought to be predominantly excreted by the kidneys. A mixed effects joint model of the pharmacokinetics of these drugs was developed, with a wide dispersion of weight, age, and serum creatinine. A dataset created from 18 sources resulted in 27,338 drug concentrations from 9,901 patients. Body size and composition, maturation and renal function were used to describe differences in drug clearance and volume of distribution.

RESULTS: This study demonstrates that GFR is a predictor of two distinct components of renal elimination clearance: (1) GFR clearance associated with normal GFR and (2) non-GFR clearance not associated with normal GFR. All three drugs had GFR clearance estimated as a drug specific percentage of normal GFR (gentamicin 39%, amikacin 90%, vancomycin 57%). The total clearance (sum of GFR and non-GFR clearance), standardized to 70 kg total body mass, 176 cm, male, renal function 1, was 5.58 L/h (95% CI 5.50-5.69) (gentamicin), 7.77 L/h (95 %CI 7.26-8.19) (amikacin) and 4.70 L/h (95 %CI 4.61-4.80) (vancomycin).

CONCLUSION: GFR provides a physiological basis for renal drug elimination. It has been used to distinguish two elimination components. This physiological approach has been applied to describe clearance and volume of distribution from premature neonates to elderly adults with a wide dispersion of size, body composition and renal function. Dose individualization has been implemented using target concentration intervention.

PMID:38031322 | DOI:10.1111/bcp.15978

Infect Agent Cancer. 2023 Nov 29;18(1):77. doi: 10.1186/s13027-023-00555-2.

ABSTRACT

It is commonly accepted that host genes show high methylation in cervical intraepithelial neoplasia 3 (CIN3) or worse (CIN3+). However, study quality varies, as does the clinical performance of markers in different populations. We aimed to validate candidate gene DNA methylation with standardized testing methods in the same batch of samples. We first compared the performance of 16 DNA methylation markers for detecting CIN3+ in the 82-sample training set, including 24 subjects with ≤ CIN1, 10 subjects with CIN2, 23 subjects with CIN3, and 25 subjects with cervical cancer (CC). Then five methylation markers were selected and subsequently validated among an independent set of 74 subjects, including 47 subjects with ≤ CIN1, 13 subjects with CIN2, 6 subjects with CIN3, and 8 subjects with CC. The results in the validation set revealed that methylation analysis of the SOX1 (SOX1m) showed a superior level of clinical performance (AUC = 0.879; sensitivity = 85.7%; specificity = 90.0%). SOX1m had better accuracy than cytology, with a reduced referral rate (23.0% vs. 31.4%) and a lower number of overtreatment (5 vs. 13) cases among high-risk human papillomavirus (hrHPV)-positive women. Importantly, among hrHPV-positive and SOX1m-negative women, only 1 CIN3 patient was at risk for follow-up after 1 year, whereas 1 CIN3 patient and 1 CC patient were at risk among hrHPV-positive and cytology-negative women. In this investigation, we screened 16 reported methylation markers to provide a basis for future studies related to potential precancerous lesion/cancer methylation markers in the Chinese population. The study also revealed that SOX1m has optimal CIN3+ detection performance, suggesting that it may be a promising biomarker for detecting CIN3+ in the Chinese population.

PMID:38031140 | DOI:10.1186/s13027-023-00555-2

Biochim Biophys Acta Mol Basis Dis. 2023 Nov 27:166971. doi: 10.1016/j.bbadis.2023.166971. Online ahead of print.

ABSTRACT

Thyroid cancer is one of the most common tumors of the endocrine system because of its rapid and steady increase in incidence and prevalence. In recent years, a growing number of studies have identified a key role for the gut, thyroid tissue and oral microbiota in the regulation of metabolism and the immune system. A growing body of evidence has conclusively demonstrated that the microbiota influences tumor formation, prevention, diagnosis, and treatment. We provide extensive information in which oral, gut, and thyroid microbiota have an effect on thyroid cancer development in this review. In addition, we thoroughly discuss the various microbiota species, their potential functions, and the underlying mechanisms for thyroid cancer. The microbiome offers a unique opportunity to improve the effectiveness of immunotherapy and radioiodine therapy thyroid cancer by maintaining the right type of microbiota, and holds great promise for improving clinical outcomes and quality of life for thyroid cancer patients.

PMID:38029942 | DOI:10.1016/j.bbadis.2023.166971

Front Pain Res (Lausanne). 2023 Nov 9;4:1279361. doi: 10.3389/fpain.2023.1279361. eCollection 2023.

ABSTRACT

Sickle cell disease (SCD) is a prevalent and complex inherited pain disorder that can manifest as acute vaso-occlusive crises (VOC) and/or chronic pain. Despite their known risks, opioids are often prescribed routinely and indiscriminately in managing SCD pain, because it is so often severe and debilitating. Integrative medicine strategies, particularly non-opioid therapies, hold promise in safe and effective management of SCD pain. However, the lack of evidence-based methods for managing SCD pain hinders the widespread implementation of non-opioid therapies. In this review, we acknowledge that implementing personalized pain treatment strategies in SCD, which is a guideline-recommended strategy, is currently fraught with limitations. The full implementation of pharmacological and biobehavioral pain approaches targeting mechanistic pain pathways faces challenges due to limited knowledge and limited financial and personnel support. We recommend personalized medicine, pharmacogenomics, and integrative medicine as aspirational strategies for improving pain care in SCD. As an organizing model that is a comprehensive framework for classifying pain subphenotypes and mechanisms in SCD, and for guiding selection of specific strategies, we present evidence updating pain research pioneer Richard Melzack's neuromatrix theory of pain. We advocate for using the updated neuromatrix model to subphenotype individuals with SCD, to better select personalized multimodal treatment strategies, and to identify research gaps fruitful for exploration. We present a fairly complete list of currently used pharmacologic and non-pharmacologic SCD pain therapies, classified by their mechanism of action and by their hypothesized targets in the updated neuromatrix model.

PMID:38028431 | PMC:PMC10666191 | DOI:10.3389/fpain.2023.1279361

Pain Rep. 2023 Oct 17;8(6):e1113. doi: 10.1097/PR9.0000000000001113. eCollection 2023 Dec.

ABSTRACT

INTRODUCTION: Individual genetic variation may influence clinical effects for pain medications. Effects of CYP2C9, CYP3A4, and CYP2D6 polymorphisms on clinical effectiveness and safety for ibuprofen and oxycodone were studied.

OBJECTIVE: Primary objectives were to AU2 evaluate if allelic variations would affect clinical effectiveness and adverse events (AEs) occurrence.

METHODS: This pragmatic prospective, observational cohort included children aged 4 to 16 years who were seen in a pediatric emergency department with an acute fracture and prescribed ibuprofen or oxycodone for at-home pain management. Saliva samples were obtained for genotyping of allelic variants, and daily telephone follow-up was conducted for 3 days. Pain was measured using the Faces Pain Scale-Revised.

RESULTS: We included 210 children (n = 140 ibuprofen and n = 70 oxycodone); mean age was 11.1 (±SD 3.5) years, 33.8% were female. Median pain reduction on day 1 was similar between groups [ibuprofen 4 (IQR 2,4) and oxycodone 4 (IQR 2,6), P = 0.69]. Over the 3 days, the oxycodone group experienced more AE than the ibuprofen group (78.3% vs 53.2%, P < 0.001). Those with a CYP2C9*2 reduced function allele experienced less adverse events with ibuprofen compared with those with a normal functioning allele CYP2C9*1 (P = 0.003). Neither CYP3A4 variants nor CYP2D6 phenotype classification affected clinical effect or AE.

CONCLUSION: Although pain relief was similar, children receiving oxycodone experienced more AE, overall, than those receiving ibuprofen. For children receiving ibuprofen or oxycodone, pain relief was not affected by genetic variations in CYP2C9 or CYP3A4/CYP2D6, respectively. For children receiving ibuprofen, the presence of CYP2C9*2 was associated with less adverse events.

PMID:38027465 | PMC:PMC10659733 | DOI:10.1097/PR9.0000000000001113

Front Pharmacol. 2023 Nov 9;14:1288068. doi: 10.3389/fphar.2023.1288068. eCollection 2023.

ABSTRACT

Drug-induced liver injury (DILI) is one of the serious adverse drug reactions (ADRs), which belongs to immune-mediated adverse drug reactions (IM-ADRs). As an essential health drug, albendazole has rarely been reported to cause serious liver damage. A young man in his 30 s developed severe jaundice, abnormal transaminases, and poor blood coagulation mechanism after taking albendazole, and eventually developed into severe liver failure. The patient was found heterozygous of HLA-B*15:02 and HLA-B*13:01 through HLA-targeted sequencing, which may have a pathogenic role in the disease. This case report summarizes his presentation, treatment, and prognosis. A useful summary of the diagnosis and associated genetic variant information is provided.

PMID:38027017 | PMC:PMC10670799 | DOI:10.3389/fphar.2023.1288068

Front Pharmacol. 2023 Nov 6;14:1222435. doi: 10.3389/fphar.2023.1222435. eCollection 2023.

ABSTRACT

Background: Osimertinib has shown greater efficacy than standard epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and fewer grade 3 or higher adverse drug reactions (ADRs) in patients with advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. However, the clinical outcomes of osimertinib treatment vary depending on the patient's ethnicity. Therefore, further research is necessary to evaluate the impact of single nucleotide polymorphisms (SNPs) in cytochrome P450 (CYP450) and drug transporters on the therapeutic outcomes and ADRs to osimertinib in Thai patients, to provide improved pharmacological treatments for cancer patients. Methods: This retrospective and prospective cohort study enrolled 63 Thai patients with NSCLC treated with 80 mg of osimertinib once daily as monotherapy. Seventeen SNPs in candidate genes related to drug metabolism and transport pathways were analyzed in each patient. Chi-square or Fisher's exact tests were used to evaluate the associations between SNPs and clinical outcomes, including ADR incidence and objective response rate (ORR). In addition, the correlation between the genotype and median time to treatment failure (TTF) or progression-free survival (PFS) was assessed using Kaplan-Meier analysis and a log-rank test. Results: We identified six SNPs (rs2231142 and rs2622604 in ABCG2, rs762551 in CYP1A2, rs1057910 in CYP2C9, rs28371759 in CYP3A4, and CYP2A6 deletion polymorphism (CYP2A6*4)) that significantly increased the incidence of ADRs. In addition, we found two SNPs (rs2069514 in CYP1A2 and rs1057910 in CYP2C9) that significantly decreased the median TTF, and two SNPs (rs28399433 in CYP2A6 and rs1057910 in CYP2C9) that significantly decreased the median progression-free survival (PFS). Specifically, we found that one of these SNPs (rs1057910 in CYP2C9) influenced ADRs, TTF, and PFS. Additionally, SNPs in the CYP2A6 heterozygous variant (non4/*4) significantly increased ADR incidence, leading to a high frequency of dose reduction (27.0%). Conclusion: Our study demonstrated significant SNPs associated with increased ADR incidence, decreased PFS, and decreased TTF in Thai patients with NSCLC treated with osimertinib. The CYP2C9 (*3) and CYP2A6 (*4) allele frequencies differed between ethnicities and were associated with an increased incidence of ADRs. These findings highlight the importance of considering genetic factors in NSCLC treatment and may facilitate personalized medicine approaches. Moreover, our study showed a higher incidence of ADRs than the previous trials, including FLAURA and AURA2, and a higher frequency of dose reduction than reported in the AURA 3 trial, possibly due to genetic differences among the study populations.

PMID:38026963 | PMC:PMC10657898 | DOI:10.3389/fphar.2023.1222435

Front Pharmacol. 2023 Oct 27;14:1307602. doi: 10.3389/fphar.2023.1307602. eCollection 2023.

NO ABSTRACT

PMID:38026952 | PMC:PMC10646187 | DOI:10.3389/fphar.2023.1307602

Front Pharmacol. 2023 Nov 13;14:1286764. doi: 10.3389/fphar.2023.1286764. eCollection 2023.

ABSTRACT

Pharmacogenomics (PGx) studies the impact of interindividual genomic variation on drug response, allowing the opportunity to tailor the dosing regimen for each patient. Current targeted PGx testing platforms are mainly based on microarray, polymerase chain reaction, or short-read sequencing. Despite demonstrating great value for the identification of single nucleotide variants (SNVs) and insertion/deletions (INDELs), these assays do not permit identification of large structural variants, nor do they allow unambiguous haplotype phasing for star-allele assignment. Here, we used Oxford Nanopore Technologies' adaptive sampling to enrich a panel of 1,036 genes with well-documented PGx relevance extracted from the Pharmacogenomics Knowledge Base (PharmGKB). By evaluating concordance with existing truth sets, we demonstrate accurate variant and star-allele calling for five Genome in a Bottle reference samples. We show that up to three samples can be multiplexed on one PromethION flow cell without a significant drop in variant calling performance, resulting in 99.35% and 99.84% recall and precision for the targeted variants, respectively. This work advances the use of nanopore sequencing in clinical PGx settings.

PMID:38026945 | PMC:PMC10679755 | DOI:10.3389/fphar.2023.1286764

Front Psychiatry. 2023 Nov 10;14:1307473. doi: 10.3389/fpsyt.2023.1307473. eCollection 2023.

ABSTRACT

Pharmacological therapy represents one of the essential approaches to treatment of Major Depressive Disorder (MDD). However, currently available antidepressant medications show high rates of first-level treatment non-response, and several attempts are often required to find an effective molecule for a specific patient in clinical practice. In this context, pharmacogenetic analyses could represent a valuable tool to identify appropriate pharmacological treatment quickly and more effectively. However, the usefulness and the practical effectiveness of pharmacogenetic testing currently remains an object of scientific debate. The present narrative and critical review focuses on exploring the available evidence supporting the usefulness of pharmacogenetic testing for the treatment of MDD in clinical practice, highlighting both the points of strength and the limitations of the available studies and of currently used tests. Future research directions and suggestions to improve the quality of available evidence, as well as consideration on the potential use of pharmacogenetic tests in everyday clinical practice are also presented.

PMID:38025425 | PMC:PMC10667493 | DOI:10.3389/fpsyt.2023.1307473

Innov Pharm. 2023 Oct 10;14(2). doi: 10.24926/iip.v14i2.5476. eCollection 2023.

ABSTRACT

Background There has been a trend in recent years toward individualized medicine. Pharmacogenomics (PGx) is the use of patient-specific genetic variations to guide medication selection and treatment. Objective: The primary objective was to characterize the population of referring department patients and identify the number of high-evidence, actionable phenotype (HEAP) genes in this referred population to help guide marketing efforts to the most applicable patient populations and departments. Practice description: Located in a destination, tertiary care clinic. Providers refer patients to a Pharmacogenomics (PGx) specialist for a comprehensive medication review using their pharmacogenomic results. Practice Innovation: The practice is innovative because it has been using PGx in the pharmacy and medical practices since 2016 and has been routinely developing and incorporating PGx best practice alerts (BPAs) into the electronic medical record (EMR) since 2020. Evaluation Methods Genetic results were analyzed from a 27-gene PGx panel test which tests for both pharmacokinetic and pharmacodynamic genes. High-Evidence Actionable Phenotypes (HEAP) are defined as phenotypes with guideline support that may suggest an action by healthcare provider. Low-Evidence Nonactionable Phenotypes (LENP) are defined as phenotypes that do not recommend action. Results There were 1,236 atypical phenotypes identified in the 154 patients referred. Of the atypical genes, 39.97% were HEAP and 60.03% were LENP. Of the HEAP's identified, the majority came from CYP2D6, VKORC1, and UGT1A1. At least 1 HEAP was found in 98.7% of patients (n=152). Conclusion There are a variety of High Evidence Actionable Phenotypes (HEAPs) with a high likelihood of at least one HEAP gene in every patient. These phenotypes can result in serious safety concerns when combined with a medication impacted by one of these HEAP genes. Thus, referral to a pharmacogenomics consultation service may lead to an overall decrease in morbidity and mortality with potential cost avoidance.

PMID:38025166 | PMC:PMC10653719 | DOI:10.24926/iip.v14i2.5476

EJHaem. 2023 Sep 27;4(4):1052-1058. doi: 10.1002/jha2.799. eCollection 2023 Nov.

ABSTRACT

Methotrexate is an essential drug in the treatment of childhood cancer that is not exempt from toxicities. Glucarpidase is a drug used to reduce the toxic concentration of plasma methotrexate in patients with delayed elimination or at risk of toxicity. We describe the characteristics of a cohort of pediatric patients that received glucarpidase and analyze its role in the treatment of toxicity induced by high doses of methotrexate (HDMTX). Retrospective observational study of all pediatric cancer patients who received glucarpidase between 2012 and 2022 at a single center. Fifteen patients were treated with a single dose of glucarpidase, eleven of them presented with acute lymphoblastic leukemia and received HDMTX at 5 g/m2 in 24-hour infusion. In eight patients, glucarpidase was administered during the first cycle of HDMTX. The indication in thirteen cases was acute renal failure with delayed elimination of plasma methotrexate. The median maximum creatinine was 1.22 mg/dl (0.68 2.01 mg/dl), with a median increase over its baseline level of 313%. All patients normalized renal function after glucarpidase administration, with a median methotrexate excretion time of 193 hours (42-312 hours). No grade ≥2 adverse events derived from carboxypeptidase administration. Eleven patients received new doses of HDMTX in subsequent cycles, without new episodes of serious toxicity. The use of glucarpidase is effective and safe in the treatment of acute renal failure and methotrexate elimination delay in pediatric cancer patients. Further HDMTX doses may be prescribed without additional toxicities.

PMID:38024601 | PMC:PMC10660123 | DOI:10.1002/jha2.799

Front Immunol. 2023 Oct 31;14:1210372. doi: 10.3389/fimmu.2023.1210372. eCollection 2023.

ABSTRACT

BACKGROUND: The optimal diagnosis and treatment of tuberculosis (TB) are challenging due to underdiagnosis and inadequate treatment monitoring. Lipid-related genes are crucial components of the host immune response in TB. However, their dynamic expression and potential usefulness for monitoring response to anti-TB treatment are unclear.

METHODOLOGY: In the present study, we used a targeted, knowledge-based approach to investigate the expression of lipid-related genes during anti-TB treatment and their potential use as biomarkers of treatment response.

RESULTS AND DISCUSSION: The expression levels of 10 genes (ARPC5, ACSL4, PLD4, LIPA, CHMP2B, RAB5A, GABARAPL2, PLA2G4A, MBOAT2, and MBOAT1) were significantly altered during standard anti-TB treatment. We evaluated the potential usefulness of this 10-lipid-gene signature for TB diagnosis and treatment monitoring in various clinical scenarios across multiple populations. We also compared this signature with other transcriptomic signatures. The 10-lipid-gene signature could distinguish patients with TB from those with latent tuberculosis infection and non-TB controls (area under the receiver operating characteristic curve > 0.7 for most cases); it could also be useful for monitoring response to anti-TB treatment. Although the performance of the new signature was not better than that of previous signatures (i.e., RISK6, Sambarey10, Long10), our results suggest the usefulness of metabolism-centric biomarkers.

CONCLUSIONS: Lipid-related genes play significant roles in TB pathophysiology and host immune responses. Furthermore, transcriptomic signatures related to the immune response and lipid-related gene may be useful for TB diagnosis and treatment monitoring.

PMID:38022579 | PMC:PMC10644770 | DOI:10.3389/fimmu.2023.1210372

Cureus. 2023 Oct 17;15(10):e47217. doi: 10.7759/cureus.47217. eCollection 2023 Oct.

ABSTRACT

Objective The aim of this study was to determine the genotypic distribution of luteinizing hormone/human chorionic gonadotropin receptor (LHCGR) N312S single-nucleotide polymorphism (SNP) and to investigate its impact on clinical and reproductive outcomes in infertile Indian women undergoing assisted reproductive technology (ART). Study design and settings This was a prospective cohort study conducted at a tertiary care university hospital. Subjects and methods Infertile women aged between 21 and 40 years undergoing ART with an antagonist protocol were enrolled in this study. A 2-ml sample of peripheral venous blood was collected from each woman and genotyped for the LHCGR N312S SNP. Participants were divided into three groups based on their SNP: NN, NS, and SS. All subjects underwent controlled ovarian hyperstimulation (COH) through a gonadotropin-releasing hormone (GnRH) antagonist protocol and intracytoplasmic sperm injection (ICSI). Of the 140 women recruited based on selection criteria, 128 underwent embryo transfer. We compared the genotypic distribution of the LHCGR N312S SNP, baseline characteristics, clinical outcomes, and reproductive outcomes in ART among the three groups. Data were analyzed using IBM SPSS Statistics for Windows, Version 29 (Released 2022; IBM Corp., Armonk, New York, United States). The chi-square test and Fisher-Irwin test were employed to evaluate significant differences among the qualitative categorical variables. A p-value of less than 0.05 was considered statistically significant. Results Among the test subjects, 19.3% were homozygous for the LHCGR N312 SNP (NN group), 38.6% were heterozygous (NS group), and 42.1% were homozygous for the LHCGR S312 SNP (SS group). Baseline characteristics were similar among the three groups. In terms of ovarian reserve tests, significantly lower anti-Müllerian hormone (AMH) levels were observed in the SS group compared to the NS and NN groups (2.8 ± 2.1 vs. 3.2 ± 2.5 vs. 4.3 ± 3.3; p=0.03). No significant differences were observed in COH outcomes such as duration of stimulation, total gonadotropin requirement, oocyte yield, or the number of good-quality embryos among the three groups. The cumulative pregnancy rate (82.9% vs. 50.0% vs. 38.2%, p=0.0005), cumulative clinical pregnancy rate (78.8% vs. 44.7% vs. 34.5%, p = 0.0005), and cumulative live birth rate (50.0% vs. 20.2% vs. 20.0%, p=0.005) were significantly higher in the NN group than in the NS and SS groups. Conclusion The study's findings suggest that LHCGR N312 may help predict reproductive outcomes in ART, which may aid in providing better counseling to infertile couples. We need more studies on individualized/personalized COH using pharmacogenomics for follicle-stimulating hormone (FSH) and luteinizing hormone (LH) supplementation based on combined FSH and LH receptor SNP and to assess their effects on ART outcomes.

PMID:38022167 | PMC:PMC10652146 | DOI:10.7759/cureus.47217

Front Med (Lausanne). 2023 Oct 31;10:1006743. doi: 10.3389/fmed.2023.1006743. eCollection 2023.

ABSTRACT

It is well known that common variants in specific genes influence drug metabolism and response, but it is currently unknown what fraction of patients are given prescriptions over a lifetime that could be contraindicated by their pharmacogenomic profiles. To determine the clinical utility of pharmacogenomics over a lifetime in a general patient population, we sequenced the genomes of 300 deceased Marshfield Clinic patients linked to lifelong medical records. Genetic variants in 33 pharmacogenes were evaluated for their lifetime impact on drug prescribing using extensive electronic health records. Results show that 93% of the 300 deceased patients carried clinically relevant variants. Nearly 80% were prescribed approximately three medications on average that may have been impacted by these variants. Longitudinal data suggested that the optimal age for pharmacogenomic testing was prior to age 50, but the optimal age is greatly influenced by the stability of the population in the healthcare system. This study emphasizes the broad clinical impact of pharmacogenomic testing over a lifetime and demonstrates the potential application of genomic medicine in a general patient population for the advancement of precision medicine.

PMID:38020121 | PMC:PMC10645151 | DOI:10.3389/fmed.2023.1006743

Pharmacogenomics. 2023 Nov 29. doi: 10.2217/pgs-2023-0168. Online ahead of print.

ABSTRACT

Aims: To evaluate the association between SLCO1B1 gene polymorphisms and susceptibility of antituberculosis drug-induced hepatotoxicity (ATDH). Methods: We searched the PubMed, Cochrane Library, Embase, Web of Science, Wan Fang and China National Knowledge Infrastructure database from inception to 2022. Results: Nine case-control studies with 1129 cases and 2203 controls were included. Among four SNPs reported in two or more studies, the final results indicated that SNP rs4149014 was significantly associated with decreased ATDH risk (dominant model, odds ratio: 0.73; 95% CI: 0.55-0.97; p = 0.03; allele model, odds ratio: 0.69; 95% CI: 0.55-0.86; p = 0.001), and the trial sequential analysis also confirmed this significant association. Conclusion: SLCO1B1 gene SNP rs4149014 was significantly associated with lower risk of ATDH susceptibility.

PMID:38019119 | DOI:10.2217/pgs-2023-0168

J Int Med Res. 2023 Nov;51(11):3000605231214065. doi: 10.1177/03000605231214065.

ABSTRACT

Adverse drug reactions represent a major health burden because they cause notable patient morbidity and mortality. From this viewpoint, several strategies have been developed to prevent or reduce adverse drug reactions. One such strategy is the use of pharmacogenomics. Interindividual variability in drug response and adverse effects is mainly attributable to genetic variation in enzymes such as sulfotransferases and cytochrome P450s. The current narrative review discusses the relationship between the structure and activity of drugs. Specifically, the activity of drugs can be increased and/or their adverse effects can be reduced by altering specific positions in their structures.

PMID:38019107 | DOI:10.1177/03000605231214065