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Vaccines represent preventative interventions amenable to immunogenetic prediction of how human variability will influence their safety and efficacy. The genetic polymorphism among individuals within any population can render possible that the immunity elicited by a vaccine is variable in length and strength. The same immune challenge (virus and/or vaccine) could provoke partial, complete or even failed protection for some individuals treated under the same conditions. We review genetic variants and mechanistic relationships among chemokines, chemokine receptors, interleukins, interferons, interferon receptors, toll-like receptors, histocompatibility antigens, various immunoglobulins and major histocompatibility complex antigens. These are the targets for variation among macrophages, dendritic cells, natural killer cells, T- and B-lymphocytes, and complement. The technology platforms (mRNA, viral vectors, proteins) utilized to produce vaccines against SARS-CoV-2 infections may each trigger genetically distinct immune reactogenic profiles. With DNA biobanking and immunoprofiling of recipients, global COVID-19 vaccinations could launch a new era of personalized healthcare.
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Vacinas contra COVID-19 , COVID-19 , Bancos de Espécimes Biológicos , Humanos , SARS-CoV-2 , VacinaçãoRESUMO
Context: Glutathione (GSH) is a major intracellular antioxidant capable of scavenging free radicals and detoxifying electrophiles from endogenous and exogenous sources via the free thiol group. GSH plays an important role in a multiple cellular process, including cell differentiation, proliferation, and apoptosis. Pharmacogenomics has demonstrated its important role as a key element in cellular health. Objective: The study intended to examine the benefits of using GSH pharmacogenomics as a therapy to prevent side effects and interactions with antineoplastic agents in the diagnosis and treatment of malignancies. Design: The research team performed a narrative review using the Google scholar and PubMed electronic databases. Conclusions: In summary, the involvement of GSH in the carcinogenesis and drug resistance of tumor cells is clear and well understood, but further studies, aimed at understanding the GSH-driven molecular pathways, might be crucial to designing new therapeutic strategies to fight cancer progression, overcoming chemoresistance, using in combination with immunotherapies, and preventing or minimizing their negative side effects.
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Antineoplásicos , Neoplasias , Acetilcisteína/uso terapêutico , Antineoplásicos/uso terapêutico , Antioxidantes/uso terapêutico , Glutationa/metabolismo , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Farmacogenética , Compostos de Sulfidrila/uso terapêuticoRESUMO
The solubility of warfarin sodium isopropanol solvate (WS·IPA), a widely used anticoagulant, was determined at temperatures ranging from 278.15 to 333.15 K in four pure solvents (acetone, ethanol, IPA, and water), five binary solvent mixtures (IPA + acetone, IPA + ethanol, IPA + water, IPA + heptane, and IPA + hexane), and five ternary solvent mixtures (IPA + acetone + heptane, IPA + acetone + hexane, IPA + ethanol + heptane, IPA + ethanol + hexane, and IPA + water + heptane) using the polythermal method. It was demonstrated that the solubility of WS·IPA increases with increasing temperature in the pure solvents and at constant solvent composition in the solvent mixtures. In addition, the solubility of WS·IPA in IPA increases with increasing content of acetone, ethanol, and water, which act as cosolvents, and decreases with increasing content of heptane and hexane, which act as antisolvents. The experimental solubility data of WS·IPA in pure solvents and binary and ternary solvent mixtures were correlated using the modified Apelblat and λh model equations. The correlated solubility data agree with the experimental data based on the relative deviation and the average relative deviation (ARD %) values. Thus, the correlated and experimentally derived solubility data of WS·IPA provide a pathway to engineer advanced pharmaceutical crystallization processes for WS·IPA.
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ATP-binding cassette subfamily C (ABCC) genes code for phase III metabolism proteins that translocate xenobiotic (e.g., particulate matter 2.5 (PM2.5)) and drug metabolites outside the cells. IL-6 secretion is related with the activation of the ABCC transporters. This study assesses ABCC1-4 gene expression changes and proinflammatory cytokine (IL-6, IL-8) release in human bronchial epithelial cells (BEAS-2B) exposed to PM2.5 organic extract, budesonide (BUD, used to control inflammation in asthmatic patients), and a cotreatment (Co-T: PM2.5 and BUD). A real-time PCR assay shows that ABCC1 was upregulated in BEAS-2B exposed after 6 and 7 hr to PM2.5 extract or BUD but downregulated after 6 hr of the Co-T. ABCC3 was downregulated after 6 hr of BUD and upregulated after 6 hr of the Co-T exposures. ABCC4 was upregulated after 5 hr of PM2.5 extract, BUD, and the Co-T exposures. The cytokine assay revealed an increase in IL-6 release by BEAS-2B exposed after 5 hr to PM2.5 extract, BUD, and the Co-T. At 7 hr, the Co-T decreases IL-6 release and IL-8 at 6 hr. In conclusion, the cotreatment showed an opposite effect on exposed BEAS-2B as compared with BUD. The results suggest an interference of the BUD therapeutic potential by PM2.5.
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Budesonida/toxicidade , Material Particulado/toxicidade , Brônquios/citologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Humanos , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Proteína 2 Associada à Farmacorresistência Múltipla , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Reação em Cadeia da PolimeraseRESUMO
The Zika Fever is a viral disease caused by a single-stranded RNA virus from the Flavivirus genus, Flaviviridae family, from the Spondweni group. Its transmission occurs through mosquito vectors, principally Aedes Aegypti. The most common symptoms of Zika are fever, rash, joint pain, and conjunctivitis (red eyes). Other common symptoms include muscle pain and headache. As of now, no vaccine exists for the virus and no official treatment has been developed aside from standard procedures of the use of acetaminophen (paracetamol) and non-steroidal anti-inflammatory drugs. This is a case report of a 54 year-old Hispanic female who arrived at the clinic with symptomatology congruent with the Zika fever. The patient was treated with high doses of intravenous vitamin C over three days. The symptoms resolved after the infusions without any side effects at day four. Recovery from this viral infection takes normally around two weeks. Based on the positive outcome in this case, we propose that intravenous vitamin C should be studied further as a potential treatment for acute viral infections.
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A healthy physiology depends on a plethora of complex interdependent biochemical reactions. In order for these reactions to occur suitably, the enzymes and cofactors that regulate their flow must be present in the proper balance. The term metabolic correction is used to describe a biochemical-physiological process that improves cellular biochemistry as a means to an individual's achieving metabolic or physiological optimization. Part 2 discusses how metabolic correction, through the increase of cofactors, can supply unmet enzyme needs and compensate for nutritional deficiencies induced by improper nutritional intake or by the increased demand for nutrients caused by genetics, health conditions, medications, or physical or environmental stressors. Nutrient insufficiencies are causing an increase in morbidity and mortality, at great cost to our society. In summary, metabolic correction improves enzymatic function and satisfies the increasing demand for nutrients. Metabolic correction can have a significant impact on the reduction of morbidity and mortality and their financial cost to our society and contribute to improving health and well-being.
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Coenzimas/metabolismo , Enzimas/metabolismo , Desnutrição/fisiopatologia , Alimentos , Humanos , Micronutrientes/metabolismo , Necessidades NutricionaisRESUMO
Human physiology depends on countless biochemical reactions, numerous of which are co-dependent and interrelated. The speed and level of completion of reactions usually depend on the availability of precursors and enzymes. The enzymatic activity depends on the bioavailability of micronutrient cofactors such as vitamins and minerals. In order to achieve a healthy physiological state, the organism requires that biochemical reactions occur at a controlled rate. To achieve this state it is required that metabolic reactions reach what can be considered an optimal metabolic equilibrium. A combination of genetic makeup, dietary patterns, trauma, disease, toxins, medications, and environmental stressors can elevate the demand for the nutrients needed to reach this optimal metabolic equilibrium. In this, part 1, the general concept of metabolic correction is presented with an elaboration explaining how this concept is increasing in importance as we become aware of the presence of genetic variants that affect enzymatic reactions causing metabolic disturbances that themselves favor or promote the disease state. In addition, part 1 reviews how prominent scientists have contributed in fundamental ways to our understanding of the importance of micronutrients in health and disease and in the development of the metabolic correction concept.
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Enzimas/metabolismo , Doenças Metabólicas/fisiopatologia , Micronutrientes/metabolismo , Alimentos , Variação Genética , Humanos , Doenças Metabólicas/genética , Minerais/metabolismo , Vitaminas/metabolismoRESUMO
Diabetes Mellitus type 2 (DM2) is a metabolic disease that develops by a decrease in sensitivity of insulin receptors as an effect of the disruption certain metabolic functions in the processing of glucose. DM2 patients have, uncontrolled glucose levels, and commonly have problems with obesity and cardiovascular disease. Patients are treated with standard diet, insulin, diabetic oral agents and antihypertensive drugs, but this approach does not completely stops tissue deterioration since it does not address the metabolic root of the disease. Metabolic correction is proposed as a suitable adjunct treatment to improve clinical outcomes. Metabolic correction is based on diet modification, proper hydration and scientific supplementation directed to improve cellular biochemistry and metabolic efficiency. In addition, other possible benefits may include reduction in medication use, disease complications and medical costs. To test the results of a metabolic correction program, 25 patients with DM2 participated in an education program about adequate food consumption that promoted control of blood glucose levels. Anthropometric measurements and blood tests were performed during a 13 week program based on a low carbohydrate diet, proper hydration and magnesium supplementation. The metabolic correction program implemented by a proprietary educational system resulted in significant reductions in glucose, triglycerides, cholesterol, weight and waist circumference. Improvements in these values could represent an important reduction of coronary heart disease risk factors as well as other chronic degenerative diseases. In addition there was medication dosage reduction in one or more medications in 21 of the 25 participating patients, which suggest that the program has the potential to improve health outcomes and reduce health care costs.
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Diabetes Mellitus Tipo 2/terapia , Educação de Pacientes como Assunto/métodos , Sistema Nervoso Autônomo/fisiopatologia , Glicemia/análise , Terapia Combinada , Comorbidade , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Dieta com Restrição de Carboidratos , Dieta para Diabéticos , Comportamento de Ingestão de Líquido , Dislipidemias/complicações , Dislipidemias/terapia , Humanos , Hiperinsulinismo/complicações , Hiperinsulinismo/dietoterapia , Hipoglicemiantes/uso terapêutico , Lipídeos/sangue , Magnésio/uso terapêutico , Obesidade/complicações , Obesidade/dietoterapia , Projetos Piloto , Avaliação de Programas e Projetos de Saúde , Resultado do Tratamento , Circunferência da Cintura , Redução de PesoRESUMO
Human development and its physiology depends on a number of complex biochemical body processes, many of which are interactive and codependent. The speed and the degree in which many physiological reactions are completed depend on enzyme activity, which in turn depends on the bioavailability of co-factors and micronutrients such as vitamins and minerals. To achieve a healthy physiological state, organism need that biochemical reactions occur in a controlled and specific way at a particular speed and level or grade fully completed. To achieve this, is required an optimal metabolic balance. Factors such as, a particular genetic composition, inadequate dietary consumption patterns, traumas, diseases, toxins and environmental stress all of these factors rising demands for nutrients in order to obtain optimal metabolic balance. Metabolic correction is a biochemical and physiological concept that explains how improvements in cellular biochemistry of an organism can help the body achieve metabolic and physiological optimization. We summarize the contribution of several pioneers in understanding the role of micronutrients in health management. The concept of metabolic correction is becoming a significant term due to the presence of genetic variants that affect the speed of reactions of enzymes, causing metabolic alterations that enhance or promote the state/development of multiple diseases. Decline in the nutritional value of the food we eat, the increase in demand for certain nutrients caused by normal development, diseases and medications induce, usually, nutrients consumption. These nutritional deficiencies and insufficiencies are causing massive economic costs due to increased morbidity and mortality in our society. In summary, metabolic correction improves the enzymatic function, which favors the physiological normal functions, thus, contributing to improving health and the welfare of the human being. The purpose of this paper is to describe and introduce the concept of optimal metabolic correction as a functional cost-effective mechanism against disease, in addition, to contribute to diseases prevention and regeneration of the body and health.
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Micronutrientes/fisiologia , Prevenção Primária/métodos , Deficiência de Vitaminas/complicações , Deficiência de Vitaminas/terapia , Coenzimas/deficiência , Coenzimas/fisiologia , Coenzimas/uso terapêutico , Dano ao DNA , Suplementos Nutricionais , Metabolismo Energético , Enzimas/fisiologia , Comportamento Alimentar , Humanos , Desnutrição/complicações , Desnutrição/terapia , Micronutrientes/deficiência , Micronutrientes/uso terapêutico , Minerais/uso terapêutico , Modelos Biológicos , Necessidades Nutricionais , Medicina de Precisão , Estados Unidos , Vitaminas/uso terapêuticoRESUMO
OBJECTIVE: This study was intended to determine the incidence rate of warfarin-related adverse events (e.g., bleeding) in Puerto Ricans and whether a genetic association between warfarin pharmacogenes and any of these adverse events was observed over the initiation period (i.e., the first 90 days of therapy). METHODS: We conducted an observational, retrospective cohort study of pharmacogenetic association in 122 warfarin-treated, male, Puerto Rican patients (69.9 +/- 9.6 years) from the Veterans Affair Caribbean Healthcare System (VACHS) who consented to participate. Genotyping was performed using the CYP2C9 and VKORC1 assays by Luminex. Event-free survival curves were estimated using the Kaplan-Meier method and analyzed by log-rank test. Cox regression models were constructed and hazard ratios (HR) calculated. RESULTS: Carriers of functional CYP2C9 and VKORC1 polymorphisms demonstrated a higher incidence rate of multiple adverse events (i.e., 5.2 vs. 1.0 cases per 100 patient-months; RR = 4.8, p = 0.12) than did wild types. A significant association was observed between multiple adverse events and carrier status (HR = 2.5; 95% CI: 1.0-6.3, p = 0.04). However, no significant associations between genotypes and individual outcomes over the first 90 days of therapy were found. CONCLUSION: The association of CYP2C9 and VKORC1 genotypes and risks for adverse events due to exposure to warfarin was examined for the first time in Puerto Ricans. Despite a lack of association with individual events in this study population, our findings revealed a potential utility of genotyping for the prevention of multiple adverse events during warfarin therapy.
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Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Hemorragia/induzido quimicamente , Hemorragia/genética , Varfarina/administração & dosagem , Varfarina/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Genótipo , Humanos , Pessoa de Meia-Idade , Porto Rico , Estudos RetrospectivosRESUMO
The Chikungunya (CHIKV) fever is a viral disease produced by a single-stranded RNA Alphavirus from the Togaviridae genus. Its transmission occurs only through mosquito vectors, principally Aedes aegypti. It requires a human-mosquito-human transmission cycle. It is associated with severe arthritis/arthralgias, myalgias, high fever, headache, and maculopapular rash. Joint ache appears to be symmetrical. The virus has an incubation period of 2 to 7 days, where the high fever is typically presented. It is followed by arthralgias and myalgias, and rashes, which last for 3 to 5 days. However, the arthralgias can persist for months after the infection, which can contribute to severe arthritis. As of now, no vaccine exists for the virus and no official treatment has been developed aside from standard procedures of the use of acetaminophen (paracetamol), and non-steroidal anti-inflammatory drugs. This is a case report of a 54-year old Hispanic individual that reported left shoulder pain, left knee pain and fever. The symptoms started on a Saturday in September 2014 in middle of the night. The patient was treated with high doses of intravenous vitamin C over two days. The symptoms resolved after the infusions without any side effects. Based on the positive outcome in this case, we propose that intravenous vitamin C should be studied further as a potential treatment for acute viral infections.
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OBJECTIVE: Neonatal abstinence syndrome (NAS) is a set of drug withdrawal symptoms suffered by neonates exposed to drugs in utero. Several studies have widely described NAS incidence and treatment approach; however, little is known regarding the incidence and manifestations of this disease in Puerto Rico (PR). The principal aim of this study was to describe NAS incidence in the neonatal units of hospitals affiliated with the University of PR in terms of occurrence, clinical manifestations, and treatment approaches. METHODS: Our study evaluated the medical records of NAS babies diagnosed from 2018 through 2020 at 2 hospitals affiliated with the University of PR Medical Sciences Campus. Descriptive and inferential statistics were employed to analyze trends. RESULTS: We identified 12 neonates diagnosed with NAS, 5 with low birthweights (<2500 g); for a NAS incidence of 2 cases per 1000 admitted for the 3 years of recollected data. The urine toxicology results revealed that 9 had experienced intrauterine polydrug exposure. Phenobarbital loading dose were determined on the day of diagnosis (indicated by Finnegan score). The first manifestation of NAS symptoms varied: 8 neonates showed symptoms within 48 hours after birth, whereas 4 had withdrawal symptoms within 72-120 hours of their births. Differences between dosing practices and guidelines were observed, ranging from a 0.69% to a 25% difference during treatment initiation. CONCLUSION: Further research on the incidence of NAS in PR (national level) is needed for a deeper understanding that we hope will lead to the development of enhanced treatment protocols in PR.
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Metadona , Síndrome de Abstinência Neonatal , Recém-Nascido , Humanos , Metadona/uso terapêutico , Síndrome de Abstinência Neonatal/tratamento farmacológico , Síndrome de Abstinência Neonatal/epidemiologia , Síndrome de Abstinência Neonatal/diagnóstico , Porto Rico/epidemiologia , Unidades de Terapia Intensiva Neonatal , Universidades , Analgésicos Opioides/uso terapêuticoRESUMO
Warfarin, an oral anticoagulant, has been used for decades to prevent thromboembolic events. The complex interplay between CYP2C9 and VKORC1 genotypes on warfarin PK and PD properties is not fully understood in special sub-groups of patients. This study aimed to externally validate a population pharmacokinetic/pharmacodynamic (PK/PD) model for the effect of warfarin on international normalized ratio (INR) and to evaluate optimal dosing strategies based on the selected covariates in Caribbean Hispanic patients. INR, and CYP2C9 and VKORC1 genotypes from 138 patients were used to develop a population PK/PD model in NONMEM. The structural definition of a previously published PD model for INR was implemented. A numerical evaluation of the parameter-covariate relationship was performed. Simulations were conducted to determine optimal dosing strategies for each genotype combinations, focusing on achieving therapeutic INR levels. Findings revealed elevated IC50 for G/G, G/A, and A/A VKORC1 haplotypes (11.76, 10.49, and 9.22 mg/L, respectively), in this population compared to previous reports. The model-guided dosing analysis recommended daily warfarin doses of 3-5 mg for most genotypes to maintain desired INR levels, although subjects with combination of CYP2C9 and VKORC1 genotypes * 2/* 2-, * 2/* 3- and * 2/* 5-A/A would require only 1 mg daily. This research underscores the potential of population PK/PD modeling to inform personalized warfarin dosing in populations typically underrepresented in clinical studies, potentially leading to improved treatment outcomes and patient safety. By integrating genetic factors and clinical data, this approach could pave the way for more effective and tailored anticoagulation therapy in diverse patient groups.
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Hidrocarboneto de Aril Hidroxilases , Varfarina , Humanos , Anticoagulantes/farmacologia , Citocromo P-450 CYP2C9/genética , Genótipo , Hispânico ou Latino/genética , Vitamina K Epóxido Redutases/genética , População do CaribeRESUMO
The Pharmacogene Variation Consortium (PharmVar) serves as a global repository providing star (*) allele nomenclature for the polymorphic human CYP4F2 gene. CYP4F2 genetic variation impacts the metabolism of vitamin K, which is associated with warfarin dose requirements, and the metabolism of drugs, such as imatinib or fingolimod, and certain endogenous compounds including vitamin E and eicosanoids. This GeneFocus provides a comprehensive overview and summary of CYP4F2 genetic variation including the characterization of 14 novel star alleles, CYP4F2*4 through *17. A description of how haplotype information cataloged by PharmVar is utilized by the Pharmacogenomics Knowledgebase (PharmGKB) and the Clinical Pharmacogenetics Implementation Consortium (CPIC) is also provided.
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Cardiovascular disease (CVD) is one of the leading causes of death in Puerto Rico, where clopidogrel is commonly prescribed to prevent ischemic events. Genetic contributors to both a poor clopidogrel response and the severity of CVD have been identified mainly in Europeans. However, the non-random enrichment of single-nucleotide polymorphisms (SNPs) associated with clopidogrel resistance within risk loci linked to underlying CVDs, and the role of admixture, have yet to be tested. This study aimed to assess the possible interaction between genetic biomarkers linked to CVDs and those associated with clopidogrel resistance among admixed Caribbean Hispanics. We identified 50 SNPs significantly associated with CVDs in previous genome-wide association studies (GWASs). These SNPs were combined with another ten SNPs related to clopidogrel resistance in Caribbean Hispanics. We developed Python scripts to determine whether SNPs related to CVDs are in close proximity to those associated with the clopidogrel response. The average and individual local ancestry (LAI) within each locus were inferred, and 60 random SNPs with their corresponding LAIs were generated for enrichment estimation purposes. Our results showed no CVD-linked SNPs in close proximity to those associated with the clopidogrel response among Caribbean Hispanics. Consequently, no genetic loci with a dual predictive role for the risk of CVD severity and clopidogrel resistance were found in this population. Native American ancestry was the most enriched within the risk loci linked to CVDs in this population. The non-random enrichment of disease susceptibility loci with drug-response SNPs is a new frontier in Precision Medicine that needs further attention.
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Doenças Cardiovasculares , Humanos , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/genética , Clopidogrel/farmacologia , Etnicidade/genética , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
Background: Recent studies suggest that lipid-lowering agents (LLA) may reduce chronic periodontitis, but it is unknown whether this benefit extends to people with type 2 diabetes (T2D). Objective: We assessed the association between LLA use and periodontitis in Hispanic adults with T2D. Design: This was a cross-sectional observational study. Methods: We assessed the association of LLA use and periodontal parameters in 253 Puerto Ricans 40-65 years with T2D who participated in the Lipid-Lowering agents use in Periodontitis and Diabetes Study study. Participants were classified as (a) none- or <1 year, (b) 1-4 years, or (c) >4 years. The primary outcome consists of a tertile percent of sites with probing pocket depth (PPD) ⩾ 4 mm and the secondary outcome includes tertiles of percent sites with clinical attachment loss (CAL) ⩾ 4 mm. Multinomial logistic regression models adjusted for age, gender, smoking status, education, waist circumference, glycosylated hemoglobin A1C (HbA1c), bleeding on probing, examiner, and anti-inflammatory agents were used to estimate the association. Results: LLA (92.5%, statins) was used by 52% of participants. LLA use 1-4 years was associated with lower odds of PPD ⩾ 4 mm (OR: 0.22, p = 0.005; high versus low tertile) or lower odds of CAL ⩾ 4 mm (OR: 0.33, p = 0.02, middle versus low tertile), compared to those with LLA minimal or no use. This association was lost for participants who used LLA for >4 years. LLA users for >4 years with periodontal disease had elevated HbA1c (OR: 1.36, p = 0.05). Conclusion: The use of LLA for 1-4 years was associated with lower values of periodontal parameters versus minimal LLA use. This association was not present among people using LLA > 4 years users, but these participants had poorer glycemic control compared to other participants. In this cross-sectional study, the finding that LLA use 1- 4 years is associated with lower values of periodontal parameters of severity in T2D individuals may help clarify some of the controversies regarding the benefit of these medications in this population.
Lipid-lowering agents and lower values of periodontal parameters in individuals with type 2 diabetes ⢠Lipid-lowering agents (LLA), such as statins, are reported to reduce chronic periodontitis, making individuals with diabetes ideal candidates for this treatment due to their high prevalence of oral disease.⢠The association between LLA use and periodontitis was assessed among Hispanic adults with type 2 diabetes (T2D).⢠Short-term LLA use (but not long-term use) was associated with lower values of periodontal parameters in individuals with T2D.⢠For long-term LLA use, high glycemic level was associated with high values of periodontitis.⢠Thus, under the study design limitations, the finding may provide clinical implications and may help clarify some of the controversies regarding the benefits of LLA use in humans.⢠Furthermore, the higher glycemic levels for periodontal patients with long-term LLA use points to the need to monitor these patients carefully.
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Accuracy of warfarin dose prediction algorithms may be improved by including data from diverse populations in genetic studies of dose variability. Here, we surveyed single nucleotide polymorphisms in vitamin K-related genetic pathways for association with warfarin dose requirements in two admixed Latino populations in standard-principal component adjusted and contemporary-local ancestry adjusted regression models. A total of five variants from vitamin K-related genes/pathways were associated with warfarin dose in both cohorts (P < 0.0125) in standard models. Local ancestry-adjusted analysis unveiled 35 associated variants with absolute effects ranging from ß = 9.04 ( ±2.23) to 39.18 ( ±10.89) per ancestral allele in the discovery cohort and ß = 6.47 (± 2.02) to 17.82 (± 6.83) in the replication cohort. Importantly, we demonstrate the technical validity of the Tractor model in cohorts with admixed ancestry from three founder populations and bring attention to the technical hurdles obstructing the inclusion of diverse, especially admixed, populations in pharmacogenomic research.
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Anticoagulantes , Varfarina , Humanos , Vitamina K Epóxido Redutases/genética , Hispânico ou Latino/genética , Polimorfismo de Nucleotídeo Único , Genótipo , Citocromo P-450 CYP2C9/genéticaRESUMO
Background: High on-treatment platelet reactivity (HTPR) with clopidogrel is predictive of ischemic events in adults with coronary artery disease. Despite strong data suggesting HTPR varies with ethnicity, including clinical and genetic variables, no genome-wide association study (GWAS) of clopidogrel response has been performed among Caribbean Hispanics. This study aimed to identify genetic predictors of HTPR in a cohort of Caribbean Hispanic cardiovascular patients from Puerto Rico. Methods: Local Ancestry inference (LAI) and traditional GWASs were performed on a cohort of 511 clopidogrel-treated patients, stratified based on their P2Y12 reaction units (PRU) into responders and non-responders (HTPR). Results: The LAI GWAS identified variants within the CYP2C19 region associated with HTPR, predominantly driven by individuals of European ancestry and absent in those with native ancestry. Incorporating local ancestry adjustment notably enhanced our ability to detect associations. While no loci reached traditional GWAS significance, three variants showed suggestive significance at chromosomes 3, 14 and 22 (OSBPL10 rs1376606, DERL3 rs5030613, and RGS6 rs9323567). In addition, a variant in the UNC5C gene on chromosome 4 was associated with an increased risk of HTPR. These findings were not identified in other cohorts, highlighting the unique genetic landscape of Caribbean Hispanics. Conclusion: This is the first GWAS of clopidogrel response in Hispanics, confirming the relevance of the CYP2C19 cluster, particularly among those with European ancestry, and also identifying novel markers in a diverse patient population. Further studies are warranted to replicate our findings in other diverse cohorts and meta-analyses.
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Background: After percutaneous coronary intervention (PCI), clopidogrel resistant patients are at an increased risk of major adverse cardiovascular and cerebrovascular events (MACCEs). We aimed to assess whether genotype-guided selection of oral antiplatelet drugs using a clinical decision support (CDS) algorithm reduces the occurrence of these ischemic events and improves outcomes among Caribbean Hispanic patients from Puerto Rico, who are underrepresented in clinical pharmacogenomic (PGx)-guided implementation studies. Methods: Individual platelet function testing (PRU) measures, CYP2C19*2 and PON1 rs662 genotypes, clinical and demographic data from 8 medical facilities were included. Patients were separated into standard of care (SoC) and genotype-guided groups (150 each). Risk scores were calculated based on a previously developed CDS risk prediction algorithm designed to make actionable treatment recommendations for each patient. Alternative therapy with ticagrelor was recommended for patients with a high risk score ≥2. Statistical associations between patient time free of MACCEs and predictor variables (i.e., treatment groups, risk scores) were tested in this population using Kaplan-Meier survival analyses and Cox proportional-hazards regression models. Results: Median age of participants is 67 years; BMI: 27.8; 48% women; 14% smokers; 59% with type-2 diabetes mellitus (T2DM). Among patients with high-risk scores who were free from MACCE events 6 months after coronary stenting, genotype-driven guidance of antiplatelet therapy showed superiority over SoC in terms of reducing the incidence rate of atherothrombotic events. Conclusions: The clinical utility of our PGx-driven CDS algorithm to reduce the incidence rate of MACCEs among post-PCI Caribbean Hispanic patients on clopidogrel was externally demonstrated. Clinical Trial Registration Unique Identifier: NCT03419325.
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BACKGROUND: The influence of CYP2C9 and VKORC1 polymorphisms on warfarin dose has been investigated in white, Asian, and African American populations but not in Puerto Rican Hispanic patients. OBJECTIVE: To test the associations between genotypes, international normalized ratio (INR) measurements, and warfarin dosing and gauge the impact of these polymorphisms on warfarin dose, using a published algorithm. METHODS: A retrospective warfarin pharmacogenetic association study in 106 Puerto Rican patients was performed. DNA samples from patients were assayed for 12 variants in both CYP2C9 and VKORC1 loci by HILOmet PhyzioType assay. Demographic and clinical nongenetic data were retrospectively collected from medical records. Allele and genotype frequencies were determined and Hardy-Weinberg equilibrium (HWE) was tested. RESULTS: Sixty-nine percent of patients were carriers of at least one polymorphism in either the CYP2C9 or the VKORC1 gene. Double, triple, and quadruple carriers accounted for 22%, 5%, and 1%, respectively. No significant departure from HWE was found. Among patients with a given CYP2C9 genotype, warfarin dose requirements declined from GG to AA haplotypes; whereas, within each VKORC1 haplotype, the dose decreased as the number of CYP2C9 variants increased. The presence of these loss-of-function alleles was associated with more out-of-range INR measurements (OR = 1.38) but not with significant INR >4 during the initiation phase. Analyses based on a published pharmacogenetic algorithm predicted dose reductions of up to 4.9 mg/day in carriers and provided better dose prediction in an extreme subgroup of highly sensitive patients, but also suggested the need to improve predictability by developing a customized model for use in Puerto Rican patients. CONCLUSIONS: This study laid important groundwork for supporting a prospective pharmacogenetic trial in Puerto Ricans to detect the benefits of incorporating relevant genomic information into a customized DNA-guided warfarin dosing algorithm.