J Cancer. 2024 May 13;15(12):3663-3674. doi: 10.7150/jca.95979. eCollection 2024.

ABSTRACT

In this study, we aimed to elucidate the role of mitochondrial calcium uptake 1/2 (MiCU1/2) in breast cancer (BRCA) by employing a comprehensive multi-omics approach. Unlike previous research, we utilized a novel web application tailored for whole tumor tissue, single-cell, and spatial transcriptomics analysis to investigate the association between MiCU1/2 and the tumor immune microenvironment (TIME). Our gene set enrichment analysis (GSEA) provided insights into the primary biological effects of MiCU1/2, while our CRISPR-based drug screening repository identified potential effective drugs. Our study revealed that high MiCU1/2 expression serves as an independent diagnostic biomarker, correlating with advanced clinical status and indicating poorer recurrence-free survival (RFS) rates in BRCA patients. Additionally, spatial transcriptome analysis highlighted the heightened expression of MiCU1/2 in tumors and its relevance in surrounding immune cells. Furthermore, using the CIBERSORT algorithm, we discovered a positive correlation between MiCU1/2 levels and macrophage infiltration, underscoring their potential impact on immune infiltration. We also identified expression patterns of immune-related genes associated with responses against various immune cell types, including CXCL, MIF, GDF, SPP1, and IL16. Finally, our pharmacogenomic screening identified potential small molecule drugs capable of effectively targeting breast cancer cells with elevated MiCU1/2 expression. Overall, our study establishes MiCU1/2 as a promising novel biomarker for BRCA diagnosis and prognostic prediction, as well as a potential therapeutic target, highlighting the importance of exploring these pathways to advance patient care and outcomes in BRCA treatment.

PMID:38911376 | PMC:PMC11190767 | DOI:10.7150/jca.95979

J Cancer. 2024 May 13;15(12):3633-3644. doi: 10.7150/jca.96100. eCollection 2024.

ABSTRACT

Background: As we delve into the intricate world of mitochondrial inner membrane proteins, particularly Optic Atrophy types 1 and 3 (OPA1/3), we uncover their pivotal role in maintaining mitochondrial dynamic equilibrium and fusion, crucial for cellular energy production and synthesis. Despite extensive scrutiny, the significance of OPA1/3 in breast cancer (BRCA) and its interplay with the immune microenvironment remain elusive. Materials and Methods: We meticulously sourced BRCA data from renowned repositories such as The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Gene Expression Omnibus (GEO), and the Human Protein Atlas (HPA), leveraging cutting-edge techniques including single-cell RNA-sequencing (scRNA-seq), spatial transcriptomics, and pharmacogenomics. Through multifaceted data analysis, we endeavored to unravel the intricate role and potential value of OPA1/3 in BRCA tumorigenesis and progression. Results: Our investigation reveals a conspicuous upregulation of OPA1/3 expression in BRCA, correlating with dismal prognoses. Kaplan-Meier plot analysis underscores that heightened OPA1/3 levels are associated with poor survival rates. Both clinical specimens and biobank biopsies corroborate the elevated expression of OPA1/3 in breast cancer patients. Moreover, scRNA-seq unveils a strong correlation between OPA1/3 and macrophage infiltration in the BRCA immune milieu, alongside its association with the cellular communication network involving CXCL, TGFb, VEGF, and IL16. Conclusion: In light of these findings, OPA1/3 emerges as a promising contender for therapeutic targeting and as a potential diagnostic, prognostic, and survival biomarker in BRCA. The implications of our study underscore the pressing need to explore these novel biomarkers to enhance patient outcomes.

PMID:38911373 | PMC:PMC11190754 | DOI:10.7150/jca.96100

Front Pharmacol. 2024 Jun 7;15:1439276. doi: 10.3389/fphar.2024.1439276. eCollection 2024.

NO ABSTRACT

PMID:38910892 | PMC:PMC11190335 | DOI:10.3389/fphar.2024.1439276

Biol Trace Elem Res. 2024 Jun 24. doi: 10.1007/s12011-024-04227-z. Online ahead of print.

ABSTRACT

Humans are exposed to various chemical elements that have been associated with the development and progression of diseases such as coronary artery disease (CAD). Unlike previous research, we employed a multi-element approach to investigate CAD patients and those with comorbid conditions such as diabetes (CAD-DM2), high blood pressure (CAD-HBP), or high blood lipids (CAD-HBL). Plasma concentrations of 21 elements, including lithium (Li), boron (B), aluminum (Al), calcium (Ca), titanium (Ti), vanadium (V), chromium (Cr), manganese (Mn), iron (Fe), cobalt (Co), nickel (Ni), copper (Cu), zinc (Zn), arsenic (As), selenium (Se), strontium (Sr), cadmium (Cd), tin (Sn), stibium (Sb), barium (Ba), and lead (Pb), were measured in CAD patients (n = 201) and healthy subjects (n = 110) using inductively coupled plasma-mass spectrometry (ICP-MS). Principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) models were utilized to analyze the ionomic profiles. Spearman correlation analysis was employed to identify the interaction patterns among individual elements. We found that levels of Ba, Li, Ni, Zn and Pb were elevated in the CAD group compared to the healthy group, while Sb, Ca, Cu, Ti, Fe, and Se were lower. Furthermore, the CAD-DM2 group exhibited higher levels of Ni and Cd, while the CAD-HBP group showed lower levels of Co and Mn. In the CAD-HBL group, Ti was increased, whereas Ba, Cr, Cu, Co, Mn, and Ni were reduced. In conclusion, ionomic profiles can be utilized to differentiate CAD patients from healthy individuals, potentially providing insights for future treatment or dietary interventions.

PMID:38910164 | DOI:10.1007/s12011-024-04227-z

Eur Neuropsychopharmacol. 2024 Jun 22;85:34. doi: 10.1016/j.euroneuro.2024.05.003. Online ahead of print.

NO ABSTRACT

PMID:38909437 | DOI:10.1016/j.euroneuro.2024.05.003

Methods Mol Biol. 2024;2809:19-36. doi: 10.1007/978-1-0716-3874-3_2.

ABSTRACT

The allele frequency net database (AFND, http://www.allelefrequencies.net ) is an online web-based repository that contains information on the frequencies of immune-related genes and their corresponding alleles in worldwide human populations. At present, the website contains data from 1784 population samples in more than 14 million individuals from 129 countries on the frequency of genes from different polymorphic regions including data for the human leukocyte antigen (HLA) system. In addition, over the last four years, AFND has also incorporated genotype raw data from 85,000 individuals comprising 215 population samples from 39 countries. Moreover, more population data sets containing next generation sequencing data spanning >3 million individuals have been added. This resource has been widely used in a variety of contexts such as histocompatibility, immunology, epidemiology, pharmacogenetics, epitope prediction algorithms for population coverage in vaccine development, population genetics, among many others. In this chapter, we present an update of the most used searching mechanisms as described in a previous volume and some of the latest developments included in AFND.

PMID:38907888 | DOI:10.1007/978-1-0716-3874-3_2

Ann Indian Acad Neurol. 2024 Jun 22. doi: 10.4103/aian.aian_886_23. Online ahead of print.

ABSTRACT

OBJECTIVE: Pharmacogenomics plays an important role in drug metabolism. A stable anticoagulation is important for primary and secondary prevention of cardioembolic stroke and cerebral venous sinus thrombosis (CVST). We report the role of cytochrome P450 (CYP2C9*2/*3) and vitamin K epoxide reductase subunit 1 (VKORC1) genotypes and acquired causes in maintaining stability of anticoagulation following acenocoumarin in cardioembolic stroke and CVST.

METHODS: The study comprised 157 individuals with cardioembolic stroke and CVST who were on acenocoumarin. Their comorbidities, comedication, and dietary habits were noted. Prothrombin time and international normalized ratio (INR) were measured during follow-up, and the coagulation status was categorized as stable (>50% occasions in therapeutic range) and unstable (>50% below and above therapeutic range). Genotyping of VKORC1, CYP2C9*2, and CYP2C9*3 was done by polymerase chain reaction-restriction fragment length polymorphism. Bleeding and embolic complications were noted. The predictors of unstable INR were evaluated using multivariate analysis.

RESULTS: INR was stable in 47.8% and unstable in 52.2% of patients. Patients with mutant genotypes required low dose of acenocoumarin. The predictors of unstable INR were metallic valve (odds ratio [OR] 4.07, 95% confidence interval [CI] 1.23-13.49, P = 0.02), use of digoxin (OR 0.031, 95% CI 0.13-0.74, P = 0.09), proton pump inhibitor (OR 0.23, 95% CI 0.06-0.91, P = 0.037), sodium valproate (OR 0.22, 95% CI 0.05-0.85, P = 0.029), and CYP2C9*2 genotype (OR 5.57, 95% CI 1.19-26.06, P = 0.02).

CONCLUSIONS: Variant genotypes of VKORC1, CYP2C9*2, and CYP2C9*3 required lower dose of acenocoumarin, and CYP2C9*2 was associated with unstable INR. Comedication is a modifiable risk factor that needs attention.

PMID:38907686 | DOI:10.4103/aian.aian_886_23

Pharmacogenomics J. 2024 Jun 21;24(4):20. doi: 10.1038/s41397-024-00341-2.

ABSTRACT

Thiopurines, an effective therapy for Crohn's disease (CD), often lead to adverse events (AEs). Gene polymorphisms affecting thiopurine metabolism may predict AEs. This retrospective study in CD patients (n = 114) with TPMT activity > 5 Units/Red Blood Cells analyzed TPMT (c.238 G > C, c.460 G > A, c.719 A > G), ITPA (c.94 C > A, IVS2 + 21 A > C), and NUDT15 (c.415 C > T) polymorphisms. All patients received azathioprine (median dose 2.2 mg/kg) with 41.2% experiencing AEs, mainly myelotoxicity (28.1%). No NUDT15 polymorphisms were found, 7% had TPMT, and 31.6% had ITPA polymorphisms. AEs led to therapy modifications in 41.2% of patients. Multivariate analysis identified advanced age (OR 1.046, p = 0.007) and ITPA IVS2 + 21 A > C (OR 3.622, p = 0.015) as independent predictors of AEs. IVS2 + 21 A > C was also associated with myelotoxicity (OR 2.863, p = 0.021). These findings suggest that ITPA IVS2 + 21 A > C polymorphism and advanced age predict AEs during thiopurine therapy for CD with intermediate-normal TPMT activity.

PMID:38906864 | DOI:10.1038/s41397-024-00341-2

J Antimicrob Chemother. 2024 Jun 21:dkae187. doi: 10.1093/jac/dkae187. Online ahead of print.

NO ABSTRACT

PMID:38905150 | DOI:10.1093/jac/dkae187

Ann Acad Med Singap. 2023 Jul 28;52(7):340-347. doi: 10.47102/annals-acadmedsg.202328.

ABSTRACT

INTRODUCTION: This study aimed to investigate the association between polymorphisms in fibrinogen genes and bleeding risk in patients receiving direct oral anticoagulants (DOACs).

METHOD: Patients treated with DOACs from June 2018 to December 2021 were enrolled in the study. Genotyping was done for rs2070011, rs6050, and rs2070022 in fibrinogen alpha chain (FGA); rs1800788, rs4220, and rs4463047 in fibrinogen beta chain (FGB); and rs2066865 and rs1800792 in fibrinogen gamma chain (FGG), along with F2 rs5896 and F10 rs5960. Multivariable logistic regression analysis was performed to investigate the risk factors for bleeding and to develop a risk scoring system.

RESULTS: A total of 468 patients were included in the analysis, 14 of whom experienced major bleeding and 36 experienced clinically relevant non-major bleeding. In the multivariable analysis, overdose, anaemia, F2 rs5896, and FGG rs1800792 were found to be significantly associated with bleeding risk. Specifically, patients with the TT genotype of F2 rs5896 and the CC genotype of FGG rs1800792 had 2.1 times (95% confidence interval [CI] 1.1-3.9) and 2.7 times (95% CI 1.2-5.9) higher bleeding risk than the C allele and T allele carriers, respectively. Based on the risk scoring system, patients with 0, 1, 2, 3, 4, and 5 points were predicted to have 5.2%, 10.8%, 22.4%, 32.3%, 42.3%, and 61.8% of bleeding risk, respectively.

CONCLUSION: To our knowledge, this is the first study to investigate the effects of polymorphisms in fibrinogen genes on DOAC response. After validation, these results will be useful for personalised DOAC therapy.

PMID:38904499 | DOI:10.47102/annals-acadmedsg.202328

Mol Cancer Ther. 2024 Jun 21:OF1-OF13. doi: 10.1158/1535-7163.MCT-23-0870. Online ahead of print.

ABSTRACT

KRAS is the most frequently mutated oncogene in human cancer and facilitates uncontrolled growth through hyperactivation of the receptor tyrosine kinase (RTK)/mitogen-activated protein kinase (MAPK) pathway. The Son of Sevenless homolog 1 (SOS1) protein functions as a guanine nucleotide exchange factor (GEF) for the RAS subfamily of small GTPases and represents a druggable target in the pathway. Using a structure-based drug discovery approach, MRTX0902 was identified as a selective and potent SOS1 inhibitor that disrupts the KRAS:SOS1 protein-protein interaction to prevent SOS1-mediated nucleotide exchange on KRAS and translates into an anti-proliferative effect in cancer cell lines with genetic alterations of the KRAS-MAPK pathway. MRTX0902 augmented the antitumor activity of the KRAS G12C inhibitor adagrasib when dosed in combination in eight out of 12 KRAS G12C-mutant human non-small cell lung cancer and colorectal cancer xenograft models. Pharmacogenomic profiling in preclinical models identified cell cycle genes and the SOS2 homolog as genetic co-dependencies and implicated tumor suppressor genes (NF1 and PTEN) in resistance following combination treatment. Lastly, combined vertical inhibition of RTK/MAPK pathway signaling by MRTX0902 with inhibitors of EGFR or RAF/MEK led to greater downregulation of pathway signaling and improved antitumor responses in KRAS-MAPK pathway-mutant models. These studies demonstrate the potential clinical application of dual inhibition of SOS1 and KRAS G12C and additional SOS1 combination strategies that will aide in the understanding of SOS1 and RTK/MAPK biology in targeted cancer therapy.

PMID:38904222 | DOI:10.1158/1535-7163.MCT-23-0870

Pediatr Hematol Oncol. 2024 Jun 21:1-9. doi: 10.1080/08880018.2024.2368007. Online ahead of print.

ABSTRACT

This study aimed to evaluate the utilization of drugs with pharmacogenomic guidelines (PGx-drugs) for personalized dosing in pediatric leukemia. A retrospective observational study of pediatric leukemia patients admitted between 2009-2019 at a single-center academic children's hospital was conducted to determine PGx-drug exposure within 3 years of diagnosis. Along with baseline demographic and clinical characteristics of these patients, data regarding dates of diagnosis, relapse, death were collected. During the study period, inclusion criteria were met by 714 patients. The most frequently given medications were ondansetron (96.1%), morphine (92.2%), and allopurinol (85.3%) during the study period. In this cohort, 82% of patients received five or more PGx-drugs. Patients diagnosed with acute myeloid leukemia and leukemia unspecified were prescribed more PGx-drugs than other types of leukemia. There was a significant relationship between age at diagnosis and the number of PGx-drugs prescribed. Adolescents and adults both received a median of 10 PGx-drugs, children received a median of 6 PGx-drugs, and infants received a median of 7 PGx-drugs (p < 0.001). Patients with recurrent leukemia had significantly more PGx-drugs prescribed compared to those without recurrent disease, 10 drugs and 6 drugs, respectively (p < 0.001). Patients diagnosed with childhood leukemia are high utilizers of PGx-drugs. There is a vital need to understand how PGx testing may be utilized to optimize treatment and enhance quality of life. Preemptive PGx testing is a tool that aids in optimization of drug therapy and decreases the need for later treatment modifications. This can result in financial savings from decreased health-care encounters.

PMID:38904214 | DOI:10.1080/08880018.2024.2368007

Toxicol Sci. 2024 Jun 20:kfae078. doi: 10.1093/toxsci/kfae078. Online ahead of print.

ABSTRACT

Drug-induced liver injury (DILI) is the most common trigger for acute liver failure and the leading cause of attrition in drug development. In this study, we developed an in-silico framework to screen drug-induced hepatocellular toxicity (INSIGHT) by integrating the post-treatment transcriptomic data from both rodent models and primary human hepatocytes. We first built an early prediction model using logistic regression with elastic net regularization for 123 compounds and established the INSIGHT framework that can screen for drug-induced hepatotoxicity. The 235 signature genes identified by INSIGHT were involved in metabolism, bile acid synthesis, and stress response pathways. Applying the INSIGHT to an independent transcriptomic dataset treated by 185 compounds predicted that 27 compounds show a high DILI risk, including zoxazolamine and emetine. Further integration with cell image data revealed that predicted DILI compounds can induce abnormal morphological changes in the endoplasmic reticulum (ER) and mitochondrion. Clustering analysis of the treatment-induced transcriptomic changes delineated distinct DILI mechanisms induced by these compounds. Our study presents a computational framework for a mechanistic understanding of long-term liver injury and the prospective prediction of DILI.

PMID:38902949 | DOI:10.1093/toxsci/kfae078

Toxicol Lett. 2024 Jun 18:S0378-4274(24)00136-X. doi: 10.1016/j.toxlet.2024.06.008. Online ahead of print.

ABSTRACT

Inorganic arsenic species exist in the environment as a result of both natural sources, such as volcanic and geothermal activities, and geological formations, as well as anthropogenic activities, including smelting, exploration of fossil fuels, coal burning, mining, and the use of pesticides. These species deposit in water, rocks, soil, sediments, and the atmosphere. Arsenic-contaminated drinking water is a global public health issue because of its natural prevalence and toxicity. Therefore, chronic exposure to arsenic can have deleterious effect on humans, including cancer and other diseases. This work describes the mechanisms of environmental exposure to arsenic, molecular regulatory factors involved in its metabolism, genetic polymorphisms affecting individual susceptibility and the toxic effects of arsenic on human health (oxidative stress, DNA damage and cancer). We conclude that the role of single nucleotide variants affecting urinary excretion of arsenic metabolites are highly relevant and can be used as biomarkers of the intracellular retention rates of arsenic, showing new avenues of research in this field.

PMID:38901734 | DOI:10.1016/j.toxlet.2024.06.008

Br J Gen Pract. 2024 Jun 20;74(suppl 1):bjgp24X737901. doi: 10.3399/bjgp24X737901.

ABSTRACT

BACKGROUND: Treatment of depression is common in primary care but not every antidepressant is effective in every patient. Adverse drug reactions are common, imposing a substantial burden on the patient and the NHS. Pharmacogenomics (PGx) utilises an individual's genetic makeup to predict their response to medications. By tailoring prescriptions to a person's genetic profile, PGx can significantly reduce adverse drug reactions, identify non-responders to medications, and enhance overall patient outcomes.

AIM: To see if PGx testing for antidepressants can be undertaken in general practice as part of 'usual care'; to increase GP and patient awareness of PGx testing; to alter patient treatment according to the results of testing; and to sustain these changes at 4 years.

METHOD: In 2019, 23 patients were recruited by GPs at the surgery. They consented and had cheek swabs to check their genetic profile to common antidepressants. Results were reviewed at 1 week by the GP and patient, treatment changes made and reviewed again at 4 years.

RESULTS: On the CYP2D pathway, 19/23 patients were extensive (normal) metabolisers, one intermediate and two poor. These two had their treatments changed. At 4-year review 19/23 were on appropriate treatment (two had been stopped) but two had inappropriate drug treatment. On CYP2C19 pathway, 10/23 were normal metabolisers, eight intermediate, zero poor but five ultrarapid (they had their treatment changed). At 4-year review, 20/23 were on appropriate treatment (two stopped) and one inappropriate.

CONCLUSION: PGx testing works in primary care, improving patient outcomes sustainably.

PMID:38902050 | DOI:10.3399/bjgp24X737901

Transfusion. 2024 Jun 20. doi: 10.1111/trf.17913. Online ahead of print.

ABSTRACT

Anti-D cannot agglutinate red cells of any Del phenotype in routine serology. Many individuals with East Asian ancestry who type D-negative in serology harbor a Del phenotype. Almost all such individuals carry one distinct DEL variant, dubbed Asian-type DEL, known as RHD*01EL.01, RHD*DEL1, RHD:c.1227G>A, formerly known as RHD(K409K). Clinical evidence strongly suggests that Asian-type DEL individuals can safely be transfused with RhD-positive blood and do not need anti-D prophylaxis in pregnancy.

PMID:38899801 | DOI:10.1111/trf.17913

Clin Transl Sci. 2024 Jun;17(6):e13837. doi: 10.1111/cts.13837.

ABSTRACT

Pharmacogenetic testing could reduce the time to identify a safe and effective medication for depression; however, it is underutilized in practice. Major depression constitutes the most common mental disorder in the US, and while antidepressant therapy can help, the current trial -and error approach can require patients to endure multiple medication trials before finding one that is effective. Tailoring the fit of pharmacogenetic testing with prescribers' needs across a variety of settings could help to establish a generalizable value proposition to improve likelihood of adoption. We conducted a study to explore the value proposition for health systems using pharmacogenetic testing for mental health medications through prescribers' real-world experiences using implementation science concepts and systematic interviews with prescribers and administrators from four health care systems. To identify a value proposition, we organized the themes according to the Triple Aim framework, a leading framework for health care policy which asserts that high-value care should focus on three key metrics: (1) better health care quality and (2) population-level outcomes with (3) reduced per capita costs. Primary care providers whom we interviewed said that they value pharmacogenetic testing because it would provide more information about medications that they can prescribe, expanding their ability to identify medications that best-fit patients and reducing their reliance on referrals to specialists; they said that this capacity would help meet patients' needs for access to mental health care through primary care. At the same time, prescribers expressed differing views about how pharmacogenetic testing can help with quality of care and whether their views about out-of-pocket cost would prevent them from offering it. Thus, implementation should focus on integrating pharmacogenetic testing into primary care and using strategies to support prescribers' interactions with patients.

PMID:38898561 | DOI:10.1111/cts.13837

J Infect Chemother. 2024 Jun 17:S1341-321X(24)00164-8. doi: 10.1016/j.jiac.2024.06.009. Online ahead of print.

ABSTRACT

BACKGROUND: Voriconazole pharmacokinetics (PK) are known to be affected by genetic polymorphisms of drug-metabolizing enzymes such as CYP2C19; however, such information is limited for the pediatric population. The primary aim of this study is to establish a voriconazole PK model incorporating CYP2C19 phenotypes in Japanese children with malignancy or inborn errors of immunity.

METHODS: CYP2C19 genotypes were assessed by whole-genome genotyping and defined as follows: *17/*17: ultrarapid metabolizer (URM), *1/*17: rapid metabolizer (RM), *1/*1:normal metabolizer (NM), *1/*2, *1/*3, *2/*17:intermediate metabolizer (IM), and *2/*2, *2/*3, *3/*3: poor metabolizer (PM). Population PK analysis was performed. The voriconazole serum concentration profile was described by a two-compartment model with first-order absorption, mixed linear and nonlinear (Michaelis-Menten) elimination.

RESULTS: Voriconazole concentration data were available from 60 patients with a median age of 5.3 years. The phenotypes predicted from CYP2C19 genotypes were RM in 1 (2%), NM in 21 (35%) patients, IM in 27 (45%) patients, and PM in 11 (18%) patients. Underlying diseases included 40 (67%) patients with malignancy and 18 (30%) patients with inborn errors of immunity. Among the CYP2C19 phenotypes, PM was predicted to show complete inhibition (the degree of Vmax inhibition [Vmax,inh] = 100%; Vmax = 0). The estimated parameters of Vmax,inh were +0.8 higher in patients with gamma-glutamyl transpeptidase (γ-GTP) Grade 2 or higher and +2.7 higher when C-reactive protein (CRP) levels were 2.0 mg/dL or higher.

CONCLUSION: CYP2C19 genetic polymorphisms, γ-GTP, and CRP affect Vmax,inh of voriconazole in children with malignancy or inborn errors of immunity.

PMID:38897411 | DOI:10.1016/j.jiac.2024.06.009

Clin Chem Lab Med. 2024 Jun 19. doi: 10.1515/cclm-2024-0317. Online ahead of print.

ABSTRACT

OBJECTIVES: Dihydropyrimidine dehydrogenase (DPD) deficiency is the main cause of severe fluoropyrimidine-related toxicities. The best strategy for identifying DPD-deficient patients is still not defined. The EMA recommends targeted DPYD genotyping or uracilemia (U) testing. We analyzed the concordance between both approaches.

METHODS: This study included 19,376 consecutive French patients with pre-treatment plasma U, UH2 and targeted DPYD genotyping (*2A, *13, D949V, *7) analyzed at Eurofins Biomnis (2015-2022).

RESULTS: Mean U was 9.9 ± 10.1 ng/mL (median 8.7, range 1.6-856). According to French recommendations, 7.3 % of patients were partially deficient (U 16-150 ng/mL) and 0.02 % completely deficient (U≥150 ng/mL). DPYD variant frequencies were *2A: 0.83 %, *13: 0.17 %, D949V: 1.16 %, *7: 0.05 % (2 homozygous patients with U at 22 and 856 ng/mL). Variant carriers exhibited higher U (median 13.8 vs. 8.6 ng/mL), and lower UH2/U (median 7.2 vs. 11.8) and UH2/U2 (median 0.54 vs. 1.37) relative to wild-type patients (p<0.00001). Sixty-six% of variant carriers exhibited uracilemia <16 ng/mL, challenging correct identification of DPD deficiency based on U. The sensitivity (% patients with a deficient phenotype among variant carriers) of U threshold at 16 ng/mL was 34 %. The best discriminant marker for identifying variant carriers was UH2/U2. UH2/U2<0.942 (29.7 % of patients) showed enhanced sensitivity (81 %) in identifying deleterious genotypes across different variants compared to 16 ng/mL U.

CONCLUSIONS: These results reaffirm the poor concordance between DPD phenotyping and genotyping, suggesting that both approaches may be complementary and that targeted DPYD genotyping is not sufficiently reliable to identify all patients with complete deficiency.

PMID:38896022 | DOI:10.1515/cclm-2024-0317

Clin Interv Aging. 2024 Jun 11;19:1041-1050. doi: 10.2147/CIA.S462786. eCollection 2024.

ABSTRACT

BACKGROUND: Genetic variation plays an important role in drug response, there are few relevant studies on patients with Alzheimer's disease continuum (ADC).

OBJECTIVE: This study focused on the associations between two single nucleotide polymorphisms (SNPs) (rs3793790 and rs2177370) located in the CHAT gene and donepezil response in ADC patients, and further evaluated the associations between the two SNPs and ADC.

MATERIAL AND METHODS: According to 2018 National Institute on Aging and Alzheimer's Association (NIA-AA) standard, amyloid β-protein positive (Aβ+) and negative (Aβ-) patients were recruited according to the Aβ-PET/CT standard. rs3793790 and rs2177370 were genotyped in buccal swab samples by using the MassARRAY system. We used the Mini Mental State Examination (MMSE) in Chinese version, caregiver evaluation, and prescribing behavior to assess therapeutic response during the 9-month period. Using logistic regression models, we analyzed the relationship between the two SNPs and donepezil response in 58 Aβ+ patients treated with donepezil alone at the initial diagnosis of ADC. We also explored a probable link between the two SNPs and ADC in 147 Aβ+ and 73 Aβ- patients using a logistic regression analysis.

RESULTS: The chance of donepezil response was higher in patients with the G allele of rs3793790 and/or the A allele of rs2177370 than in those without (odds ratio (OR) 6.83, 95% confidence interval (CI): 1.64-28.49). Additionally, the rs3793790 variant was not associated with ADC, whereas the A allele in rs2177370 increased 1.51-fold the ADC risk (OR 2.51, 95% CI: 1.28-4.95).

CONCLUSION: The genetic variants of rs3793790 and rs2177370 were associated with the donepezil response, and rs2177370 may have a moderate relationship with the risk of ADC.

PMID:38894884 | PMC:PMC11182730 | DOI:10.2147/CIA.S462786