Br J Clin Pharmacol. 2024 Jun 12. doi: 10.1111/bcp.16122. Online ahead of print.

ABSTRACT

AIMS: Pharmacogenetics (PGx) is increasingly recognized as a strategy for medicines optimisation and prevention of adverse drug reactions. According to guidelines produced by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetic Working Group (DPWG), most medicines with drug-gene interactions (DGIs) are prescribed in primary care. This study aimed to estimate the prevalence of potential and actionable DGIs involving all medicines dispensed in Irish primary care.

METHODS: Dispensings of 46 drugs to General Medical Services (GMS) patients in the Health Service Executive Primary Care Reimbursement Service Irish pharmacy claims database from 01 January 2021 to 31 December 2021 were analysed to estimate the national prevalence of total dispensings and incidence of first-time dispensings of drugs with potential DGIs according to the CPIC and/or DPWG guidelines. Phenotype frequency data from the UK Biobank and the CPIC were used to estimate the incidence of actionable DGIs.

RESULTS: One in five dispensings (12 443 637 of 62 754 498, 19.8%) were medicines with potential DGIs, 1 878 255 of these dispensed for the first time. On application of phenotype frequencies and linked guideline based therapeutic recommendations, 2 349 055 potential DGIs (18.9%) required action, such as monitoring and guarding against maximum dose, drug or dose change. One in five (369 700, 19.7%) first-time dispensings required action, with 139 169 (7.4%) requiring a change in prescribing. Antidepressants, weak opioids and statins were most commonly identified as having actionable DGIs.

CONCLUSIONS: This study estimated a high prevalence of DGIs in primary care in Ireland, identifying the need and opportunity to optimize drug therapy through PGx testing.

PMID:38864275 | DOI:10.1111/bcp.16122

Head Neck. 2024 Jun 12. doi: 10.1002/hed.27847. Online ahead of print.

ABSTRACT

BACKGROUND: Tracheoesophageal speech is one of the most effective method used for voice rehabilitation after laryngectomy. The main limitation is the need for periodic voice prothesis (VP) replacements. The process of developing VP usage complications is still unexplored. The aim of this study was to assess the level of cytokines (IL-1β, IL-6, IL-8, IL-10, TNFα) and pepsin in saliva as potential factors reducing VP longevity.

METHODS: Prospective double-blind randomized clinical trial was conducted (NCT04268459). Patients were randomly divided into two groups depending on VP replacement regimen (regular-every 3 months, or irregular-when complications occur). Levels of IL-1β, IL-6, IL-8, IL-10, TNFα, and pepsin in saliva samples (fasting and after eating) of laryngectomized patients were measured using ELISA tests.

RESULTS: Fifty-two patients (26 in both groups) with control group (7 patients) participated in the study. The level of IL-1β, IL-6, IL-8, IL-10, TNFα, and pepsin did not differ according to regularity of VP replacements (p = 0.301-0.801). IL-6 levels were significantly higher when VP complications occurs (p = 0.012).

CONCLUSIONS: The saliva components were not significantly different depending on the frequency of VP replacements. IL-6 plays an important role in the development of VP use complications.

PMID:38864228 | DOI:10.1002/hed.27847

Clin Pharmacol Ther. 2024 Jun 11. doi: 10.1002/cpt.3338. Online ahead of print.

ABSTRACT

Methadone is a mu (μ) opioid receptor agonist used clinically in adults and children to manage opioid use disorder, neonatal abstinence syndrome, and acute and chronic pain. It is typically marketed as a racemic mixture of R- and S-enantiomers. R-methadone has 30-to 50-fold higher analgesic potency than S-methadone, and S-methadone has a greater adverse effect (prolongation) on the cardiac QTc interval. Methadone undergoes stereoselective metabolism. CYP2B6 is the primary enzyme responsible for catalyzing the metabolism of both enantiomers to the inactive metabolites, S- and R-2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (S- and R-EDDP). Genetic variation in the CYP2B6 gene has been investigated in the context of implications for methadone pharmacokinetics, dose, and clinical outcomes. Most CYP2B6 variants result in diminished or loss of CYP2B6 enzyme activity, which can lead to higher plasma methadone concentrations (affecting S- more than R-methadone). However, the data do not consistently indicate that CYP2B6-based metabolic variability has a clinically significant effect on methadone dose, efficacy, or QTc prolongation. Expert analysis of the published literature does not support a change from standard methadone prescribing based on CYP2B6 genotype (updates at www.cpicpgx.org).

PMID:38863207 | DOI:10.1002/cpt.3338

Transl Psychiatry. 2024 Jun 11;14(1):252. doi: 10.1038/s41398-024-02870-7.

ABSTRACT

Excessive and persistent aggressiveness is the most common behavioral problem that leads to psychiatric referrals among children. While half of the variance in childhood aggression is attributed to genetic factors, the biological mechanism and the interplay between genes and environment that results in aggression remains elusive. The purpose of this systematic review is to provide an overview of studies examining the genetics of childhood aggression irrespective of psychiatric diagnosis. PubMed, PsycINFO, and MEDLINE databases were searched using predefined search terms for aggression, genes and the specific age group. From the 652 initially yielded studies, eighty-seven studies were systematically extracted for full-text review and for further quality assessment analyses. Findings show that (i) investigation of candidate genes, especially of MAOA (17 studies), DRD4 (13 studies), and COMT (12 studies) continue to dominate the field, although studies using other research designs and methods including genome-wide association and epigenetic studies are increasing, (ii) the published articles tend to be moderate in sizes, with variable methods of assessing aggressive behavior and inconsistent categorizations of tandem repeat variants, resulting in inconclusive findings of genetic main effects, gene-gene, and gene-environment interactions, (iii) the majority of studies are conducted on European, male-only or male-female mixed, participants. To our knowledge, this is the first study to systematically review the effects of genes on youth aggression. To understand the genetic underpinnings of childhood aggression, more research is required with larger, more diverse sample sets, consistent and reliable assessments and standardized definition of the aggression phenotypes. The search for the biological mechanisms underlying child aggression will also benefit from more varied research methods, including epigenetic studies, transcriptomic studies, gene system and genome-wide studies, longitudinal studies that track changes in risk/ameliorating factors and aggression-related outcomes, and studies examining causal mechanisms.

PMID:38862490 | DOI:10.1038/s41398-024-02870-7

Nature. 2024 Jun 11. doi: 10.1038/s41586-024-07586-8. Online ahead of print.

ABSTRACT

The recent acceleration of commercial, private, and multi-national spaceflight has created an unprecedented level of activity in low Earth orbit (LEO), concomitant with the highest-ever number of crewed missions entering space and preparations for exploration-class (>1 year) missions. Such rapid advancement into space from many new companies, countries, and space-related entities has enabled a"Second Space Age." This new era is also poised to leverage, for the first time, modern tools and methods of molecular biology and precision medicine, thus enabling precision aerospace medicine for the crews. The applications of these biomedical technologies and algorithms are diverse, encompassing multi-omic, single-cell, and spatial biology tools to investigate human and microbial responses to spaceflight. Additionally, they extend to the development of new imaging techniques, real-time cognitive assessments, physiological monitoring, and personalized risk profiles tailored for astronauts. Furthermore, these technologies enable advancements in pharmacogenomics (PGx), as well as the identification of novel spaceflight biomarkers and the development of corresponding countermeasures. In this review, we highlight some of the recent biomedical research from the National Aeronautics and Space Administration (NASA), Japan Aerospace Exploration Agency (JAXA), European Space Agency (ESA), and other space agencies, and also detail the commercial spaceflight sector's (e.g. SpaceX, Blue Origin, Axiom, Sierra Space) entrance into aerospace medicine and space biology, the first aerospace medicine biobank, and the myriad upcoming missions that will utilize these tools to ensure a permanent human presence beyond LEO, venturing out to other planets and moons.

PMID:38862027 | DOI:10.1038/s41586-024-07586-8

Semergen. 2024 Jun 10;50(6):102273. doi: 10.1016/j.semerg.2024.102273. Online ahead of print.

NO ABSTRACT

PMID:38861920 | DOI:10.1016/j.semerg.2024.102273

Clin Transl Sci. 2024 Jun;17(6):e13822. doi: 10.1111/cts.13822.

ABSTRACT

Specific selective serotonin reuptake inhibitors (SSRIs) metabolism is strongly influenced by two pharmacogenes, CYP2D6 and CYP2C19. However, the effectiveness of prospectively using pharmacogenetic variants to select or dose SSRIs for depression is uncertain in routine clinical practice. The objective of this prospective, multicenter, pragmatic randomized controlled trial is to determine the effectiveness of genotype-guided selection and dosing of antidepressants on control of depression in participants who are 8 years or older with ≥3 months of depressive symptoms who require new or revised therapy. Those randomized to the intervention arm undergo pharmacogenetic testing at baseline and receive a pharmacy consult and/or automated clinical decision support intervention based on an actionable phenotype, while those randomized to the control arm have pharmacogenetic testing at the end of 6-months. In both groups, depression and drug tolerability outcomes are assessed at baseline, 1 month, 3 months (primary), and 6 months. The primary end point is defined by change in Patient-Reported Outcomes Measurement Information System (PROMIS) Depression score assessed at 3 months versus baseline. Secondary end points include change inpatient health questionnaire (PHQ-8) measure of depression severity, remission rates defined by PROMIS score < 16, medication adherence, and medication side effects. The primary analysis will compare the PROMIS score difference between trial arms among those with an actionable CYP2D6 or CYP2C19 genetic result or a CYP2D6 drug-drug interaction. The trial has completed accrual of 1461 participants, of which 562 were found to have an actionable phenotype to date, and follow-up will be complete in April of 2024.

PMID:38860639 | DOI:10.1111/cts.13822

CNS Neurol Disord Drug Targets. 2024 Jun 7. doi: 10.2174/0118715273298953240529100325. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: The association between carbamazepine (CBZ) metabolism and resistance in epilepsy and the genetic polymorphisms of CYP3A5 (rs776746 and rs15524) and CYP3A4 (rs2242480, rs2740574, rs35599367, rs12721627, and rs28371759) has been the subject of previous investigations with controversial results. We conducted a systematic review to assess the potential link between these polymorphisms and CBZ metabolism and resistance.

METHODS: Identifying relevant studies, was carried out bay searching PubMed, Scopus, PharmGKB, EPIGAD, and PHARMAADME databases up until June 2023. The studies included in our analysis investigated the connection between CYP3A5 (rs776746 and rs15524) and CYP3A4 (rs2242480, rs2740574, rs35599367, rs12721627, and rs28371759) polymorphisms and CBZ metabolism and resistance.

RESULTS: This review included a total of 23 studies and more than 2177 epilepsy patients. As a result the CYP3A4 (rs12721627 and rs28371759) polymorphisms are associated with reduced catalytic activity, where the CYP3A4 (rs2740574) polymorphism is linked to lower levels of CBZ-diol and decreased activity. It's been found also that the CYP3A5 (rs776746) polymorphism influences the dose-adjusted plasma levels of CBZ.

CONCLUSION: Although these findings highlight the impact of genetic variations in the CYP3A4 and CYP3A5 genes on CBZ pharmacokinetics and pharmacodynamics, further studies across diverse populations are essential to enhance personalized epilepsy therapy in clinical settings.

PMID:38859787 | DOI:10.2174/0118715273298953240529100325

Clin Pharmacol Ther. 2024 Jun 10. doi: 10.1002/cpt.3343. Online ahead of print.

ABSTRACT

In this study, we investigated the combined influence of pregnancy and genetic polymorphisms on efavirenz pharmacokinetics in cervicovaginal fluid (CVF) of women receiving antiretroviral therapy. Women receiving efavirenz-containing antiretroviral therapy were recruited from two hospitals in Nigeria during 2017-2020. Sparse CVF and plasma samples were obtained during pregnancy to assess the possible association between drug concentration and CYP2B6 polymorphisms (stage I). Participants were stratified into three CYP2B6 516G>T (rs3745274) genotype groups and re-enrolled for intensive pharmacokinetic sampling (stage II). Overall, 159 women (142 pregnant and 12 postpartum) contributed samples in stage I (88 CVF, 81 plasma and 73 paired). CYP2B6 516G>T (rs3745274) remained independently associated with log10 efavirenz CVF concentration during pregnancy after adjusting for plasma concentration, with β (Log10 efavirenz concentration, 95%CI) of 0.204 (0.027, 0.382), P = 0.025). Median (IQR) efavirenz Cmin in CVF during pregnancy (n = 12) vs. postpartum (n = 12) was 243 ng/mL (168-402) vs. 447 ng/mL (159-974), Cmax was 1,031 ng/mL (595-1,771) vs. 1,618 ng/mL (675-2,695), and AUC0-24h was 16,465 ng.h/mL (9,356-30,417) vs. 30,715 ng.h/mL (10,980-43,714). CVF-to-plasma AUC ratio was 0.36 during pregnancy and 0.46 postpartum. Upon stratification, efavirenz clearance during pregnancy was 57.9% higher than postpartum in patients with the CYP2B6 516GT genotype; the AUC0-24h and Cmax were 33.8% and 8.6% lower, respectively. Efavirenz Cmin in CVF exceeded the protein binding-adjusted IC90 (PBIC90) of 126 ng/mL during pregnancy and postpartum. Efavirenz is well distributed into the CVF; both pregnancy and CYP2B6 polymorphisms affect the extent of exposure.

PMID:38859656 | DOI:10.1002/cpt.3343

Breast Cancer Res. 2024 Jun 10;26(1):97. doi: 10.1186/s13058-024-01848-z.

ABSTRACT

BACKGROUND: Tumor immune infiltration and peripheral blood immune signatures have prognostic and predictive value in breast cancer. Whether distinct peripheral blood immune phenotypes are associated with response to neoadjuvant chemotherapy (NAC) remains understudied.

METHODS: Peripheral blood mononuclear cells from 126 breast cancer patients enrolled in a prospective clinical trial (NCT02022202) were analyzed using Cytometry by time-of-flight with a panel of 29 immune cell surface protein markers. Kruskal-Wallis tests or Wilcoxon rank-sum tests were used to evaluate differences in immune cell subpopulations according to breast cancer subtype and response to NAC.

RESULTS: There were 122 evaluable samples: 47 (38.5%) from patients with hormone receptor-positive, 39 (32%) triple-negative (TNBC), and 36 (29.5%) HER2-positive breast cancer. The relative abundances of pre-treatment peripheral blood T, B, myeloid, NK, and unclassified cells did not differ according to breast cancer subtype. In TNBC, higher pre-treatment myeloid cells were associated with lower pathologic complete response (pCR) rates. In hormone receptor-positive breast cancer, lower pre-treatment CD8 + naïve and CD4 + effector memory cells re-expressing CD45RA (TEMRA) T cells were associated with more extensive residual disease after NAC. In HER2 + breast cancer, the peripheral blood immune phenotype did not differ according to NAC response.

CONCLUSIONS: Pre-treatment peripheral blood immune cell populations (myeloid in TNBC; CD8 + naïve T cells and CD4 + TEMRA cells in luminal breast cancer) were associated with response to NAC in early-stage TNBC and hormone receptor-positive breast cancers, but not in HER2 + breast cancer.

TRIAL REGISTRATION: NCT02022202 . Registered 20 December 2013.

PMID:38858721 | DOI:10.1186/s13058-024-01848-z

Appetite. 2024 Jun 8:107551. doi: 10.1016/j.appet.2024.107551. Online ahead of print.

ABSTRACT

BACKGROUND: A growing body of evidence suggests that children of mothers with eating disorders (EDs) have a greater risk of early feeding problems. Recognizing and reacting adequately to the infant's signals during feeding is crucial for the child's development of internal and external regulatory mechanisms of food intake. Parental EDs might affect this ability. Therefore, we investigated the quality of mother-infant interactions during feeding using video recording and a structured coding system.

METHODS: The data of this pilot study was collected in a prospective cohort study investigating the influence of maternal EDs on child outcomes. Twenty women with ED history and 31 control women were videotaped while feeding their infant during a main meal at ten months postpartum. The mother-infant interactions were evaluated by two raters using the Chatoor Feeding Scale. We assessed birth outcomes, the mother's ED and depression status, breastfeeding practices, infant feeding problems and infant temperament by maternal self-report.

RESULTS: Mothers with and without ED history scored very similar on the Feeding Scale, however mothers from the control group experienced more struggle for control with their infants during feeding (p = .046) and made more negative comments about the infant's food intake (p = .010). Mothers with ED history were more concerned about infant feeding at three months postpartum and reported significantly more problems with solid foods in their children. Birth outcomes were comparable between groups, except for lower weight-for-length birth percentiles in children of women with ED history.

CONCLUSION: Whilst examined mothers with ED history are more concerned about feeding their children, ED psychopathology does not affect the quality of mother-infant interaction during feeding at the transition to autonomous eating at ten months of age.

PMID:38857768 | DOI:10.1016/j.appet.2024.107551

Rev Neurosci. 2024 Jun 11. doi: 10.1515/revneuro-2024-0045. Online ahead of print.

ABSTRACT

Migraine is a multidimensional disease affecting a large portion of the human population presenting with a variety of symptoms. In the era of personalized medicine, successful migraine treatment presents a challenge, as several studies have shown the impact of a patient's genetic profile on therapy response. However, with the emergence of contemporary treatment options, there is promise for improved outcomes. A literature search was conducted in PubMed and Scopus, in order to obtain studies investigating the impact of genetic factors on migraine therapy outcome. Overall, 23 studies were included in the current review, exhibiting diversity in the treatments used and the genetic variants investigated. Divergent genes were assessed for each category of migraine treatment. Several genetic factors were identified to contribute to the heterogeneous response to treatment. SNPs related to pharmacodynamic receptors, pharmacogenetics and migraine susceptibility loci were the most investigated variants, revealing some interesting significant results. To date, various associations have been recorded correlating the impact of genetic factors on migraine treatment responses. More extensive research needs to take place with the aim of shedding light on the labyrinthine effects of genetic variations on migraine treatment, and, consequently, these findings can promptly affect migraine treatment and improve migraine patients' life quality in the vision of precise medicine.

PMID:38856190 | DOI:10.1515/revneuro-2024-0045

Transl Androl Urol. 2024 May 31;13(5):748-758. doi: 10.21037/tau-24-10. Epub 2024 May 28.

ABSTRACT

BACKGROUND: The association between psoriasis and erectile dysfunction (ED) is currently inconsistent in epidemiological and observational studies and the causal relationship between them has not been established. The aim of our study is to explore the potential genetic association between ED and psoriasis.

METHODS: We explored the putative causality between psoriasis and ED by bidirectional Mendelian randomization (MR). The single nucleotide polymorphisms (SNPs) associated with psoriasis were retrieved from a large-scale public genome-wide association study (GWAS). The summary statistics of ED were obtained from individuals of European ancestry with 6,175 cases vs. 217,630 controls. Inverse-variant weighted (IVW), weighted median (WM), MR-Egger, MR-Steiger, and MR pleiotropy residual sum and outlier (MR-PRESSO) test were employed in MR analyses to investigate the bidirectional causal relationship between psoriasis and ED. Several sensitivity analyses were employed to confirm the findings of the MR analysis.

RESULTS: Our MR analysis indicated that genetically predicted psoriasis showed no association with a higher risk of ED [odds ratio (OR) 2.878, 95% confidence interval (CI): 0.175-47.289, P=0.46]. As for the other direction, no causal association was disclosed between ED and psoriasis (OR 0.999, 95% CI: 0.997-1.002, P=0.62). These findings remained consistent in sensitivity analyses.

CONCLUSIONS: The study revealed a negative genetic association between psoriasis and ED. Certain acquired factors may contribute to a strong clinical connection between the two, highlighting the need for comprehensive management of these risk factors.

PMID:38855583 | PMC:PMC11157395 | DOI:10.21037/tau-24-10

medRxiv [Preprint]. 2024 Jun 2:2024.06.01.24308310. doi: 10.1101/2024.06.01.24308310.

ABSTRACT

INTRODUCTION: Tuberculosis (TB) is the leading infectious cause of death globally. Despite WHO recommendations for Tuberculosis Preventive Therapy (TPT), challenges persist, including incompletion of treatment and adverse drug reactions (ADRs). There is limited data on the 3-month isoniazid and rifapentine (3HP) pharmacokinetics, pharmacogenomics and their relation with ADRs. Our study aims to describe the pharmacokinetic and pharmacogenomics of 3HP used for TPT, the ADRs and their association with completion rates, and TPT outcomes, providing vital insights for TB control strategies in resource-limited settings.

METHODS: This is an observational cohort study with a nested case-control study. We enrolled consecutive patients initiated on TPT using the 3HP regimen. These are followed up bi-weekly and then monthly during the active phase of treatment and 3 monthly for 2 years following completion of TPT. ADR evaluation includes clinical assessment and liver function tests. Cases are selected from those who experience ADRs, and controls from those who do not. Serum isoniazid and rifapentine concentrations are measured and pharmacogenomic analysis for NAT2 and CYP2E1 polymorphisms are done. Participants are followed up for 2 years to determine TPT outcomes.

ANALYSIS: The safety profile of 3HP will be assessed using descriptive statistics, including proportions of patients experiencing ADRs and grade 3 or above events related to treatment. Chi-square tests and regression models will determine predictors of ADRs and their impact on treatment completion. Pharmacokinetic-pharmacodynamic modeling will establish population parameters and factors influencing rifapentine and isoniazid concentrations.

PMID:38853861 | PMC:PMC11160854 | DOI:10.1101/2024.06.01.24308310

Clin Transl Sci. 2024 Jun;17(6):e13830. doi: 10.1111/cts.13830.

ABSTRACT

Computational methods analyze genomic data to identify genetic variants linked to drug responses, thereby guiding personalized medicine. This study analyzed 942 whole-genome sequences from the Electricity Generating Authority of Thailand (EGAT) cohort to establish a population-specific pharmacogenomic database (TPGxD-1) in the Thai population. Sentieon (version 201808.08) implemented the GATK best workflow practice for variant calling. We then annotated variant call format (VCF) files using Golden Helix VarSeq 2.5.0 and employed Stargazer v2.0.2 for star allele analysis. The analysis of 63 very important pharmacogenes (VIPGx) reveals 85,566 variants, including 13,532 novel discoveries. Notably, we identified 464 known PGx variants and 275 clinically relevant novel variants. The phenotypic prediction of 15 VIPGx demonstrated a varied metabolic profile for the Thai population. Genes like CYP2C9 (9%), CYP3A5 (45.2%), CYP2B6 (9.4%), NUDT15 (15%), CYP2D6 (47%) and CYP2C19 (43%) showed a high number of intermediate metabolizers; CYP3A5 (41%), and CYP2C19 (9.9%) showed more poor metabolizers. CYP1A2 (52.7%) and CYP2B6 (7.6%) were found to have a higher number of ultra-metabolizers. The functional prediction of the remaining 10 VIPGx genes reveals a high frequency of decreased functional alleles in SULT1A1 (12%), NAT2 (84%), and G6PD (12%). SLCO1B1 reports 20% poor functional alleles, while PTGIS (42%), SLCO1B1 (4%), and TPMT (5.96%) showed increased functional alleles. This study discovered new variants and alleles in the 63 VIPGx genes among the Thai population, offering insights into advancing clinical pharmacogenomics (PGx). However, further validation is needed using other computational and genotyping methods.

PMID:38853370 | DOI:10.1111/cts.13830

Gene. 2024 Jun 7:148648. doi: 10.1016/j.gene.2024.148648. Online ahead of print.

ABSTRACT

PURPOSE: To investigate the allelic and genotypic frequencies of the two genetic variations, NC_000006.12: g.160275887C > T (rs662301) and NC_000006.12:g.160231826 T > C (rs315978), in the SLC22A2 gene among the Saudi population. The primary goal is to elucidate potential associations with these genetic variations and the response to metformin therapy over 6 months to enhance our knowledge of the genetic basis of Type 2 Diabetes Mellitus (T2DM) and its clinical management in the Saudi population.

MATERIALS/METHODS: 76 newly diagnosed T2DM patients, aged 30 to 60, of both sexes and Saudi origin, were treated with metformin monotherapy. Blood samples were collected before and after 6 months of therapy,80 healthy individuals were included as controls. Genomic DNA was extracted. Genotyping of the SLC22A2 genetic variations was performed using TaqMan® SNP Genotyping Assays. Binary logistic regression was utilized to evaluate how certain clinical parameters influence T2DM concerning the presence of SLC22A2 gene variants.

RESULTS: Among these patients, 73.3 % were responders, and 26.7 % were non-responders. For these variants, no statistically significant differences in genotype or allele frequencies were observed between responders and non-responders (p = 0.375 and p = 0.384 for rs662301; p = 0.473 and p = 0.481 for rs315978, respectively). For the SLC22A2 variant rs662301, the C/C genotype was significantly associated with increased T2DM risk with age and elevated HbA1c levels. Similarly, rs315978 revealed higher T2DM susceptibility and HbA1c elevation in C/C genotype carriers, specifically with advancing age compared to individuals with C/T and T/T genotypes.

CONCLUSION: The study offers insights into the genetic landscape of T2DM in Saudi Arabia. Despite the absence of significant associations with treatment response, the study suggests potential age-specific associations, this highlights the complexity of the disease. This research underscores the necessity for expanded research, considering diverse populations and genetic factors, to develop personalized treatment approaches. This study serves as a foundation for future investigations into the Saudi population, recognizing the need for a larger sample size.

PMID:38852696 | DOI:10.1016/j.gene.2024.148648

Farm Hosp. 2024 Jun 7:S1130-6343(24)00046-1. doi: 10.1016/j.farma.2024.03.010. Online ahead of print.

ABSTRACT

INTRODUCTION: Pharmacogenetics evaluates how genetic variations influence drug responses. Nowadays, genetic tests have advanced, becoming more affordable, and its integration is supported by stronger clinical evidence. Guidelines such as those from CPIC (Clinical Pharmacogenetics Implementation Consortium) and resources like PharmGKB facilitate genotype-based prescribing; and organizations like the FDA promote genetic testing before initiating certain medications. Preventive pharmacogenetic panels seem promising, but further research on biomarkers and diverse populations is needed. The aim of this review is to analyze recent evidence on the genotype-drug response relationship to examine how the genetic profile of patients influences the clinical response to treatments, and analyze the areas of research that need further study to advance towards a genetic-based precision medicine.

MATERIALS AND METHODS: A systematic search was conducted on PubMed to identify articles investigating the genotype-drug response relationship. The search strategy included terms such as "pharmacogenetics", "personalized treatment", "precision medicine", "dose adjustment", "individualized dosing", "clinical routine" and "clinical practice." Clinical trials, observational studies, and meta-analyses published in English or Spanish between 2013 and 2023 were included. The initial search resulted in a total of 136 articles for analysis.

RESULTS: 49 articles were included for the final analysis following review by two investigators. A relationship between genetic polymorphisms and drug response or toxicity was found for drugs such as opioids, GLP-1 agonists, tacrolimus, oral anticoagulants, antineoplastics, atypical antipsychotics, efavirenz, clopidogrel, lamotrigine, anti-TNF-α agents, voriconazole, antidepressants, or statins. However, for drugs like metformin, quetiapine, irinotecan, bisoprolol, and anti-VEGF agents, no statistically significant association between genotype and response was found.

CONCLUSION: The studies analyzed in this review suggest a strong correlation between genetic variability and individual drug responses, supporting the use of pharmacogenetics for treatment optimization. However, for certain drugs like metformin or quetiapine, the influence of genotype on their response remains unclear. More studies with larger sample sizes, greater ethnic diversity, and consideration of non-genetic factors are needed. The lack of standardization in analysis methods and accessibility to genetic testing are significant challenges in this field. As a conclusion, pharmacogenetics shows immense potential in personalized medicine, but further research is required.

PMID:38851909 | DOI:10.1016/j.farma.2024.03.010

Psychiatry Res. 2024 May 27;338:115982. doi: 10.1016/j.psychres.2024.115982. Online ahead of print.

ABSTRACT

Given that anxiety disorders (AD) are associated with reduced vagally-mediated heart rate variability (HRV), genetic variants related to HRV may provide insight into anxiety etiology. This study used polygenic risk scores (PRS) to explore the genetic overlap between AD and HRV, and investigated whether HRV-related polymorphisms influence anxiety risk. Resting vagally-mediated HRV was measured using a wearable device in 188 European individuals (AD=101, healthy controls=87). AD PRS was tested for association with resting HRV, and HRV PRS for association with AD. We also investigated 15 significant hits from an HRV genome-wide association study (GWAS) for association with resting HRV and AD and if this association is mediated through resting HRV. The AD PRS and HRV PRS showed nominally significant associations with resting HRV and anxiety disorders, respectively. HRV GWAS variants associated with resting HRV were rs12980262 (NDUFA11), rs2680344 (HCN4), rs4262 and rs180238 (GNG11), and rs10842383 (LINC00477). Mediation analyses revealed that NDUFA11 rs12980262 A-carriers and GNG11 rs180238 and rs4262 C-carriers had higher anxiety risk through lower HRV. This study supports an anxiety-HRV genetic relationship, with HRV-related genetic variants translating to AD. This study encourages exploration of HRV genetics to understand mechanisms and identify novel treatment targets for anxiety.

PMID:38850888 | DOI:10.1016/j.psychres.2024.115982

Hum Mol Genet. 2024 Jun 9:ddae094. doi: 10.1093/hmg/ddae094. Online ahead of print.

ABSTRACT

Alterations in Dp71 expression, the most ubiquitous dystrophin isoform, have been associated with patient survival across tumours. Intriguingly, in certain malignancies, Dp71 acts as a tumour suppressor, while manifesting oncogenic properties in others. This diversity could be explained by the expression of two Dp71 splice variants encoding proteins with distinct C-termini, each with specific properties. Expression of these variants has impeded the exploration of their unique roles. Using CRISPR/Cas9, we ablated the Dp71f variant with the alternative C-terminus in a sarcoma cell line not expressing the canonical C-terminal variant, and conducted molecular (RNAseq) and functional characterisation of the knockout cells. Dp71f ablation induced major transcriptomic alterations, particularly affecting the expression of genes involved in calcium signalling and ECM-receptor interaction pathways. The genome-scale metabolic analysis identified significant downregulation of glucose transport via membrane vesicle reaction (GLCter) and downregulated glycolysis/gluconeogenesis pathway. Functionally, these molecular changes corresponded with, increased calcium responses, cell adhesion, proliferation, survival under serum starvation and chemotherapeutic resistance. Knockout cells showed reduced GLUT1 protein expression, survival without attachment and their migration and invasion in vitro and in vivo were unaltered, despite increased matrix metalloproteinases release. Our findings emphasise the importance of alternative splicing of dystrophin transcripts and underscore the role of the Dp71f variant, which appears to govern distinct cellular processes frequently dysregulated in tumour cells. The loss of this regulatory mechanism promotes sarcoma cell survival and treatment resistance. Thus, Dp71f is a target for future investigations exploring the intricate functions of specific DMD transcripts in physiology and across malignancies.

PMID:38850567 | DOI:10.1093/hmg/ddae094

Biochem Genet. 2024 Jun 8. doi: 10.1007/s10528-024-10748-y. Online ahead of print.

ABSTRACT

Genetic polymorphisms of very important pharmacogenes (VIP) are a significant factor contributing to inter-individual variability in drug therapy. The purpose of this study was to identify significantly different loci in the Yi population and to enrich their pharmacogenomic information. 54 VIP variants were selected from the Pharmacogenomics Knowledge Base (PharmGKB) and genotyped in 200 Yi individuals. Then, we compared their genotype distribution between the Yi population and the other 26 populations using the χ2 test. Compared with the other 26 populations, the genotype frequencies of 4 single nucleotide polymorphisms (SNPs), rs2108622 (CYP4F2), rs1065852 (CYP2D6), rs2070676 (CYP2E1), and rs4291 (ACE), had significant differences in the Yi population. For example, the TT genotype frequency of rs2108622 (8.1%) was higher than that of African populations, and the AA genotype frequency of rs1065852 (27.3%) was higher than that of other populations except East Asians. We also found that the Yi populations differed the least from East Asians and the most from Africans. Furthermore, the differences in these variants might be related to the effectiveness and toxicity risk of using warfarin, iloperidone, cisplatin cyclophosphamide, and other drugs in the Yi population. Our data complement the pharmacogenomic information of the Yi population and provide theoretical guidance for their personalized treatment.

PMID:38850376 | DOI:10.1007/s10528-024-10748-y