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1.
Annu Rev Pharmacol Toxicol ; 64: 1-26, 2024 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-37788491

RESUMO

I am deeply honored to be invited to write this scientific autobiography. As a physician-scientist, pediatrician, molecular biologist, and geneticist, I have authored/coauthored more than 600 publications in the fields of clinical medicine, biochemistry, biophysics, pharmacology, drug metabolism, toxicology, molecular biology, cancer, standardized gene nomenclature, developmental toxicology and teratogenesis, mouse genetics, human genetics, and evolutionary genomics. Looking back, I think my career can be divided into four distinct research areas, which I summarize mostly chronologically in this article: (a) discovery and characterization of the AHR/CYP1 axis, (b) pharmacogenomics and genetic prediction of response to drugs and other environmental toxicants, (c) standardized drug-metabolizing gene nomenclature based on evolutionary divergence, and (d) discovery and characterization of the SLC39A8 gene encoding the ZIP8 metal cation influx transporter. Collectively, all four topics embrace gene-environment interactions, hence the title of my autobiography.


Assuntos
Genômica , Médicos , Humanos , Animais , Camundongos , Proteínas de Membrana Transportadoras , Farmacogenética
2.
Pharmacol Rev ; 2024 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-39406507

RESUMO

Precision cancer medicine is widely established, and numerous molecularly targeted drugs for various tumor entities are approved or in development. Personalized pharmacotherapy in oncology has so far been based primarily on tumor characteristics, e.g., somatic mutations. However, the response to drug treatment also depends on pharmacological processes summarized under the term ADME (absorption, distribution, metabolism, and excretion). Variations in ADME genes have been the subject of intensive research for more than five decades, considering individual patients' genetic makeup, referred to as pharmacogenomics (PGx). The combined impact of a patient's tumor and germline genome is only partially understood and often not adequately considered in cancer therapy. This may be attributed, in part, to the lack of methods for combined analysis of both data layers. Optimized personalized cancer therapies should, therefore, aim to integrate molecular information about the tumor and the germline, taking into account existing PGx guidelines for drug therapy. Moreover, such strategies should provide the opportunity to consider genetic variants of previously unknown functional significance. Bioinformatic analysis methods and corresponding algorithms for data interpretation need to be developed to consider PGx data in interdisciplinary molecular tumor boards, where cancer patients are discussed to provide evidence-based recommendations for clinical management based on individual tumor profiles. Significance Statement The era of personalized oncology has seen the emergence of drugs tailored to genetic variants associated with cancer biology. However, full potential of targeted therapy remains untapped due to the predominant focus on acquired tumor-specific alterations. Optimized cancer care must integrate tumor and patient genomes, guided by pharmacogenomic principles. An essential prerequisite for realizing truly personalized drug treatment of cancer patients is the development of bioinformatic tools for comprehensive analysis of all data layers generated in modern precision oncology programs.

3.
Annu Rev Pharmacol Toxicol ; 63: 211-229, 2023 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-35914768

RESUMO

Antiplatelet therapy is used in the treatment of patients with acute coronary syndromes, stroke, and those undergoing percutaneous coronary intervention. Clopidogrel is the most widely used antiplatelet P2Y12 inhibitor in clinical practice. Genetic variation in CYP2C19 may influence its enzymatic activity, resulting in individuals who are carriers of loss-of-function CYP2C19 alleles and thus have reduced active clopidogrel metabolites, high on-treatment platelet reactivity, and increased ischemic risk. Prospective studies have examined the utility of CYP2C19 genetic testing to guide antiplatelet therapy, and more recently published meta-analyses suggest that pharmacogenetics represents a key treatment strategy to individualize antiplatelet therapy. Rapid genetic tests, including bedside genotyping platforms that are validated and have high reproducibility, are available to guide selection of P2Y12 inhibitors in clinical practice. The aim of this review is to provide an overview of the background and rationale for the role of a guided antiplatelet approach to enhance patient care.


Assuntos
Farmacogenética , Inibidores da Agregação Plaquetária , Humanos , Inibidores da Agregação Plaquetária/efeitos adversos , Clopidogrel/uso terapêutico , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Estudos Prospectivos , Reprodutibilidade dos Testes , Genótipo , Resultado do Tratamento
4.
Am J Hum Genet ; 110(10): 1628-1647, 2023 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-37757824

RESUMO

Pharmacogenomics (PGx) is an integral part of precision medicine and contributes to the maximization of drug efficacy and reduction of adverse drug event risk. Accurate information on PGx allele frequencies improves the implementation of PGx. Nonetheless, curating such information from published allele data is time and resource intensive. The limited number of allelic variants in most studies leads to an underestimation of certain alleles. We applied the Pharmacogenomics Clinical Annotation Tool (PharmCAT) on an integrated 200K UK Biobank genetic dataset (N = 200,044). Based on PharmCAT results, we estimated PGx frequencies (alleles, diplotypes, phenotypes, and activity scores) for 17 pharmacogenes in five biogeographic groups: European, Central/South Asian, East Asian, Afro-Caribbean, and Sub-Saharan African. PGx frequencies were distinct for each biogeographic group. Even biogeographic groups with similar proportions of phenotypes were driven by different sets of dominant PGx alleles. PharmCAT also identified "no-function" alleles that were rare or seldom tested in certain groups by previous studies, e.g., SLCO1B1∗31 in the Afro-Caribbean (3.0%) and Sub-Saharan African (3.9%) groups. Estimated PGx frequencies are disseminated via the PharmGKB (The Pharmacogenomics Knowledgebase: www.pharmgkb.org). We demonstrate that genetic biobanks such as the UK Biobank are a robust resource for estimating PGx frequencies. Improving our understanding of PGx allele and phenotype frequencies provides guidance for future PGx studies and clinical genetic test panel design, and better serves individuals from wider biogeographic backgrounds.


Assuntos
Bancos de Espécimes Biológicos , Farmacogenética , Humanos , Farmacogenética/métodos , Alelos , Medicina de Precisão/métodos , Frequência do Gene/genética , Transportador 1 de Ânion Orgânico Específico do Fígado
5.
Am J Hum Genet ; 110(2): 228-239, 2023 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-36681081

RESUMO

Glucose-6-phosphate dehydrogenase (G6PD) deficiency affects over 500 million individuals who can experience anemia in response to oxidative stressors such as certain foods and drugs. Recently, the World Health Organization (WHO) called for revisiting G6PD variant classification as a priority to implement genetic medicine in low- and middle-income countries. Toward this goal, we sought to collect reports of G6PD variants and provide interpretations. We identified 1,341 G6PD variants in population and clinical databases. Using the ACMG standards and guidelines for the interpretation of sequence variants, we provided interpretations for 268 variants, including 186 variants that were not reported or of uncertain significance in ClinVar, bringing the total number of variants with non-conflicting interpretations to 400. For 414 variants with functional or clinical data, we analyzed associations between activity, stability, and current classification systems, including the new 2022 WHO classification. We corroborated known challenges with classification systems, including phenotypic variation, emphasizing the importance of comparing variant effects across individuals and studies. Biobank data made available by All of Us illustrate the benefit of large-scale sequencing and phenotyping by adding additional support connecting variants to G6PD-deficient anemia. By leveraging available data and interpretation guidelines, we created a repository for information on G6PD variants and nearly doubled the number of variants with clinical interpretations. These tools enable better interpretation of G6PD variants for the implementation of genetic medicine.


Assuntos
Deficiência de Glucosefosfato Desidrogenase , Saúde da População , Humanos , Glucosefosfato Desidrogenase/genética , Deficiência de Glucosefosfato Desidrogenase/genética , Deficiência de Glucosefosfato Desidrogenase/epidemiologia , Variação Biológica da População , Catalogação
6.
J Neurosci ; 44(12)2024 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-38320853

RESUMO

Gonadotropin-releasing hormone (GnRH)-synthesizing neurons orchestrate reproduction centrally. Early studies have proposed the contribution of acetylcholine (ACh) to hypothalamic control of reproduction, although the causal mechanisms have not been clarified. Here, we report that in vivo pharmacogenetic activation of the cholinergic system increased the secretion of luteinizing hormone (LH) in orchidectomized mice. 3DISCO immunocytochemistry and electron microscopy revealed the innervation of GnRH neurons by cholinergic axons. Retrograde viral labeling initiated from GnRH-Cre neurons identified the medial septum and the diagonal band of Broca as exclusive sites of origin for cholinergic afferents of GnRH neurons. In acute brain slices, ACh and carbachol evoked a biphasic effect on the firing rate in GnRH neurons, first increasing and then diminishing it. In the presence of tetrodotoxin, carbachol induced an inward current, followed by a decline in the frequency of miniature postsynaptic currents (mPSCs), indicating a direct influence on GnRH cells. RT-PCR and whole-cell patch-clamp studies revealed that GnRH neurons expressed both nicotinic (α4ß2, α3ß4, and α7) and muscarinic (M1-M5) AChRs. The nicotinic AChRs contributed to the nicotine-elicited inward current and the rise in firing rate. Muscarine via M1 and M3 receptors increased, while via M2 and M4 reduced the frequency of both mPSCs and firing. Optogenetic activation of channelrhodopsin-2-tagged cholinergic axons modified GnRH neuronal activity and evoked cotransmission of ACh and GABA from a subpopulation of boutons. These findings confirm that the central cholinergic system regulates GnRH neurons and activates the pituitary-gonadal axis via ACh and ACh/GABA neurotransmissions in male mice.


Assuntos
Acetilcolina , Hormônio Liberador de Gonadotropina , Camundongos , Animais , Masculino , Acetilcolina/farmacologia , Carbacol/farmacologia , Neurônios/fisiologia , Colinérgicos/farmacologia , Nicotina/farmacologia , Hormônio Luteinizante , Ácido gama-Aminobutírico/farmacologia
7.
Annu Rev Pharmacol Toxicol ; 62: 509-529, 2022 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-34516290

RESUMO

Human leukocyte antigen (HLA) is a hallmark genetic marker for the prediction of certain immune-mediated adverse drug reactions (ADRs). Numerous basic and clinical research studies have provided the evidence base to push forward the clinical implementation of HLA testing for the prevention of such ADRs in susceptible patients. This review explores current translational progress in using HLA as a key susceptibility factor for immune ADRs and highlights gaps in our knowledge. Furthermore, relevant findings of HLA-mediated drug-specific T cell activation are covered, focusing on cellular approaches to link genetic associations to drug-HLA binding as a complementary approach to understand disease pathogenesis.


Assuntos
Hipersensibilidade a Drogas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Alelos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Antígenos HLA/genética , Humanos , Farmacogenética
8.
Annu Rev Genomics Hum Genet ; 23: 449-473, 2022 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-35537468

RESUMO

Pharmacogenomic testing can be an effective tool to enhance medication safety and efficacy. Pharmacogenomically actionable medications are widely used, and approximately 90-95% of individuals have an actionable genotype for at least one pharmacogene. For pharmacogenomic testing to have the greatest impact on medication safety and clinical care, genetic information should be made available at the time of prescribing (preemptive testing). However, the use of preemptive pharmacogenomic testing is associated with some logistical concerns, such as consistent reimbursement, processes for reporting preemptive results over an individual's lifetime, and result portability. Lessons can be learned from institutions that have implemented preemptive pharmacogenomic testing. In this review, we discuss the rationale and best practices for implementing pharmacogenomics preemptively.


Assuntos
Farmacogenética , Medicina de Precisão , Genótipo , Humanos , Farmacogenética/métodos , Medicina de Precisão/métodos
9.
Biostatistics ; 25(4): 1034-1048, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-38365980

RESUMO

Combination antiretroviral therapy (ART) with at least three different drugs has become the standard of care for people with HIV (PWH) due to its exceptional effectiveness in viral suppression. However, many ART drugs have been reported to associate with neuropsychiatric adverse effects including depression, especially when certain genetic polymorphisms exist. Pharmacogenetics is an important consideration for administering combination ART as it may influence drug efficacy and increase risk for neuropsychiatric conditions. Large-scale longitudinal HIV databases provide researchers opportunities to investigate the pharmacogenetics of combination ART in a data-driven manner. However, with more than 30 FDA-approved ART drugs, the interplay between the large number of possible ART drug combinations and genetic polymorphisms imposes statistical modeling challenges. We develop a Bayesian approach to examine the longitudinal effects of combination ART and their interactions with genetic polymorphisms on depressive symptoms in PWH. The proposed method utilizes a Gaussian process with a composite kernel function to capture the longitudinal combination ART effects by directly incorporating individuals' treatment histories, and a Bayesian classification and regression tree to account for individual heterogeneity. Through both simulation studies and an application to a dataset from the Women's Interagency HIV Study, we demonstrate the clinical utility of the proposed approach in investigating the pharmacogenetics of combination ART and assisting physicians to make effective individualized treatment decisions that can improve health outcomes for PWH.


Assuntos
Teorema de Bayes , Infecções por HIV , Farmacogenética , Humanos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/genética , Farmacogenética/métodos , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/efeitos adversos , Quimioterapia Combinada , Terapia Antirretroviral de Alta Atividade/métodos , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Depressão/genética , Depressão/tratamento farmacológico
10.
Brief Bioinform ; 25(1)2023 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-38055839

RESUMO

Here, we will provide our insights into the usage of PharmCAT as part of a pharmacogenetic clinical decision support pipeline, which addresses the challenges in mapping clinical dosing guidelines to variants to be extracted from genetic datasets. After a general outline of pharmacogenetics, we describe some features of PharmCAT and how we integrated it into a pharmacogenetic clinical decision support system within a clinical information system. We conclude with promising developments regarding future PharmCAT releases.


Assuntos
Sistemas de Apoio a Decisões Clínicas , Farmacogenética
11.
Hum Genomics ; 18(1): 78, 2024 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-38987819

RESUMO

Pharmacogenetics investigates sequence of genes that affect drug response, enabling personalized medication. This approach reduces drug-induced adverse reactions and improves clinical effectiveness, making it a crucial consideration for personalized medical care. Numerous guidelines, drawn by global consortia and scientific organizations, codify genotype-driven administration for over 120 active substances. As the scientific community acknowledges the benefits of genotype-tailored therapy over traditionally agnostic drug administration, the push for its implementation into Italian healthcare system is gaining momentum. This evolution is influenced by several factors, including the improved access to patient genotypes, the sequencing costs decrease, the growing of large-scale genetic studies, the rising popularity of direct-to-consumer pharmacogenetic tests, and the continuous improvement of pharmacogenetic guidelines. Since EMA (European Medicines Agency) and AIFA (Italian Medicines Agency) provide genotype information on drug leaflet without clear and explicit clinical indications for gene testing, the regulation of pharmacogenetic testing is a pressing matter in Italy. In this manuscript, we have reviewed how to overcome the obstacles in implementing pharmacogenetic testing in the clinical practice of the Italian healthcare system. Our particular emphasis has been on germline testing, given the absence of well-defined national directives in contrast to somatic pharmacogenetics.


Assuntos
Farmacogenética , Humanos , Itália , Farmacogenética/métodos , Farmacogenética/tendências , Medicina de Precisão/tendências , Medicina de Precisão/métodos , Testes Farmacogenômicos/métodos , Genótipo
12.
Hum Genomics ; 18(1): 8, 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-38291455

RESUMO

BACKGROUND: Community pharmacists must be well-equipped to advance pharmacogenomics services. Nevertheless, limited data is available regarding pharmacists' knowledge and attitudes toward pharmacogenomics testing. The present study aimed to evaluate community pharmacists' knowledge and attitudes toward pharmacogenomics testing in the UAE. METHODS: In this cross-sectional study, a validated, online, self-administered survey, was randomly distributed to community pharmacists across the United Arab Emirates (UAE). RESULTS: The participants demonstrated poor knowledge about pharmacogenomic testing (median score < 8). Having 10-29 (Adjusted odds ration [AOR]: 0.038; 95% CI: 0.01-0.146, p = 0.001) and 30-49 (AOR: 0.097; 95% CI: 0.04-0.237, p = 0.001) patients per day was associated with poorer knowledge. Also, receiving 10-29 (AOR: 0.046; 95% CI: 0.005-0.401, p = 0.005), 30-49 (AOR: 0.025; 95% CI: 0.003-0.211, p = 0.001), and > 50 (AOR: 0.049; 95% CI: 0.005-0.458, p = 0.008) prescriptions decreased the odds of having good knowledge. Around half (43.9%) of the participants did not show a positive attitude toward pharmacogenomic testing (median score < 11). Having 30-49 patients per day (AOR: 5.351; 95% CI: 2.414-11.860, p = 0.001) increased the odds of good knowledge while receiving 10-29 (AOR: 0.133; 95% CI: 0.056-0.315, p = 0.001) and 30-49 (AOR: 0.111; 95% CI: 0.049-0.252, p = 0.001) prescriptions a day were associated with decreased odds of positive attitude toward the pharmacogenomics testing. CONCLUSIONS: The findings indicate a lack of knowledge and less-than-ideal attitudes among community pharmacists regarding pharmacogenomics testing. Enhanced efforts focused on educational initiatives and training activities related to pharmacogenomics testing is needed. Additionally, reducing workload can facilitate better knowledge acquisition and help mitigate unfavorable attitudes.


Assuntos
Farmacogenética , Testes Farmacogenômicos , Humanos , Farmacêuticos , Estudos Transversais , Conhecimentos, Atitudes e Prática em Saúde
13.
Hum Genomics ; 18(1): 30, 2024 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-38523294

RESUMO

BACKGROUND: SLCO1B1 plays an important role in mediating hepatic clearance of many different drugs including statins, angiotensin-converting enzyme inhibitors, chemotherapeutic agents and antibiotics. Several variants in SLCO1B1 have been shown to have a clinically significant impact, in relation to efficacy of these medications. This study provides a comprehensive overview of SLCO1B1 variation in Saudi individuals, one of the largest Arab populations in the Middle East. METHODS: The dataset of 11,889 (9,961 exomes and 1,928 pharmacogenetic gene panel) Saudi nationals, was used to determine the presence and frequencies of SLCO1B1 variants, as described by the Clinical Pharmacogenetic Implementation Consortium (CPIC). RESULTS: We identified 141 previously described SNPs, of which rs2306283 (50%) and rs4149056 (28%), were the most common. In addition, we observed six alleles [*15 (24.7%) followed by *20 (8.04%), *14 (5.86%), *5 (3.84%), *31 (0.21%) and *9 (0.03%)] predicted to be clinically actionable. Allele diplotype to phenotype conversion revealed 41 OATP1B1 diplotypes. We estimated the burden of rare, and novel predicted deleterious variants, resulting from 17 such alterations. CONCLUSIONS: The data we present, from one of the largest Arab cohorts studied to date, provides the most comprehensive overview of SLCO1B1 variants, and the subsequent OATP1B1 activity of this ethnic group, which thus far remains relatively underrepresented in available international genomic databases. We believe that the presented data provides a basis for further clinical investigations and the application of personalized statin drug therapy guidance in Arabs.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Farmacogenética , Humanos , Arábia Saudita , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Polimorfismo de Nucleotídeo Único/genética
14.
Hum Genomics ; 18(1): 40, 2024 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-38650020

RESUMO

BACKGROUND: CYP2C8 is responsible for the metabolism of 5% of clinically prescribed drugs, including antimalarials, anti-cancer and anti-inflammatory drugs. Genetic variability is an important factor that influences CYP2C8 activity and modulates the pharmacokinetics, efficacy and safety of its substrates. RESULTS: We profiled the genetic landscape of CYP2C8 variability using data from 96 original studies and data repositories that included a total of 33,185 unrelated participants across 44 countries and 43 ethnic groups. The reduced function allele CYP2C8*2 was most common in West and Central Africa with frequencies of 16-36.9%, whereas it was rare in Europe and Asia (< 2%). In contrast, CYP2C8*3 and CYP2C8*4 were common throughout Europe and the Americas (6.9-19.8% for *3 and 2.3-7.5% for *4), but rare in African and East Asian populations. Importantly, we observe pronounced differences (> 2.3-fold) between neighboring countries and even between geographically overlapping populations. Overall, we found that 20-60% of individuals in Africa and Europe carry at least one CYP2C8 allele associated with reduced metabolism and increased adverse event risk of the anti-malarial amodiaquine. Furthermore, up to 60% of individuals of West African ancestry harbored variants that reduced the clearance of pioglitazone, repaglinide, paclitaxel and ibuprofen. In contrast, reduced function alleles are only found in < 2% of East Asian and 8.3-12.8% of South and West Asian individuals. CONCLUSIONS: Combined, the presented analyses mapped the genetic and inferred functional variability of CYP2C8 with high ethnogeographic resolution. These results can serve as a valuable resource for CYP2C8 allele frequencies and distribution estimates of CYP2C8 phenotypes that could help identify populations at risk upon treatment with CYP2C8 substrates. The high variability between ethnic groups incentivizes high-resolution pharmacogenetic profiling to guide precision medicine and maximize its socioeconomic benefits, particularly for understudied populations with distinct genetic profiles.


Assuntos
Alelos , Carbamatos , Citocromo P-450 CYP2C8 , Piperidinas , Citocromo P-450 CYP2C8/genética , Humanos , Frequência do Gene/genética , Polimorfismo de Nucleotídeo Único/genética , Europa (Continente) , Tiazolidinedionas/efeitos adversos
15.
Arterioscler Thromb Vasc Biol ; 44(4): 784-793, 2024 04.
Artigo em Inglês | MEDLINE | ID: mdl-38385287

RESUMO

Hypertension is a prevalent public health problem, contributing to >10 million deaths annually. Though multiple therapeutics exist, many patients suffer from treatment-resistant hypertension or try several medications before achieving blood pressure control. Genomic advances offer mechanistic understanding of blood pressure variability, therapeutic targets, therapeutic response, and promise a stratified approach to treatment of primary hypertension. Cyclic guanosine monophosphate augmentation, aldosterone synthase inhibitors, and angiotensinogen blockade with silencing RNA and antisense therapies are among the promising novel approaches. Pharmacogenomic studies have also been done to explore the genetic bases underpinning interindividual variability in response to existing therapeutics. A polygenic approach using risk scores is likely to be the next frontier in stratifying responses to existing therapeutics.


Assuntos
Hipertensão , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/genética , Pressão Sanguínea/genética , Herança Multifatorial , Genômica , Farmacogenética
16.
Diabetologia ; 2024 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-39422716

RESUMO

AIMS/HYPOTHESIS: Metformin is an important first-line treatment for type 2 diabetes and acts by increasing the body's ability to dispose of glucose. Metformin's efficacy can be affected by genetic variants in the transporters that regulate its uptake into cells. The SLC22A3 gene (also known as EMT; EMTH; OCT3) codes for organic cation transporter 3 (OCT3), which is a broad-specificity cation transporter that also transports metformin. Most SLC22A3 variants reduce the rate of metformin transport but the rs8187715 variant (p.Thr44Met) is reported to increase uptake of metformin in vitro. However, the impact of this on in vivo metformin transport and efficacy is unknown. Very few carriers of this variant have been reported globally, but, notably, all were of Pacific Island descent. Therefore, this study aims to understand the prevalence of this variant in Polynesian peoples (Maori and Pacific peoples) and to understand its impact on metformin transport and efficacy in vivo. METHODS: rs8187715 was genotyped in 310 individuals with Maori and Pacific ancestry recruited in Aotearoa New Zealand. To study this variant in a physiological context, an orthologous knockin mouse model with C57BL/6J background was used. Pharmacokinetic analysis compared uptake rate of metformin into tissues. Plasma growth/differentiation factor 15 (GDF-15) was also measured as a marker of metformin efficacy. Glucose and insulin tolerance was assessed after acute or sustained metformin treatment in knockin and wild-type control mice to examine the impact of the variant on metformin's glycaemic control. RESULTS: The minor allele frequency of this variant in the Maori and Pacific participants was 15.4%. There was no association of the variant with common metabolic parameters including diabetes status, BMI, blood pressure, lipids, or blood glucose and HbA1c. However, in the orthologous knockin mouse model, the rate of metformin uptake into the blood and tissues was increased. Acute metformin dosing increased insulin sensitivity in variant knockin mice but this effect was lost after longer-term metformin treatment. Metformin's effects on GDF-15 levels were also lost in variant knockin mice with longer-term metformin treatment. CONCLUSIONS/INTERPRETATION: These data provide evidence that the SLC22A3 rs8187715 variant accelerates metformin uptake rate in vivo. While this acutely improves insulin sensitivity, there was no increased effect of metformin with longer-term dosing. Thus, our finding of a high prevalence of this variant specifically in Maori and Pacific peoples identifies it as a potential population-specific pharmacogenetic marker with potential to guide metformin therapy in these peoples.

17.
Curr Issues Mol Biol ; 46(7): 6951-6959, 2024 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-39057056

RESUMO

Asthma is a chronic inflammatory respiratory condition, characterized by variable airflow limitation, leading to clinical symptoms such as dyspnea and chest tightness. These symptoms result from an underlying inflammatory process. The ß2 agonists are bronchodilators prescribed for the relief of the disease. Nevertheless, their efficacy exhibits substantial interindividual variability. Currently, there is widespread recognition of the association between specific genetic variants, predominantly located within the ADRB2 and ADCY9 genes and their efficacy. This association, usually represented by the presence of non-synonymous single nucleotide polymorphisms (SNPs) have a strong impact in the protein functionality. The prevalence of these mutations varies based on the ethnic composition of the population and thus understanding the profiles of variability in different populations would contribute significantly to standardizing the use of these medications. In this study, we conducted a sequence-based genotyping of the relevant SNPs within the ADRB2 and ADCY9 genes in patients undergoing treatment with bronchodilators and/or corticosteroids at two healthcare facilities in the state of Rio de Janeiro, Brazil. We investigated the presence of c.46A>G, c.79C>G, c.252G>A, and c.491C>T SNPs within the ADRB2, and c.1320018 A>G within the ADCY9. Our results were in line with existing literature data with both for individuals in Brazil and Latin American.

18.
Curr Issues Mol Biol ; 46(3): 2263-2277, 2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38534761

RESUMO

Prostate cancer remains a significant public health concern in sub-Saharan Africa, particularly impacting South Africa with high mortality rates. Despite many years of extensive research and significant financial expenditure, there has yet to be a definitive solution to prostate cancer. It is not just individuals who vary in their response to treatment, but even different nodules within the same tumor exhibit unique transcriptome patterns. These distinctions extend beyond mere differences in gene expression levels to encompass the control and networking of individual genes. Escalating chemotherapy resistance in prostate cancer patients has prompted increased research into its underlying mechanisms. The heterogeneous nature of transcriptomic organization among men makes the pursuit of universal biomarkers and one-size-fits-all treatments impractical. This study delves into the expression of drug resistance-associated genes, ABCB1 and CYP1B1, in cancer cells. Employing bioinformatics, we explored the molecular pathways and cascades linked to drug resistance following upregulation of these genes. Samples were obtained from archived prostate cancer patient specimens through pre-treatment biopsies of two categories: good vs. poor responders, with cDNAs synthesized from isolated RNAs subjected to qPCR analysis. The results revealed increased ABCB1 and CYP1B1 expression in tumor samples of the poor responders. Gene enrichment and network analysis associated ABCB1 with ABC transporters and LncRNA-mediated therapeutic resistance (WP3672), while CYP1B1 was linked to ovarian steroidogenesis, tryptophan metabolism, steroid hormone biosynthesis, benzo(a)pyrene metabolism, the sulindac metabolic pathway, and the estrogen receptor pathway, which are associated with drug resistance. Both ABCB1 and CYP1B1 correlated with microRNAs in cancer and the Nuclear Receptors Meta-Pathway. STRING analysis predicted protein-protein interactions of ABCB1 and CYP1B1 with Glutathione S-transferase Pi, Catechol O-methyltransferase, UDP-glucuronosyltransferase 1-6, Leucine-rich Transmembrane and O-methyltransferase (LRTOMT), and Epoxide hydrolase 1, with scores of 0.973, 0.971, 0.966, 0.966, and 0.966, respectively. Furthermore, molecular docking analysis of the chemotherapy drug, docetaxel, with CYP1B1 and ABCB1 revealed robust molecular interactions, with binding energies of -20.37 and -15.25 Kcal/mol, respectively. These findings underscore the susceptibility of cancer patients to drug resistance due to increased ABCB1 and CYP1B1 expression in tumor samples from patients in the poor-responders category that affects associated molecular pathways. The potent molecular interactions of ABCB1 and CYP1B1 with docetaxel further emphasize the potential basis for chemotherapy resistance.

19.
Annu Rev Pharmacol Toxicol ; 61: 679-699, 2021 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-32976737

RESUMO

Cancer is the leading cause of death in American children older than 1 year of age. Major developments in drugs such as thiopurines and optimization in clinical trial protocols for treating cancer in children have led to a remarkable improvement in survival, from approximately 30% in the 1960s to more than 80% today. Short-term and long-term adverse effects of chemotherapy still affect most survivors of childhood cancer. Pharmacogenetics plays a major role in predicting the safety of cancer chemotherapy and, in the future, its effectiveness. Treatment failure in childhood cancer-due to either serious adverse effects that limit therapy or the failure of conventional dosing to induce remission-warrants development of new strategies for treatment. Here, we summarize the current knowledge of the pharmacogenomics of cancer drug treatment in children and of statistically and clinically relevant drug-gene associations and the mechanistic understandings that underscore their therapeutic value in the treatment of childhood cancer.


Assuntos
Antineoplásicos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Neoplasias , Antineoplásicos/uso terapêutico , Criança , Pré-Escolar , Humanos , Neoplasias/tratamento farmacológico , Farmacogenética
20.
Annu Rev Pharmacol Toxicol ; 61: 65-84, 2021 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-33006916

RESUMO

The clinical implementation of pharmacogenetic biomarkers continues to grow as new genetic variants associated with drug outcomes are discovered and validated. The number of drug labels that contain pharmacogenetic information also continues to expand. Published, peer-reviewed clinical practice guidelines have also been developed to support the implementation of pharmacogenetic tests. Incorporating pharmacogenetic information into health care benefits patients as well as clinicians by improving drug safety and reducing empiricism in drug selection. Barriers to the implementation of pharmacogenetic testing remain. This review explores current pharmacogenetic implementation initiatives with a focus on the challenges of pharmacogenetic implementation and potential opportunities to overcome these challenges.


Assuntos
Farmacogenética , Testes Farmacogenômicos , Atenção à Saúde , Humanos
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