Pharmgenomics Pers Med. 2024 Nov 11;17:487-496. doi: 10.2147/PGPM.S485452. eCollection 2024.

ABSTRACT

INTRODUCTION: Africa, a continent considered to be the cradle of human beings has the largest genetic diversity among its population than other continents. This review discusses the implications of this high African genetic diversity to the development of personalized and precision medicine.

METHODOLOGY: A comprehensive search across PubMed, Google Scholar, Science Direct, DOAJ, AJOL, and the Cochrane Library electronic databases and manual Google searches was conducted using key terms "genetics", "genetic diversity", "Africa", "precision medicine", and "personalized medicine". Updated original and review studies focusing on the implications of African high genetic diversity on personalized and precision medicine were included. Included studies were thematically synthesized to elucidate their positive or negative implications for personalized healthcare, aiming to foster informed clinical practice and scientific inquiry.

RESULTS: African populations' high genetic diversity presents opportunities for personalized and precision medicine including improving pharmacogenomics, understanding gene interactions, discovering new variants, mapping disease genes, creating updated genomic reference panels, and validating biomarkers. However, challenges include underrepresentation in studies, scarcity of reference genomes, inaccuracy of genetic testing and interpretation, and ancestry misclassification. Addressing these requires the establishment of genomic research centers, increasing funding, creating biobanks and repositories, education, infrastructure, and international cooperation to enhance healthcare equity and outcomes through personalized and precision medicine.

CONCLUSION: High African genetic diversity presents both positive and negative implications for personalized and precision medicine. Deep further research is recommended to harness the challenges and use the opportunities to develop customized treatments.

PMID:39555236 | PMC:PMC11566596 | DOI:10.2147/PGPM.S485452

Front Pharmacol. 2024 Nov 1;15:1466394. doi: 10.3389/fphar.2024.1466394. eCollection 2024.

ABSTRACT

BACKGROUND: Metformin is the first-line antidiabetic therapy for type 2 diabetes in Mexico, despite recent recommendations highlighting alternatives like GLP-1 receptor agonists for individuals with obesity. Metformin elimination is reliant on liver and kidney function, and variants in transport proteins such as Multidrug and Toxin Extrusion Protein 1 (MATE1), MATE2, and Organic Cation Transporter 2 (OCT2) can influence its pharmacokinetics. Understanding these variants' frequencies in the Mexican population is crucial for tailoring personalized treatment strategies.

OBJECTIVE: This study aimed to determine the genotypic and allelic frequencies of key variants in metformin transporters within a Mexican population, addressing the interindividual variability in drug response.

METHODOLOGY: Genetic analysis was conducted on 101 healthy, unrelated Mexican subjects who were genotyped for the MATE1, MATE2, and OCT2 variants using allele-specific real-time PCR assays.

RESULTS: The allele frequencies were 0.07 for OCT2, 0.23 for MATE1, and 0.67 for MATE2. The g.-66T→C variant was found only in wild-type and heterozygous forms. Comparative analysis indicated significant differences in allele frequencies between this Mexican population and other ethnic groups, highlighting potential implications for metformin efficacy and safety.

CONCLUSION: This study provides crucial insights into the genetic variability of metformin transporter genes in a Mexican population, offering a foundation for personalized therapeutic approaches in type 2 diabetes management.

PMID:39555090 | PMC:PMC11565514 | DOI:10.3389/fphar.2024.1466394

Future Microbiol. 2024 Nov 18:1-9. doi: 10.1080/17460913.2024.2417608. Online ahead of print.

ABSTRACT

Aim: Transplant rejection and failure are the primary causes of shortened lifespan in transplant patients and are closely associated with the status of the human immune system. Gut microbiota have the capacity to modulate the human immune system. However, it remains unclear whether any gut microbiota can influence the risk of transplant failure.Materials & methods: A Mendelian randomization study was conducted to explore the causal relationship between gut microbiota and transplant failure. This study utilized three Genome-Wide Association Study results focusing on the gut microbiome, transplant failure and transplantation status. Single nucleotide polymorphisms that were strongly associated with gut microbiota abundance were selected as instrumental variables.Results: The abundance of Bifidobacteriaceae demonstrated a significant causal relationship with transplant failure (inverse variance weighted [IVW] p = 0.049, OR = 0.658, 95% CI: 0.433-0.998), but was not related to the risk of transplantation status (IVW p > 0.200). Notably, a higher intestinal abundance of Bifidobacteriaceae corresponded to a decreased risk of transplant failure. Bifidobacteriaceae instrumental variables were enriched in pathways related to synapses and membranes.Conclusion: The Bifidobacteriaceae may play a crucial role in the mechanism of transplant failure. These study results contribute to elucidating the mechanisms underlying transplant failure.

PMID:39552557 | DOI:10.1080/17460913.2024.2417608

Parkinsonism Relat Disord. 2024 Nov 13:107206. doi: 10.1016/j.parkreldis.2024.107206. Online ahead of print.

ABSTRACT

INTRODUCTION: The first-line treatment for Parkinson's disease (PD) involves dopamine-replacement therapies; however, significant variability exists in patient responses. Pharmacogenomics has been explored as a potential approach to understanding and predicting treatment outcomes. This review aims to evaluate the current state of knowledge regarding the role of pharmacogenomics in PD, focusing on identifying challenges and proposing future directions.

METHODS: We conducted a systematic review following PRISMA 2020 guidelines. The PubMed database was searched for original, English-language studies using the R package 'RISmed.' Data were extracted and analyzed based on sample size, population origin, evaluated genes and polymorphisms, outcomes, and methodological approaches.

RESULTS: Out of 183 identified articles, 76 met the inclusion criteria. The COMT-rs4680 polymorphism was the most frequently studied, and levodopa-related motor complications were the most commonly assessed outcomes. All but two studies employed a candidate gene approach. In 75 % of the studies, the sample size was fewer than 225 individuals. There was a notable underrepresentation of Latino participants, with a lack of studies from Latin American countries other than Brazil. None of the studies produced consistent results across investigations.

CONCLUSIONS: The variability in patient responses to PD treatments suggests a genetic predisposition. While current research has enhanced our understanding of PD medication metabolism, it has not yet fully elucidated the complex genetic interactions involved in PD pharmacogenomics. Novel approaches, larger and more genetically diverse cohorts, and improved data collection are essential for advancing pharmacogenomics in PD clinical practice.

PMID:39551668 | DOI:10.1016/j.parkreldis.2024.107206

Sci Rep. 2024 Nov 16;14(1):28333. doi: 10.1038/s41598-024-79994-9.

ABSTRACT

This study explores the association between genetic variations in the vitamin D pathway and autism spectrum disorder (ASD) susceptibility and severity in Thai children. A total of 276 participants, including 169 children with ASD and 107 healthy controls, were recruited. Genotyping of vitamin D pathway genes (CYP2R1, CYP27B1, GC, and VDR) was conducted using TaqMan-based real-time PCR, while serum vitamin D levels were measured by chemiluminescence immunoassay. ASD severity was assessed via the Childhood Autism Rating Scale, 2nd Edition. Results reveal that the VDR gene (ApaI) rs7975232 is linked to a reduced ASD risk. In contrast, the GC gene rs7041 (A > C) polymorphism shows a significant association with increased ASD risk and severity, particularly in individuals with both the GC gene polymorphism and vitamin D insufficiency. Additionally, there was a higher prevalence of the GC1s isoform and GC1s-GC1s haplotype in children with ASD, associated with ASD severity. This study identified that individuals possessing GC rs7041 C alleles and the GC1s genotype (rs7041C/rs4588G) exhibit an increased susceptibility to and more severity of ASD. Further studies with larger cohorts are essential to fully understand these genetic polymorphisms' roles.

PMID:39550459 | DOI:10.1038/s41598-024-79994-9

Am J Health Syst Pharm. 2024 Oct 12:zxae295. doi: 10.1093/ajhp/zxae295. Online ahead of print.

ABSTRACT

PURPOSE: Pharmacogenomics is the study of how individual responses to medication are influenced by genetics. As medication experts, pharmacists are uniquely suited to practicing this application of precision medicine. Fundamental operational aspects of developing a pharmacy clinical pharmacogenomics practice are described, and the specific experience of a multisite health system in developing a pharmacogenomics service is discussed.

SUMMARY: Considerations for the development of a clinical pharmacy-driven pharmacogenomics service include understanding testing selection, targeting the appropriate patient population, exploration of reimbursement, design of the practice, and education of the pharmacogenomics workforce. Testing can be preemptive or reactive, can occur in house or as a send-out service, and can be panel based or specific to a single gene. Pharmacogenomics is applicable to many medicine specialties, making deployment of services to strategic groups essential. Reimbursement for pharmacogenomics is variable and may pose a barrier to implementation. The demand for pharmacogenomics education for pharmacy students and as a formal postgraduate career path is growing. Pharmacogenomics service planning and implementation details for a multisite health system are described.

CONCLUSION: The practice of pharmacogenomics presents a remarkable opportunity for clinical pharmacists and health systems to improve patient care outcomes and experiences.

PMID:39549284 | DOI:10.1093/ajhp/zxae295

Am J Health Syst Pharm. 2024 Nov 9:zxae337. doi: 10.1093/ajhp/zxae337. Online ahead of print.

ABSTRACT

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time.

PURPOSE: To evaluate the impact of dose-specific logic for tricyclic antidepressant (TCA) pharmacogenomic (PGx) clinical decision support (CDS). We aimed to provide guidance in an area with limited supporting literature, ensure optimal dosing through CDS, and limit alert fatigue. The primary outcome was the reduction in alerts prescribers encountered, while the secondary outcome included an analysis across specialties.

METHODS: A retrospective chart review was conducted to examine TCA PGx CDS before and after implementation of dosing criteria for alerts. Data were abstracted from the electronic medical record. A χ2 test was performed to analyze the frequency of alerts in behavioral health and other specialties.

RESULTS: In the cohort lacking dose criteria, most TCA orders were for indications other than depression (76%) and guidelines would not apply to the majority of these orders. Using dosing criteria to refine CDS reduced the volume of TCA alerts by 74.8%. Alert volume decreased the most in specialties other than behavioral health due to prescriptions for indications other than anxiety or depression (P = 0.035).

CONCLUSION: Dose-centric alerts may be used as a strategy to achieve optimal dosing. Alerting clinicians when dose modifications should occur contributes to getting the right dose to the right patient. Future efforts should focus on optimal dosing of medication through CDS enhancements.

PMID:39549283 | DOI:10.1093/ajhp/zxae337

Pharmacotherapy. 2024 Nov 16. doi: 10.1002/phar.4626. Online ahead of print.

ABSTRACT

Pediatric obesity is a growing health concern that has many secondary adverse health implications. Personalized medicine is a tool that can be used to optimize diagnosis and treatments of many diseases. In this review, we will focus on three areas related to the genetics of pediatric obesity: (i) genetic causes predisposing to pediatric obesity, (ii) pharmacogenomics that may predict weight gain associated with pharmacotherapy, and (iii) pharmacogenomics of anti-obesity pharmacotherapy. This narrative review evaluates genetic cause of pediatric obesity and how genetic findings can be used to optimize pharmacotherapy to minimize weight gain and optimize obesity treatment in pediatric patients. Pediatric obesity has many genetic causes including genomic obesity syndromes and monogenic obesity disorders. Several genetic etiologies of obesity have current or emerging targeted genetic therapies. Pharmacogenomic (PGx) targets associated with pharmacotherapy-induced weight gain have been identified for antipsychotic, antiepileptic, antidepressant therapies, and steroids, yet to date no clinical guidelines exist for application use of PGx to tailor pharmacotherapy to avoid weight gain. As legislation evolves for genetic testing coverage and technology advances, this will decrease cost and expand access to genetic testing. This will result in identification of potential genetic causes of obesity and genes that predispose to pharmacotherapy-induced weight gain. Advances in precision medicine can ultimately lead to development of clinical practice guidelines on how to apply genetic findings to optimize pharmacotherapy to treat genetic targets of obesity and avoid weight gain as an adverse event associated with pharmacotherapy.

PMID:39548737 | DOI:10.1002/phar.4626

J Transl Med. 2024 Nov 15;22(1):1028. doi: 10.1186/s12967-024-05786-4.

ABSTRACT

PURPOSE: Intestinal flora promotes the pathogenesis of colorectal cancer (CRC) through microorganisms and their metabolites. This study aimed to investigate the composition of intestinal flora in different stages of CRC progression and the effect of fecal microbiota transplantation (FMT) on CRC mice.

METHODS: The fecal microbiome from healthy volunteers (HC), colorectal adenoma (CRA), inflammatory bowel disease (IBD), and CRC patients were analyzed by 16s rRNA gene sequencing. In an azoxymethane (AOM)/dextran-sulfate-sodium (DSS)-induced CRC mouse, the effect of FMT from HC, CRA, CRC, and IBD patients on CRC mice was assessed by histological analysis. Expression of inflammation- EMT-associated proteins and Wnt/β-catenin pathway were assessed using qRT-PCR and western blot. The ratio of the fecal microorganisms and metabolomics alteration after FMT were also assessed.

RESULT: Prevotella, Faecalibacterium, Phascolarctobacterium, Veillonella, Alistipes, Fusobacterium, Oscillibacter, Blautia, and Ruminococcus abundance was different among HC, IBD, CRC, and CRA patients. HC-FMT alleviated disease progression and inflammatory response in CRC mice, inhibited splenic T help (Th)1 and Th17 cell numbers, and suppressed the EMT and Wnt/β-catenin pathways in tumor tissues of CRC mice. IBD-FMT, CRA-FMT, and CRC-FMT played deleterious roles; the CRC-FMT mice exhibited the most malignant phenotype. Compared with the non-FMT CRC mice, Muribaculaceae abundance was lower after FMT, especially lowest in the IBD-FMT group; while Lactobacillus abundance was higher after FMT and especially high in HC-FMT. Akkermansia and Ileibacterium abundance increased after FMT-HC compared to other groups. Metabolite correlation analysis revealed that Muribaculaceae abundance was significantly correlated with metabolites such as Betaine, LysoPC, and Soyasaponin III. Lactobacillus abundance was positively correlated with Taurocholic acid 3-sulfate, and Ileibacterium abundance was positively correlated with Linoleoyl ethanolamide.

CONCLUSION: The different intestinal microbiota communities of HC, IBD, CRA, and CRC patients may be attributed to the different modulation effects of FMT on CRC mice. CRC-FMT promoted, while HC-FMT inhibited the progress of CRC. Increased linoleoyl ethanolamide levels and abundance of Muribaculaceae, Akkermansia, and Ileibacterium and reduced Fusobacterium might participate in inhibiting CRC initiation and development. This study demonstrated that FMT intervention could restore the intestinal microbiota and metabolomics of CRC mice, suggesting FMT as a potential strategy for CRC therapy.

PMID:39548468 | DOI:10.1186/s12967-024-05786-4

BMC Anesthesiol. 2024 Nov 15;24(1):416. doi: 10.1186/s12871-024-02797-y.

ABSTRACT

BACKGROUND: In clinical practice, family medication history is not routinely assessed as part of a patient's family health history (FHH). The information is self-reported and can depend on the individual's subjective perception. To illustrate how pharmacogenetic (PGx) testing results could be used to validate self-reported family medication history on drug-related problems (DRP), as well as to inform medication-related decisions, we herein present a case involving ten members of the same family.

CASE PRESENTATION: Prior to a planned surgery, a preemptive PGx panel test was performed for a nine-year-old girl due to self-reported family medication history. The PGx panel test was also performed for her three siblings, parents, and grandparents. The focus was directed to the paternal grandmother, as she reported DRP from the hypnotic agent propofol, and to the maternal grandmother, as she described DRP after the administration of codeine and tramadol. A commercial PGx panel test of 100 variations in 30 different genes was conducted and analyzed focusing on genetic variants in cytochrome P450 enzyme 2B6 (CYP2B6), and CYP2D6 as they are involved in the biotransformation of propofol and the bioactivation of codeine and tramadol, respectively. The girl was identified as (1) CYP2B6 intermediate metabolizer (IM) with reduced enzyme activity and (2) CYP2D6 poor metabolizer (PM) with no enzyme activity. Regarding the planned surgery, it was recommended (1) to carefully titrate propofol dosage with increased monitoring of potential DRP and (2) to avoid opioids whose activation is mediated by CYP2D6 (e.g. codeine and tramadol). Further PGx testing revealed (1) the paternal grandmother as CYP2B6 normal metabolizer (NM) and (2) the maternal grandmother as CYP2D6 NM.

CONCLUSION: The original trigger for PGx testing was the self-reported, conspicuous family medication history of DRP reported by the grandmothers. However, the girl's genotype predicted phenotypes of CYP2B6 IM and CYP2D6 PM, differed from the grandmothers'. With this exemplary case, we propose that hereditary concerns based on self-reported information on DRP should be verified by a PGx panel test, when the respective drug exhibits a PGx association. Also, the girl's PGx testing results provided important medication recommendations, which were considered perioperatively by the anesthetist suggesting to use PGx testing results preemptively to inform medication-related decisions.

PMID:39548363 | DOI:10.1186/s12871-024-02797-y

J Am Heart Assoc. 2024 Nov 19;13(22):e036544. doi: 10.1161/JAHA.124.036544. Epub 2024 Nov 15.

ABSTRACT

BACKGROUND: The association of lipid-lowering drug targets and their gene variants with cardiovascular diseases has been previously clarified. However, the relationship between gene variants of lipid-lowering drug targets and the adverse prognosis of ischemic stroke patients remains unclear.

METHODS AND RESULTS: Multiple single-nucleotide polymorphisms associated with 6 lipid-lowering drug targets were genotyped for patients with ischemic stroke. The primary outcome was death or major disability within 2 years after ischemic stroke. Genetic risk score was constructed from significant single-nucleotide polymorphisms identified via additive models, which was calculated by multiplying the number of risk alleles at each locus by the corresponding beta coefficient and then summing the products. The rs2006760-C of the HMGCR, rs11206510-T of PCSK9, and rs1864163-G and rs9929488-G of CETP were associated with increased odds of adverse outcomes within 2 years after ischemic stroke. Each additional risk allele was associated with higher odds of adverse outcomes. Genetic risk score was positively associated with the odds of primary outcome (odds ratio [OR], 1.48 [95% CI, 1.15-1.90]; Ptrend = 0.001), major disability (OR, 1.56 [95% CI, 1.16-2.08]; Ptrend = 0.002), death (hazard ratio [HR], 1.58 [95% CI, 1.12-2.25]; Ptrend = 0.011), and the composite outcome of death or cardiovascular events (HR, 1.41 [95% CI, 1.08-1.85]; Ptrend = 0.010) when 2 extreme quartiles were compared.

CONCLUSIONS: rs2006760-C of HMGCR, rs11206510-T of PCSK9, and rs1864163-G and rs9929488-G of CETP were associated with increased odds of adverse outcomes within 2 years after ischemic stroke. Furthermore, higher GRS was positively related to the odds of poor outcomes in patients with ischemic stroke. Registration: URL: https://www.clinicaltrials.gov; Identifier: NCT01840072.

PMID:39547981 | DOI:10.1161/JAHA.124.036544

Nat Rev Cardiol. 2024 Nov 15. doi: 10.1038/s41569-024-01098-8. Online ahead of print.

ABSTRACT

Heart failure (HF) remains a leading cause of mortality, responsible for 13% of all deaths worldwide. The prognosis for patients with HF is poor, with only a 50% survival rate within 5 years. A major challenge of ischaemia-driven HF is the loss of cardiomyocytes, compounded by the minimal regenerative capacity of the adult heart. To date, replacement of irreversibly damaged heart muscle can only be achieved by complete heart transplantation. In the past 20 years, cell therapy has emerged and evolved as a promising avenue for cardiac repair and regeneration. During this time, cell therapy for HF has encountered substantial barriers in both preclinical studies and clinical trials but the field continues to progress and evolve from lessons learned from such research. In this Review, we provide an overview of ongoing trials of cell-based and cell product-based therapies for the treatment of HF. Findings from these trials will facilitate the clinical translation of cardiac regenerative and reparative therapies not only by evaluating the safety and efficacy of specific cell-based therapeutics but also by establishing the feasibility of novel or underexplored treatment protocols such as repeated intravenous dosing, personalized patient selection based on pharmacogenomics, systemic versus intramural cell delivery, and epicardial engraftment of engineered tissue products.

PMID:39548233 | DOI:10.1038/s41569-024-01098-8

Transl Psychiatry. 2024 Nov 15;14(1):471. doi: 10.1038/s41398-024-03177-3.

ABSTRACT

Weight-inducing psychotropic treatments are risk factors for age-related diseases such as cardiovascular disorders, which are associated with both inflammation and telomere length shortening. With a longitudinal design, the present study evaluates telomere length trajectories after 1 year of weight-inducing psychotropic medication, accounting for weight changes and the inflammatory biomarker high-sensitivity C-Reactive Protein (CRP). Among 200 patients, an overall median telomere shortening of -41.2 bp was observed (p = 0.014), which is comparable with the general population's yearly telomere attrition. Linear regression showed on average -93.1 and -58.9 bp of further telomere shortening per five units of BMI for BMI values < or ≥30 kg/m2, respectively (p = 0.003 and p = 0.009, respectively). Importantly, the overall telomere shortening was predicted to be increased four-fold among patients with low baseline weight (i.e., 50 kg) and with clinically relevant weight gain (≥ 7%) after 1 year of treatment (interaction term between relevant weight gain and baseline weight: +6.3 bp, p = 0.016). Patients with relevant weight gain showed greater CRP levels (+ 49%; p = 0.016), and a telomere shortening of -36.2 bp (p = 0.010) was estimated whenever CRP level doubled. Mendelian randomization using UKBiobank data showed a causal effect of BMI on telomere shortening, notably stronger among patients receiving weight-inducing psychotropic treatments (n = 9798) than among psychiatric patients without such drugs (n = 16228) and non-psychiatric controls (n = 252932) (beta: -0.37, -0.12, -0.06, respectively; p = 0.004, p < 0.001, p < 0.001, respectively). Ultimately, telomere trajectories were associated with 1 year weight gain and increases in CRP levels, with telomere shortening strongly enhanced by BMI increments among patients receiving weight-inducing psychotropic treatments.

PMID:39548087 | DOI:10.1038/s41398-024-03177-3

J Urol. 2024 Nov 15:101097JU0000000000004333. doi: 10.1097/JU.0000000000004333. Online ahead of print.

ABSTRACT

BACKGROUND.: The contribution of 11-oxygenated androgens to the progression of lethal prostate cancer (PCa) remains unresolved. We hypothesized that evaluating circulating levels of 11-oxygenated androgens, such as the androgen receptor agonist 11-ketotestosterone (11KT), could serve as a potential predictor of the onset of castration resistant prostate cancer (CRPC).

METHODS.: We used mass spectrometry to quantify 11-oxygenated androgens in post-operative plasma samples acquired from 145 patients who subsequently received androgen deprivation therapy (ADT) for biochemical recurrence (BCR) and achieved castrated testosterone (T) levels. Kaplan-Meier survival analyses and multivariable Cox models were used to investigate relationships between steroids and CRPC.

RESULTS.: Of 145 patients, 31 developed CRPC with a median time to CRPC of 57 months. 11-oxygenated androgens levels were unaffected by ADT, which stands in contrast to the observed changes in T and other steroids. 11KT was the most abundant androgen but was not linked to clinical features. Kaplan-Meier analysis revealed that 11KT levels above the median of 273 pg/mL were associated with a shorter time to CRPC (P = 0.03). In multivariable analyses, this was supported with an adjusted hazard ratio of 2.17 (95% confidence interval (CI) 0.99-4.71; P = 0.05).

CONCLUSION.: 11KT is a key component of the hormonal profile predictive of earlier onset of CRPC. Enhancing our understanding of the specific role of 11KT in the progression to CRPC could help optimize hormonal therapy for castration sensitive PCa and CRPC patients.

PMID:39546743 | DOI:10.1097/JU.0000000000004333

Pharmacogenomics. 2024 Nov 15:1-8. doi: 10.1080/14622416.2024.2428585. Online ahead of print.

ABSTRACT

OBJECTIVE: This study aimed to estimate the clinical utility of performing multi-gene pharmacogenetic testing on patients undergoing gynecologic surgery/procedure by evaluating the prescribing rate of Clinical Pharmacogenetics Implementation Consortium (CPIC) level A medications and frequency of drug-gene interactions (DGIs).

METHODS: The electronic health record was queried for 76 current procedural terminology codes to identify gynecologic surgeries/procedures that occurred between 1 January 2015 to 31 December 2020 in patients with at least one of 152 international classification of disease codes. Prescription data for CPIC level A medications was extracted. Those enrolled in the Penn Medicine Biobank were assessed for DGIs.

RESULTS: The cohort consisted of 7798 female patients and 682 were in the biobank. Up to 6 years following their surgery or procedure, 80% were ordered ≥1 CPIC level A medication. Over half (54%) of these medications were ordered within 3 days after their surgery or procedure. The most common CPIC level A medications ordered were ibuprofen (57%) and ondansetron (42%). Overall, 7% of the cohort had ≥1 known or predicted DGI with medications they were prescribed.

CONCLUSION: Multi-gene pharmacogenetic testing may be beneficial to gynecologic surgery/procedure patients by assisting clinicians with prescribing postoperative analgesics and future medications.

PMID:39545769 | DOI:10.1080/14622416.2024.2428585

Pharmacogenomics. 2024 Nov 15:1-12. doi: 10.1080/14622416.2024.2428587. Online ahead of print.

ABSTRACT

Artificial Intelligence (AI) and Machine Learning (ML) are revolutionizing various scientific and clinical disciplines including pharmacogenomics (PGx) by enabling the analysis of complex datasets and the development of predictive models. The integration of AI and ML with PGx has the potential to provide more precise, data-driven insights into new drug targets, drug efficacy, drug selection, and risk of adverse events. While significant effort to develop and validate these tools remain, ongoing advancements in AI technologies, coupled with improvements in data quality and depth is anticipated to drive the transition of these tools into clinical practice and delivery of individualized treatments and improved patient outcomes. The successful development and integration of AI-assisted PGx tools will require careful consideration of ethical, legal, and social issues (ELSI) in research and clinical practice. This paper explores the intersection of PGx with AI, highlighting current research and potential clinical applications, and ELSI including privacy, oversight, patient and provider knowledge and acceptance, and the impact on patient-provider relationship and new roles.

PMID:39545629 | DOI:10.1080/14622416.2024.2428587

Expert Opin Biol Ther. 2024 Nov 15. doi: 10.1080/14712598.2024.2431088. Online ahead of print.

ABSTRACT

INTRODUCTION: Recently, immunotherapy has offered new hope for treating biliary tract cancer (BTC). However, several issues are to be considered, including the lack of validated predictive biomarkers that could help to identify patient groups which are most likely to benefit from such therapeutic approaches.

AREAS COVERED: In the current article, we will provide an overview of recent results and ongoing and future research directions of immunotherapy in BTC, with a special focus on recently published, practice-changing data, and ongoing active and recruiting clinical trials.

EXPERT OPINION: At this moment, dozens of clinical trials in phases I to III are evaluating the role of cancer immunotherapy in this setting, with the hope of adding more therapeutic options for BTC patients. Future research must focus on the development of novel agents and combinations, but the validation of biomarkers remains an urgent need. As more research results emerge, novel combinatorial strategies are destined to further transform the treatment paradigm for this heterogeneous and aggressive tumor type.

PMID:39545466 | DOI:10.1080/14712598.2024.2431088

Pharmacogenomics J. 2024 Nov 15;24(6):34. doi: 10.1038/s41397-024-00357-8.

ABSTRACT

The current study aimed to identify the potential biomarker for the diagnosis of ovarian cancer within plasma cell-free RNA (cfRNA) species and to characterize their oncogenic properties. cfRNAs were isolated from the peripheral blood of ovarian cancer patients and sequenced using an NGS platform. Principal component analysis (PCA) was performed using Salmon software. Gene ontology (GO) analysis was conducted with clusterProfiler. The relative abundance of TMEM158 transcripts was determined by real-time PCR. Cell viability and proliferation was monitored using the MTT and cell counting assays, respectively. The protein levels of TMEM158 and ABCG2 were quantified by immunoblotting. We observed a clear separation of cfRNAs between ovarian cancer patients and healthy individuals. Additionally, we identified TMEM158 as the most significantly differential gene in both peripheral blood and tumor tissues. Overexpression of TMEM158 stimulated cell viability and promoted cell proliferation in ovarian cancer cells. Notably, the aberrant upregulation of TMEM158 was closely associated with doxorubicin resistance in ovarian cancer. Mechanistically, we demonstrated that TMEM158 positively regulates ABCG2 expression, which consequently contributes to drug resistance. In summary, we identified cfRNA TMEM158 as a potential diagnostic biomarker for ovarian cancer and elucidated the critical involvement of TMEM158-ABCG2 signaling axis in the development of doxorubicin resistance.

PMID:39543089 | DOI:10.1038/s41397-024-00357-8

Pharmacogenomics. 2024 Nov 14:1-17. doi: 10.1080/14622416.2024.2421743. Online ahead of print.

ABSTRACT

Aim: Pharmacogenomics is emerging in South Asia, including Sri Lanka, with potential to optimize drug therapy and reduce adverse effects. This review evaluates the state of pharmacogenomics research in Sri Lanka, emphasizing population-specific factors to guide future advancements.Materials & methods: A literature search was performed across PubMed/Web-of-Science/SciVerse-Scopus/Embase, and Sri Lanka Journals Online, along with searches for relevant theses in local health repositories/university databases. Studies were categorized into clinical correlational, descriptive or novel assay development studies.Results: Eleven published articles and eight theses were included. One study examined somatic variants (KRAS gene), while all others focused on germline variants. There were two clinical correlational studies: tamoxifen adverse effects and CYP2D6 variants and FTO gene rs9939609 variants and weight gain caused by second-generation antipsychotics. Eight descriptive studies evaluated prevalence of CYP2D6 variants, HLA-B*15:02 allele, KRAS gene mutations and variants related to statin, warfarin and anticancer drug metabolism. Additionally, nine studies developed, validated and tested novel assays for detecting key pharmacogenomically important variants.Conclusion: While pharmacogenomics research in Sri Lanka has made strides, more clinical studies and broader genomic research are needed. Overcoming challenges related to funding, public awareness and regional collaboration is essential to advance personalized medicine and improve therapeutic outcomes in Sri Lanka and South Asia.

PMID:39540556 | DOI:10.1080/14622416.2024.2421743

Nucleic Acids Res. 2024 Nov 14:gkae1016. doi: 10.1093/nar/gkae1016. Online ahead of print.

ABSTRACT

Genetic polymorphisms in drug metabolizing enzymes, drug transporters as well as in genes encoding the human major histocompatibility complex contribute to inter-individual differences in drug efficacy and safety. The extent, pattern and complexity of such pharmacogenetic variation differ drastically across human populations. Here, we present PharmFreq, a global repository of pharmacogenetic frequency information that aggregates frequency data of 658 allelic variants from over 10 million individuals collected from >1200 studies across 144 countries. Most investigations were conducted in East Asian and European populations, accounting for 29.4 and 26.6% of all studies, respectively. We find that the number of studies per country and aggregated cohort size correlated significantly with population size (R = 0.55, P= 3*10-9) and country gross domestic product (R = 0.43, P= 2*10-6) with overall population coverage varying between 5% in Estonia to < 0.001% in many countries in Sub-Saharan Africa and Asia. All frequency data are openly accessible via a web-based interactive dashboard at pharmfreq.com that facilitates the exploration, visualization and analysis of country- and population-specific data and their inferred phenotypic consequences. PharmFreq thus presents a comprehensive, freely available resource for pharmacogenetic variant frequencies that can inform about ethnogeographic pharmacogenomic diversity and reveal important inequities that help to focus future research efforts into underrepresented populations.

PMID:39540424 | DOI:10.1093/nar/gkae1016