Ann Rheum Dis. 2025 Feb 19:S0003-4967(25)00184-0. doi: 10.1016/j.ard.2025.01.034. Online ahead of print.

ABSTRACT

OBJECTIVES: Mosaic chromosomal alterations (mCAs) increase with age and are associated with age-related diseases. The association between mCAs and rheumatoid arthritis (RA), particularly late-onset RA (LORA), has not been explored.

METHODS: mCAs were detected in peripheral blood samples from 2 independent Japanese datasets (Set 1: 2107 RA cases and 86,998 controls; Set 2: 2359 RA cases and 86,998 controls). The associations between mCAs and RA were evaluated in each dataset using logistic regression models and meta-analysis. In each dataset, the effect sizes of mosaic loss of Y (mLOY) and polygenic risk score (PRS) of RA in males was evaluated, and a meta-analysis was subsequently performed. The interaction between mLOY and PRS was assessed. These models were applied separately to RA, LORA, and young-onset RA (YORA).

RESULTS: mLOY increased significantly in LORA (odds ratio [OR] = 1.43, P = .0070). We observed a negative association between mLOY and YORA (OR = 0.66, P = .0034). On the other hand, we found consistently negative associations of autosomal mCAs or mosaic loss of X with RA, LORA, and YORA. The PRS effect sizes were lower for LORA than for YORA. mLOY with a high cell fraction strengthened the association between PRS and LORA (P = .0036), whereas the association with YORA was independent of mLOY.

CONCLUSIONS: LORA was characterised by the presence of a high burden of mLOY. The observed interaction between mLOY and PRS in LORA, but not in YORA, supports different gene-environment interactions between the subsets. These data suggest that distinct pathophysiological mechanisms underlie the development of LORA and YORA.

PMID:39986957 | DOI:10.1016/j.ard.2025.01.034

Biochem Pharmacol. 2025 Feb 19:116809. doi: 10.1016/j.bcp.2025.116809. Online ahead of print.

ABSTRACT

The importance of the intestinal microbita in a multitude of physiological processes is well-evidenced. These include metabolism of nutrients and xenobiotics, biosynthesis of vitamin K and vitamin B12, immunomodulation, maintenance of the gut mucosal barrier integrity and protection against some pathogens. Interindividual differences in the intestinal microbiota composition have impacts on health. The bioavailability and activity of some pharmaceuticals are heavily influenced by interindividual variability in metabolism, which has a genetic basis. This variability, primarily occurring in the liver but also in the intestine, has been studied extensively. Despite the advancement of this field - pharmacogenetics - its integration into clinical practice remains limited for reasons discussed herein. This highlights the even greater challenge of applying emerging knowledge on variability in the gut microbiota to drug therapy. However, ignoring these opportunities would be a mistake. While clinical applications of microbiota-guided drug therapy are currently absent and the ideas in this article are largely theoretical, research is uncovering that in cases where a substantial portion of a drug or its metabolites reaches the colon, or where drugs are formulated for colonic delivery, the gut microbiota can significantly affect drug metabolism and activity. Greater focus should be placed on research into how interindividual variability in the intestinal microbiome can modify pharmaceutical bioavailability and activity. This article is deliberately speculative and exploratory but proposes that, though there are still no clinical examples of microbiome-guided drug therapy, these interactions could afford opportunities for improvements in personalised medicine and also for drug design.

PMID:39983848 | DOI:10.1016/j.bcp.2025.116809

Pharmacogenomics. 2025 Feb 21:1-9. doi: 10.1080/14622416.2025.2466413. Online ahead of print.

ABSTRACT

INTRODUCTION: Pharmacogenetic (PGx) screening is intended to optimize drug efficacy and reduce adverse drug reactions. Current screening options include genotyping assays for preselected PGx variants and broader next-generation sequencing panels (NGS). Few studies have directly compared preemptive PGx screening methods.

MATERIALS AND METHODS: The two PGx methods were compared in a cross-sectional study of adult Military Health System (MHS) clinic beneficiaries. Participants had initial targeted CYP2C19/CYP2D6 genotyping at a Military Health System Laboratory. Genotyping was followed by multi-gene NGS testing. Current prescriptions were recorded and potential drug-drug interactions screened to evaluate prescribing risk.

RESULTS: All participants (100%) had at least one clinically actionable NGS panel result compared to 81% with targeted CYP2C19/CYP2D6 genotyping. Participants (n = 162) had an average of 6.6 (range 0-22) prescriptions and 2.7 (range 0-24) drug-drug interactions. Among those with at least one clinically actionable NGS result, 42% were currently taking medication with actionable CPIC guidelines (Level A/B), compared with 24% with CYP2C19/CYP2D6 genotyping. Sixteen participants (10%) had uncertain NGS panel results, with none for CYP2C19/CYP2D6 genotyping.

CONCLUSIONS: Preemptive multi-gene NGS detected more clinically actionable PGx results than targeted CYP2C19/CYP2D6 genotyping. Effective PGx screening in the MHS may decrease preventable adverse effects and improve military readiness.

PMID:39981562 | DOI:10.1080/14622416.2025.2466413

JHEP Rep. 2024 Nov 14;7(3):101271. doi: 10.1016/j.jhepr.2024.101271. eCollection 2025 Mar.

ABSTRACT

BACKGROUND & AIMS: This study used the Global Burden of Disease data (2010-2021) to analyze the rates and trends of point prevalence, annual incidence, and years lived with disability (YLDs) for metabolic dysfunction-associated steatotic liver disease (MASLD) in 204 countries.

METHODS: Total numbers and age-standardized rates per 100,000 population for MASLD prevalence, annual incidence, and YLDs were compared across regions and countries by age, sex, and sociodemographic index (SDI). Smoothing spline models were used to evaluate the relationship between the burden of MASLD and SDI. Estimates were reported with uncertainty intervals (UI).

RESULTS: Globally, in 2021, the age-standardized rates per 100,000 population of point prevalence of MASLD were 15,018.1 cases (95% UI 13,756.5-16,361.4), annual incidence rates were 608.5 cases (598.8-617.7), and YLDs were 0.5 (0.3-0.8) years. MASLD point prevalence was higher in men than women (15,731.4 vs. 14,310.6 cases per 100,000 population). Prevalence peaked at ages 45-49 for men and 50-54 for women. Kuwait (32,312.2 cases per 100,000 people; 95% UI: 29,947.1-34,839.0), Egypt (31,668.8 cases per 100,000 people; 95% UI: 29,272.5-34,224.7), and Qatar (31,327.5 cases per 100,000 people; 95% UI: 29,078.5-33,790.9) had the highest prevalence rates in 2021. The largest increases in age-standardized point prevalence estimates from 2010 to 2021 were in China (16.9%, 95% UI 14.7%-18.9%), Sudan (13.3%, 95% UI 9.8%-16.7%) and India (13.2%, 95% UI 12.0%-14.4%). MASLD incidence varied with SDI, peaking at moderate SDI levels.

CONCLUSIONS: MASLD is a global health concern, with the highest prevalence reported in Kuwait, Egypt, and Qatar. Raising awareness about risk factors and prevention is essential in every country, especially in China, Sudan and India, where disease incidence and prevalence are rapidly increasing.

IMPACT AND IMPLICATIONS: This research provides a comprehensive analysis of the global burden of MASLD, highlighting its rising prevalence and incidence, particularly in countries with varying sociodemographic indices. The findings are significant for both clinicians and policymakers, as they offer critical insights into the regional disparities in MASLD burden, which can inform targeted prevention and intervention strategies. However, the study's reliance on modeling and available data suggests cautious interpretation, and further research is needed to validate these findings in clinical and real-world settings.

PMID:39980749 | PMC:PMC11840544 | DOI:10.1016/j.jhepr.2024.101271

Pharmacogenomics J. 2025 Feb 20;25(2):3. doi: 10.1038/s41397-024-00360-z.

ABSTRACT

Prediction of treatment response by genetic biomarkers has potential for clinical use and contributes to the understanding of pathophysiology and drug mechanism of action. The purpose of this study is to detect genetic biomarkers possibly associated with response to lurasidone, during the first four weeks of treatment. One-hundred and seventy-one acutely psychotic patients from two placebo-controlled clinical trials of lurasidone were included. Genetic associations with changes in Positive and Negative Syndrome Scale total score at weeks one, two, and four were examined. Genotyping was done with the Affymetrix 6.0 microarray and associations were computed using PLINK regression model. Although genome-wide significance was not reached with a limited sample size, signals of potential interest for further studies were with genes important for neurogenesis. Possible week one marker, rs6459950 (p = 7.05 × 10-7), was close to the sonic hedgehog gene (SHH), involved in neuronal differentiation and neurogenesis. Possible week two marker, rs7435958, was a SNP of GABRB1, encoding the GABAA Receptor β1. Notably, possible week four signals included a SNP within PTCH1, a specific receptor for the SHH, the possible week one marker. Pathway analysis supported the possibility that neurogenesis might be involved in early antipsychotic response. Tissue enrichment analysis suggested that potential signals were enriched in anterior cingulate cortex, reported to be relevant in antipsychotic action. This is the first study to examine genes possibly associated with very early response to lurasidone. Further replication studies in larger sample size should be required.

PMID:39979276 | DOI:10.1038/s41397-024-00360-z

Am J Manag Care. 2025 Feb 1;31(2):e47-e55. doi: 10.37765/ajmc.2025.89683.

ABSTRACT

OBJECTIVES: To evaluate medical policy determinations for pharmacogenetic (PGx) testing for 65 clinically relevant drug-gene pairs and evidence cited to support determinations across major US health plans and laboratory benefit managers (LBMs).

STUDY DESIGN: Landscape analysis of available PGx medical policies to determine coverage status of certain drug-gene pairs.

METHODS: PGx medical policies as of February 1, 2024, were ascertained through Policy Reporter for top national insurers, LBMs, and the Palmetto GBA Molecular Diagnostic Services (MolDX) Program, which determines whether a molecular diagnostic test is covered by Medicare. Data elements included date of last policy update, coverage status for each drug-gene pair, and evidence cited for or against coverage. A drug-gene pair was considered covered if the policy indicated that a PGx test was deemed medically necessary and/or meets coverage criteria.

RESULTS: Policies from 8 insurers, 3 LBMs, and MolDX were available and reviewed. MolDX covered all 65 individual drug-gene pairs, followed by Avalon Healthcare Solutions (n = 50) and UnitedHealthcare (n = 45); these 3 also covered multigene panels. Eight policies covered 10 or fewer drug-gene pairs. HLA-B*57:01 testing prior to abacavir initiation and HLA-B*15:02 testing prior to carbamazepine initiation were covered across all policies. Drug-gene pairs with Clinical Pharmacogenetics Implementation Consortium guidelines and/or included in the FDA's Table of Pharmacogenetic Associations Section 1 were more commonly covered. Society guidelines were the most frequently cited evidence (413 times), and cost-effectiveness studies were infrequently cited (43 times).

CONCLUSIONS: We found significant variability in medical policy determinations and evidence cited for clinically relevant PGx tests among major US health insurers and LBMs. A collaborative effort between payers and the PGx community to standardize evidence evaluation may lead to more consistent coverage and improve patient access to PGx tests meeting evidence requirements.

PMID:39977287 | DOI:10.37765/ajmc.2025.89683

Mol Med. 2025 Feb 19;31(1):62. doi: 10.1186/s10020-024-01049-6.

ABSTRACT

BACKGROUND: With fatal malignant peculiarities and poor survival rate, outcomes of pancreatic adenocarcinoma (PAAD) were frustrated by non-response and even resistance to therapy due to heterogeneity across clinical patients. Nevertheless, pharmacogenomics has been developed for individualized-treatment and still maintains obscure in PAAD.

METHODS: A total of 964 samples from 10 independent multi-center cohorts were enrolled in our study. With drug response data from the profiling of relative inhibition simultaneously in mixtures (PRISM) and genomics of drug sensitivity in cancer (GDSC) databases, we established and validated multidimensionally three pharmacogenomics-classified subtypes using non-negative matrix factorization (NMF) and nearest template prediction (NTP) algorithms, separately. The heterogenous biological characteristics and precision medicine strategies among subtypes were further investigated.

RESULTS: Three pharmacogenomics-classified subtypes after stable and reproducible validation, distinguished in six aspects of prognosis, biological peculiarities, immune landscapes, genomic variations, immunotherapy and individualized management strategies. Subtype 2 was close to immunocompetent phenotype and projected to immunotherapy; Subtype 3 held most favorable outcomes and metabolic pathways distinctively, promising to be treated with first-line agents. Subtype 1 with worst prognosis, was anticipated to chromosome instability (CIN) phenotype and resistant to chemotherapeutic agents. In addition, ITGB6 contributed to subtype 1 resistance to 5-fluorouracil, and knockdown of ITGB6 enhanced sensitivity to 5-fluorouracil in in vitro experiments. Ultimately, appropriate clinical stratified treatments were assigned to corresponding subtypes according to pharmacogenomic transcripts. Some limitations were not taken into account, thus needs to be supported by more research.

CONCLUSION: A span-new molecular subtype exploited for PAAD uncovered an insight into precise medication on ground of pharmacogenomics, and highly refined multiple clinical management strategies for specific patients.

PMID:39972282 | DOI:10.1186/s10020-024-01049-6

NPJ Breast Cancer. 2025 Feb 19;11(1):18. doi: 10.1038/s41523-025-00733-y.

ABSTRACT

The role of germline genetics in adjuvant aromatase inhibitor (AI) treatment efficacy in ER-positive breast cancer is poorly understood. We employed a two-stage candidate gene approach to examine associations between survival endpoints and common germline variants in 753 endocrine resistance-related genes. For a discovery cohort, we screened the Breast Cancer Association Consortium database (n ≥ 90,000 cases) and retrieved 2789 AI-treated patients. Cox model-based analysis revealed 125 variants associated with overall, distant relapse-free, and relapse-free survival (p-value ≤ 1E-04). In validation analysis using five independent cohorts (n = 8857), none of the six selected candidates representing major linkage blocks at CELA2B/CASP9, NR1I2/GSK3B, LRP1B, and MIR143HG (CARMN) were validated. We discuss potential reasons for the failed validation and replication of published findings, including study/treatment heterogeneity and other limitations inherent to genomic treatment outcome studies. For the future, we envision prospective longitudinal studies with sufficiently long follow-up and endpoints that reflect the dynamic nature of endocrine resistance.

PMID:39971965 | DOI:10.1038/s41523-025-00733-y

Pharmacogenomics J. 2025 Feb 19;25(2):2. doi: 10.1038/s41397-025-00361-6.

ABSTRACT

The pathogenesis of cancer is complicated, and different types of cancer often exhibit different gene mutations resulting in different omics profiles. The purpose of this study was to systematically identify cancer-specific biological pathways and potential cancer-targeting drugs. We collectively analyzed the transcriptomics and proteomics data from 16 common types of human cancer to study the mechanism of carcinogenesis and seek potential treatment. Statistical approaches were applied to identify significant molecular targets and pathways related to each cancer type. Potential anti-cancer drugs were subsequently retrieved that can target these pathways. The number of significant pathways linked to each cancer type ranged from four (stomach cancer) to 112 (acute myeloid leukemia), and the number of therapeutic drugs that can target these cancer related pathways, ranged from one (ovarian cancer) to 97 (acute myeloid leukemia and non-small-cell lung carcinoma). As a validation of our method, some of these drugs are FDA approved therapies for their corresponding cancer type. Our findings provide a rich source of testable hypotheses that can be applied to deconvolute the complex underlying mechanisms of human cancer and used to prioritize and repurpose drugs as anti-cancer therapies.

PMID:39971899 | DOI:10.1038/s41397-025-00361-6

Basic Clin Pharmacol Toxicol. 2025 Mar;136(3):e70009. doi: 10.1111/bcpt.70009.

ABSTRACT

Precision medicine has significantly advanced through the development of predictive biomarkers based on pharmacogenetic (PGx) testing. These tests identify interactions between drugs and genetic variants that influence patient responses to treatments. Understanding genetic variations in drug-metabolizing enzymes, receptors and transporters and their impact on pharmacokinetics and pharmacodynamics allows for the prediction of drug effects and side effects, enabling tailored treatments for different patient groups. This review focuses on drugs metabolized by cytochrome P450 (CYP450) enzymes, for example, citalopram and clopidogrel or transported by the solute carrier organic anion transporter family member 1B1 (SLCO1B1), for example, atorvastatin and simvastatin, with PGx dosing guidelines, in the context of consumption in Scandinavian countries. A major barrier to the widespread adoption of PGx tests in clinical practice has been healthcare professionals' uncertainty about their efficacy, complexity in result interpretation and questions regarding the evidence base. However, recent studies have demonstrated PGx testing has the potential to improve treatment outcomes, reduce adverse drug reactions and achieve cost savings. These findings underscore the potential of PGx testing as a valuable tool in clinical decision making, promoting its use in a pre-emptive manner to enhance patient care.

PMID:39971612 | DOI:10.1111/bcpt.70009

QJM. 2025 Feb 20:hcaf035. doi: 10.1093/qjmed/hcaf035. Online ahead of print.

ABSTRACT

BACKGROUND: Variation in DNA is known to contribute to medication response, impacting both medicine effectiveness and incidence of adverse drug reactions (ADRs). However, clinical implementation of pharmacogenomics (PGx) has been slow, and the views of the public are not well understood.

AIM: To assess UK national public attitudes around pharmacogenetics.

DESIGN AND METHODS: The survey was co-designed with the Participant Panel at Genomics England and the data were collected by the National Centre for Social Research, using its nationally representative panel of UK adults. Multivariable logistic regression analyses were used to analyse relationships between selected survey reported variables, controlled for age and sex.

RESULTS: The survey response rate was 58%. Two thousand seven hundred and nineteen responses were obtained. Most respondents (59%) had experienced either no benefit or a side effect. Forty-five per cent of respondents reported having experienced no benefit and 46% of respondents reported having experienced a side effect, with female respondents more likely to be in both groups (P < 0.0001). Despite variability in interindividual medicine response being well understood (89%), the involvement of DNA in predicting benefit or risk of a side effect is not (understood by 52% and 48%, respectively). Eighty-nine per cent would complete a PGx test, with 91% wanting direct access to this information. Eighty-five per cent of UK adults think that the NHS should offer PGx to those regularly taking many medicines. Respondents were not more worried overall about misuse of PGx data compared with other routine medical data. Experience with prescription medication impacted on views with those who were prescribed medication almost twice as likely to want a PGx test for any reason.

CONCLUSION: Most respondents reported experience with either a medication not working for them or ADRs. There was a high level of understanding of variable medication response but a relatively low level of awareness of the role genetics plays in that variability. Most respondents would want a PGx test, to have direct access to results, and think the NHS should offer this form of testing. Importantly, respondents were not more concerned about PGx data use than that of any other routinely generated medical data. Notably, this study highlights a relationship between individuals' experiences with prescription medications and their interest in PGx testing, underscoring the potential for personalized medicine to address public healthcare needs.

PMID:39971322 | DOI:10.1093/qjmed/hcaf035

Prog Neuropsychopharmacol Biol Psychiatry. 2025 Feb 17:111292. doi: 10.1016/j.pnpbp.2025.111292. Online ahead of print.

ABSTRACT

Response to antidepressants (ADs) is highly variable and partly genetically driven, but the utility of pharmacogenetic testing in guiding ADs treatment is still controversial. We conducted a retrospective, naturalistic study to explore the utility of CYP2C6 and CYP2C19 genotyping in ADs treatment in a sample of 156 patients diagnosed with major depressive disorder from South Sardinia (Italy). Clinical data, including history of medication regimens, adverse reactions, and response to ADs, were collected over the last five years preceding recruitment. Patients received pharmacogenetic testing at recruitment and were classified depending on whether their history of treatment regimen followed the recommendations of the Clinical Pharmacogenetics Implementation Consortium (CPIC)). Non-responders to ADs had a larger number of therapeutic regimens and of medication changes due to lack of response compared to responders. Patients with at least one incongruent regimen had a larger number of total therapeutic changes and fewer congruent regimens. Metabolizing phenotypes of CYP2D6 were not associated with response to ADs or changes in regimen of any kind. However, the group of ultra-rapid metabolizers for CYP2C19 showed significantly smaller improvement in symptoms while the poor-metabolizers showed a larger number of medication changes for side effects compared to normal, intermediate and rapid metabolizers. Our findings suggest that the implementation of pharmacogenetic testing based on CYP2C19 could be clinically useful in guiding AD treatment, but further studies are warranted to investigate the clinical implications of implementing PGx testing in depression.

PMID:39971121 | DOI:10.1016/j.pnpbp.2025.111292

Benef Microbes. 2025 Feb 12:1-14. doi: 10.1163/18762891-bja00058. Online ahead of print.

ABSTRACT

Faecalibacterium is an essential probiotic in the human gut; changes in its abundance are associated with various disease states in many studies. However, the causal nature of such associations remains obscure. Therefore, we aimed to thoroughly investigate the causal relationships between Faecalibacterium and its related diseases. A two-sample bi-directional Mendelian randomisation analysis was conducted using publicly available genome-wide association studies summary statistics for Faecalibacterium and its related diseases. We found that Faecalibacterium was negatively correlated with the risk of ankylosing spondylitis (odds ratio [OR] = 0.526, 95% confidence interval [CI]:0.304-0.908, P = 0.021), atopic dermatitis (OR = 0.484, 95%CI: 0.261-0.898, P = 0.021) and heart failure (OR = 0.657, 95%CI: 0.467-0.924, P = 0.016), while Faecalibacterium was positively associated with autism spectrum disorder risk (OR = 2.529, 95%CI: 1.012-6.319, P = 0.047). The results of reverse Mendelian randomisation analysis showed that acute sinusitis (OR = 0.902, 95%CI: 0.839-0.970, P = 0.005) and Alzheimer's disease (OR = 0.976, 95%CI: 0.958-0.993, P = 0.008) was causally associated with lower Faecalibacterium abundance, respectively, while cirrhosis (OR = 1.154, 95%CI: 1.028-1.295, P = 0.015) and multiple myeloma (OR = 2.619 × 1012, 95%CI: 2.492-2.754 × 1024, P = 0.043) was causally associated with higher Faecalibacterium abundance. Our findings firstly showed that changes in Faecalibacterium abundance may contribute to the risk of ankylosing spondylitis, atopic dermatitis, heart failure and autism spectrum disorders, and potentially as a result of acute sinusitis, Alzheimer's disease, cirrhosis and multiple myeloma.

PMID:39970929 | DOI:10.1163/18762891-bja00058

Pharmgenomics Pers Med. 2025 Feb 14;18:55-69. doi: 10.2147/PGPM.S502355. eCollection 2025.

ABSTRACT

BACKGROUND: Pharmacogenomics holds significant promise in improving the efficacy and safety of chemotherapy for childhood cancers. However, the field remains underexplored in Africa, where high genetic diversity and substantial disease burdens, including cancers, create unique challenges. This review investigates the current state of pharmacogenomics research in childhood cancer chemotherapies across Africa, focusing on genetic variations influencing chemotherapy efficacy and adverse drug reactions. It also highlights critical gaps, such as limited infrastructure and insufficient healthcare worker knowledge, and emphasizes the importance of capacity-building initiatives in the region.

METHODS: A scoping review was conducted encompassing studies published up to September 2024 that examined pharmacogenomic variations associated with chemotherapies in childhood cancer patients across Africa. The review included laboratory genetic analyses and surveys assessing healthcare workers' knowledge, attitudes, and perceptions regarding pharmacogenomics, particularly in the context of pediatric oncology.

RESULTS: A total of 12 genes were identified across eight studies, including TPMT, CYP3A5, MDR1, MAPT, NUDT15, ITPA, IMPDH1, SLC29A1, SLC28A2, SLC28A3, ABCC4, and MTHFR. The most studied genes were TPMT and CYP3A5, which are involved in the metabolism of 6-mercaptopurine (6-MP) and vincristine, respectively. These studies spanned five African countries, including Kenya, Egypt, Zimbabwe, Nigeria, Tunisia, and Libya, and focused primarily on childhood cancers, particularly acute lymphoblastic leukemia. Chemotherapies frequently studied were 6-MP (reported in five studies), vincristine, cyclophosphamide, and methotrexate. Knowledge of pharmacogenomics among healthcare workers in Africa remains low, though a positive attitude towards its clinical applications was observed.

CONCLUSION: Pharmacogenomic variants, such as TPMT*3A, 3C, and CYP3A53, *6, significantly impact drug metabolism in African children with cancer. However, research remains regionally limited, and gaps in infrastructure and healthcare worker training persist. Expanding research efforts and improving pharmacogenomics capacity through pharmacist training and capacity-building initiatives are essential to advancing personalized medicine in Africa, ultimately improving treatment outcomes for pediatric cancer patients.

PMID:39968370 | PMC:PMC11834739 | DOI:10.2147/PGPM.S502355

J Public Health Afr. 2025 Jan 24;16(1):786. doi: 10.4102/jphia.v16i1.786. eCollection 2025.

ABSTRACT

The intersection of mpox and mental health is a critical concern, particularly for individuals with pre-existing mental disorders, who face heightened psychological stress and exacerbation of symptoms. This study explores the potential of genetic testing, such as Polygenic Risk Scores and pharmacogenetics, in enhancing mental disorders and mpox management. By tailoring treatment and prevention strategies to an individual's genetic profile, clinicians can provide more personalised care, reducing adverse effects and improving outcomes. Furthermore, genetic insights can inform the development of safer vaccines and early interventions, particularly for vulnerable populations. The study underscores the importance of integrating mental and public health strategies, advocating for targeted research and fostering interdisciplinary collaboration to effectively address these complex health challenges.

PMID:39968354 | PMC:PMC11830839 | DOI:10.4102/jphia.v16i1.786

Arch Med Sci. 2022 Jun 30;20(6):1993-2001. doi: 10.5114/aoms/150867. eCollection 2024.

ABSTRACT

INTRODUCTION: Cholecystokinin (CCK) is involved in several metabolic pathways, and CCK agonists are considered as a potential novel treatment option in populations with increased metabolic risk, including polycystic ovary syndrome (PCOS). As genetic variability of cholecystokinin A and B receptor genes (CCKAR and CCKBR, respectively) may modify their biological actions, we investigated the impact of CCKAR and CCKBR genetic variability on anthropometric and metabolic parameters in patients with PCOS.

MATERIAL AND METHODS: Our cross-sectional study included 168 patients with PCOS and 82 healthy female controls genotyped for polymorphisms in CCKAR (rs6448456 and rs1800857) and CCKBR (rs2929180, rs1800843, rs1042047 and rs1042048) genes.

RESULTS: The investigated polymorphisms were not associated with anthropometric characteristics of patients with PCOS. However, among healthy controls, carriers of at least one polymorphic CCKBR rs1800843 allele had a larger waist circumference (p = 0.027) and more visceral fat (p = 0.046). Among PCOS patients, carriers of at least one polymorphic CCKAR rs6448456 C allele had significantly higher total blood cholesterol and LDL, and significantly lower blood glucose levels after 30, 60 and 90 min of the oral glucose tolerance test (all p < 0.05). Healthy controls with at least one polymorphic CCKAR rs1800857 C allele were less likely to have a high metabolic syndrome burden (p = 0.029).

CONCLUSIONS: Genetic variability in CCKAR affects lipid profile and post-load glucose levels in patients with PCOS and is associated with metabolic syndrome burden in healthy young women. Further investigation of the role of genetic variability in CCKAR and CCKBR could contribute to development of individually tailored treatment strategies with CCK receptor agonists.

PMID:39967955 | PMC:PMC11831332 | DOI:10.5114/aoms/150867

Clin Transl Sci. 2025 Feb;18(2):e70126. doi: 10.1111/cts.70126.

ABSTRACT

Pharmacogenetic testing provides patient genotype information which could influence medication selection and dosing for optimal patient care. Insurance coverage for pharmacogenetic testing varies widely. A better understanding of the commonly used medications with clinically important pharmacogenetic recommendations can inform which medications and/or genes should be prioritized for coverage and reimbursement in the context of finite healthcare resources. The aim of this scoping review was to collate previous studies that investigated the utilization rate of medications that could be guided by pharmacogenetic testing. Included studies utilized electronic medical records or claims data to assess pharmacogenetic medication prescription rates for older adults (≥ 65 years old). Identified pharmacogenetic medications were classified according to therapeutic class and assessed for actionability based on the Clinical Pharmacogenetics Implementation Consortium guidelines. Across the 31 included studies, analgesic (n = 29), psychotropic (n = 29), and cardiovascular (n = 27) therapeutic classes were most commonly investigated. Study populations were primarily generalized (48%); however, some studies focused on specific populations, such as, cancer (n = 6), mental health (n = 1), and nursing home (n = 2) cohorts. A total of 215 unique pharmacogenetic medications were reported, of which, 82 were associated with actionable pharmacogenetic recommendations. The most frequent genes implicated in potential drug-gene interactions with these actionable pharmacogenetic drugs were CYP2D6 (25.6%), CYP2C19 (18.3%), and CYP2C9 (11%). Medications most frequently prescribed included pantoprazole (range 0%-49.6%), simvastatin (range 0%-54.9%), and ondansetron (range 0.1%-62.6%). Overall, the frequently prescribed medications and associated genes identified in this review could guide pharmacogenetic testing implementation into clinical practice, including insurer subsidization.

PMID:39967300 | DOI:10.1111/cts.70126

Nat Genet. 2025 Feb 18. doi: 10.1038/s41588-025-02087-4. Online ahead of print.

ABSTRACT

Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality with both monogenic and polygenic components. Here, we report results from a large genome-wide association study and multitrait analysis including 5,900 HCM cases, 68,359 controls and 36,083 UK Biobank participants with cardiac magnetic resonance imaging. We identified 70 loci (50 novel) associated with HCM and 62 loci (20 novel) associated with relevant left ventricular traits. Among the prioritized genes in the HCM loci, we identify a novel HCM disease gene, SVIL, which encodes the actin-binding protein supervillin, showing that rare truncating SVIL variants confer a roughly tenfold increased risk of HCM. Mendelian randomization analyses support a causal role of increased left ventricular contractility in both obstructive and nonobstructive forms of HCM, suggesting common disease mechanisms and anticipating shared response to therapy. Taken together, these findings increase our understanding of the genetic basis of HCM, with potential implications for disease management.

PMID:39966646 | DOI:10.1038/s41588-025-02087-4

Pharmacogenomics J. 2025 Feb 18;25(2):1. doi: 10.1038/s41397-025-00362-5.

ABSTRACT

Patients carrying specific HLA risk alleles are at higher risk for developing drug hypersensitivity reactions, yet pre-therapeutic screening is uncommon. We examined whether patients with a history of drug allergies have more HLA risk alleles to assess whether these patients are potential candidates for pre-therapeutic HLA screening. We performed a case-control study with patients who had a self-reported history of drug allergy (N = 94) and patients without such a history (N = 185). HLA regions were sequenced by use of Alloseq Tx for HLA-A -B, -C, -DP, -DQ and -DR genotypes. A logistic regression was performed to investigate whether the number of HLA risk alleles differed between cases and controls. Sequencing data of 279 patients were available for this analysis. There was no statistically significant difference in the mean number of unique HLA risk alleles between the cases and controls (5.31 vs 5.31, p = 0.9397). Therefore, patients with a self-reported history of drug allergy do not form a suitable group for pre-therapeutic screening for HLA risk alleles to prevent future drug allergies.

PMID:39966354 | DOI:10.1038/s41397-025-00362-5

Pharmacol Res. 2025 Feb 15:107660. doi: 10.1016/j.phrs.2025.107660. Online ahead of print.

ABSTRACT

Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant embryonal brain tumor driven by genetic alterations inactivating the SMARCB1 or, less commonly, the SMARCA4 gene. Large-scale molecular profiling studies have identified distinct molecular subtypes termed AT/RT-TYR, -SHH and -MYC. Despite the increasing knowledge of AT/RT biology, curative treatment options are still lacking for certain risk groups and outcomes of these patients remain poor. We performed an in vitro high-throughput drug screen of 768 small molecule drugs covering conventional chemotherapeutic agents and late-stage developmental drugs in 13 AT/RT cell lines and determined intra- and inter-entity differential responses to unravel specific vulnerabilities. Our data demonstrated in vitro preferential activity of mitogen-activated protein kinase kinase (MEK) and mouse double minute 2 homolog (MDM2) inhibitors in AT/RT cell lines compared to other high-grade brain tumor cell lines including medulloblastoma and malignant glioma models. Moreover, we were able to link distinct drug response patterns to AT/RT molecular subtypes through integration of drug response data with large-scale DNA methylation and RNASeq-based expression profiles. Subtype-dependent drug response profiles demonstrated sensitivity of AT/RT-SHH cell lines to B-cell lymphoma 2 (BCL2) and heat shock protein 90 (HSP90) inhibitors, and increased activity of microtubule inhibitors, kinesin spindle protein (KSP) inhibitors, and the eukaryotic translation initiation factor 4E (eIF4E) inhibitor briciclib in a subset of AT/RT-MYC cell lines. In summary, our in vitro pharmacogenomic approach revealed preclinical evidence of tumor type- and subtype-specific therapeutic vulnerabilities in AT/RT cell lines that may inform future in vivo and clinical evaluations of novel pharmacological strategies.

PMID:39961404 | DOI:10.1016/j.phrs.2025.107660