RESUMEN
This systematic review and meta-analysis aimed to verify the association between the genetic variants of adenosine triphosphate (ATP)-binding cassette subfamily B member 1 (ABCB1) and ATP-binding cassette subfamily G member 2 (ABCG2) genes and the presence and severity of gefitinib-associated adverse reactions. We systematically searched PubMed, Virtual Health Library/Bireme, Scopus, Embase, and Web of Science databases for relevant studies published up to February 2024. In total, five studies were included in the review. Additionally, eight genetic variants related to ABCB1 (rs1045642, rs1128503, rs2032582, and rs1025836) and ABCG2 (rs2231142, rs2231137, rs2622604, and 15622C>T) genes were analyzed. Meta-analysis showed a significant association between the ABCB1 gene rs1045642 TT genotype and presence of diarrhea (OR = 5.41, 95% CI: 1.38-21.14, I2 = 0%), the ABCB1 gene rs1128503 TT genotype and CT + TT group and the presence of skin rash (OR = 4.37, 95% CI: 1.51-12.61, I2 = 0% and OR = 6.99, 95%CI: 1.61-30.30, I2= 0%, respectively), and the ABCG2 gene rs2231142 CC genotype and presence of diarrhea (OR = 3.87, 95% CI: 1.53-9.84, I2 = 39%). No ABCB1 or ABCG2 genes were positively associated with the severity of adverse reactions associated with gefitinib. In conclusion, this study showed that ABCB1 and ABCG2 variants are likely to exhibit clinical implications in predicting the presence of adverse reactions to gefitinib.
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Subfamilia B de Transportador de Casetes de Unión a ATP , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Gefitinib , Proteínas de Neoplasias , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Humanos , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Gefitinib/efectos adversos , Proteínas de Neoplasias/genética , Polimorfismo de Nucleótido Simple , Antineoplásicos/efectos adversos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/genética , GenotipoRESUMEN
BACKGROUND: Adverse drug reactions (ADRs) are of great concern in clinical practice. Pharmacogenetics can identify individuals and groups at increased risk of developing ADRs, enabling treatment adjustments to improve outcomes. The study aimed to determine the prevalence of ADRs related to drugs with pharmacogenetic evidence level 1A in a public hospital in Southern Brazil. RESEARCH DESIGN AND METHODS: ADR information was collected from the pharmaceutical registries from 2017 to 2019. Drugs that have pharmacogenetic evidence level 1A were selected. Public genomic databases were used to estimate the genotypes/phenotypes frequency. RESULTS: During the period, 585 ADRs were spontaneously notified. Most were moderate (76.3%), whereas severe reactions accounted for 33.8%. Additionally, 109 ADRs caused by 41 drugs presented pharmacogenetic evidence level 1A, representing 18.6% of all notified reactions. Depending on the drug-gene pair, up to 35% of individuals from Southern Brazil could be at risk of developing ADRs. CONCLUSIONS: Relevant amount of ADRs were related to drugs with pharmacogenetic recommendations on drug labels and/or guidelines. Genetic information could guide and improve clinical outcomes, decreasing ADR incidence and reducing treatment costs.
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Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Farmacogenética , Humanos , Brasil/epidemiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/genética , Etiquetado de Medicamentos , Hospitales Públicos , Sistemas de Registro de Reacción Adversa a Medicamentos , FarmacovigilanciaRESUMEN
BACKGROUND: Thiopurines are effectively prescribed for immune and oncology diseases but their toxicity leads to severe myelosuppression. Therefore, TPMT genetic variants have been used to adjust dosing for poor and intermediate metabolizers, significantly preventing adverse drug reactions. In 2018, the Clinical Pharmacogenetics Implementation Consortium included NUDT15 rs116855232 to also guide thiopurines dosing. This variant is not present in Caucasians but have been identified in 10% of Asian and Latin American populations. Despite research efforts to portrait the world's genetic variation, few studies include the investigation of NUDT15 in large samples. METHODS: Fifteen NUDT15 and TPMT variants were retrieved for 1270 Mestizos and 20 Natives genotyped from previous studies using the GSA-Illumina microarray. After bioinformatic quality controls, genotypes were available for 12 variants, TPMT rs2842949, rs2842950, rs2842934, rs1800460, rs12201199, rs12663332, rs2518463, rs4449636, rs12529220, rs3931660, rs200591577, and NUD15 rs116855232. Allele frequencies and haplotypes were assessed using PLINK, R, and Haploview. Dosing inferences were described according to the Clinical Pharmacogenomics Implementation Consortium. RESULTS: We report relevant populations differences in actionable TPMT*3B and NUDT15 rs116855232 as the allele frequency of the former is higher in Mestizos compared to Caucasians, and for the latter we report twofold and 1.35-fold higher allele frequencies in Natives and Mestizos compared to Mexicans from Los Angeles. CONCLUSIONS: TPMT*3B and NUDT15 rs116855232 actionable markers showed population differences that ought to be considered as dosing inferences highlight the relevance of routine genotyping of these variants for the prescription of thiopurines in Mexican populations.
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Mercaptopurina/farmacología , Metiltransferasas/genética , Pirofosfatasas/genética , Relación Dosis-Respuesta a Droga , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/genética , Femenino , Frecuencia de los Genes , Humanos , Masculino , México/epidemiología , Farmacogenética/métodos , Variantes FarmacogenómicasAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/genética , Neoplasias Pulmonares/tratamiento farmacológico , MicroARNs/genética , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores de Tumor/sangre , Carcinoma de Pulmón de Células no Pequeñas/genética , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/sangre , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/diagnóstico , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/genéticaRESUMEN
Radiotherapy and cisplatin lead to cell killing in head and neck squamous cell carcinoma patients, but adverse events and response to treatment are not the same in patients with similar clinicopathological aspects. The aim of this prospective study was to evaluate the roles of TP53 c.215G > C, FAS c.-671A > G, FAS c.-1378G > A, FASL c.-844 C > T, CASP3 c.-1191A > G, and CASP3 c.-182-247G > T single nucleotide variants in toxicity, response rate, and survival of cisplatin chemoradiation-treated head and neck squamous cell carcinoma patients. Genomic DNA was analyzed by polymerase chain reaction for genotyping. Differences between groups of patients were analyzed by chi-square test or Fisher's exact test, multiple logistic regression analysis, and Cox hazards model. One hundred nine patients with head and neck squamous cell carcinoma were enrolled in study. All patients were smokers and/or alcoholics. Patients with FAS c.-671GG genotype, FAS c.-671AG or GG genotype, and FASL c.-844CC genotype had 5.52 (95% confidence interval (CI): 1.42-21.43), 4.03 (95% CI: 1.51-10.79), and 5.77 (95% CI: 1.23-27.04) more chances of presenting chemoradiation-related anemia of grades 2-4, lymphopenia of grade 3 or 4, and ototoxicity of all grades, respectively, than those with the remaining genotypes. FAS c.-671GG genotype was also seen as an independent predictor of shorter event-free survival (hazard ratio (HR): 2.05; P = 0.007) and overall survival (HR: 1.83; P = 0.02) in our head and neck squamous cell carcinoma patients. These findings present, for the first time, preliminary evidence that inherited abnormalities in apoptosis pathway, related to FAS c.-671A > G and FASL c.-844 C > T single nucleotide variants, can alter toxicity and survival of tobacco- and alcohol-related head and neck squamous cell carcinoma patients homogeneously treated with cisplatin chemoradiation.
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Proteína Ligando Fas/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/radioterapia , Receptor fas/genética , Adulto , Anciano , Alcoholes/efectos adversos , Quimioradioterapia/efectos adversos , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/genética , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Pronóstico , Carcinoma de Células Escamosas de Cabeza y Cuello/inducido químicamente , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Nicotiana/efectos adversos , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Oseltamivir, a pro-drug, is the best option for treatment and chemoprophylaxis for influenza outbreaks. However, many patients treated with oseltamivir developed adverse reactions, including hypersensitivity, gastritis, and neurological symptoms. The aim of this study was to determine the adverse drug reactions (ADRs) in Mexican patients treated with oseltamivir and whether these ADRs are associated with SNPs of the genes involved in the metabolism, transport, and interactions of oseltamivir. This study recruited 310 Mexican patients with acute respiratory diseases and treated them with oseltamivir (75 mg/day for 5 days) because they were suspected to have influenza A/H1N1 virus infection. Clinical data were obtained from medical records and interviews. Genotyping was performed using real-time polymerase chain reaction and TaqMan probes. The association was assessed under genetic models with contingency tables and logistic regression analysis. Out of 310 patients, only 38 (12.25%) presented ADRs to oseltamivir: hypersensitivity (1.9%), gastritis (10%), and depression and anxiety (0.9%). The polymorphism ABCB1-rs1045642 was associated with adverse drug reactions under the recessive model (P = 0.017); allele C was associated with no adverse drug reactions, while allele T was associated with adverse drug reactions. The polymorphisms SLC15A1-rs2297322, ABCB1-rs2032582, and CES1-rs2307243 were not consistent with Hardy-Weinberg equilibrium, and no other associations were found for the remaining polymorphisms. In conclusion, the polymorphism rs1045642 in the transporter encoded by the ABCB1 gene is a potential predictive biomarker of ADRs in oseltamivir treatment.
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Antivirales/metabolismo , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/genética , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/metabolismo , Oseltamivir/metabolismo , Polimorfismo de Nucleótido Simple/genética , Trastornos Respiratorios/genética , Trastornos Respiratorios/metabolismo , Enfermedad Aguda , Adolescente , Adulto , Antivirales/efectos adversos , Transporte Biológico/fisiología , Niño , Interacciones Farmacológicas/fisiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Femenino , Estudios de Asociación Genética/métodos , Humanos , Subtipo H1N1 del Virus de la Influenza A/aislamiento & purificación , Gripe Humana/tratamiento farmacológico , Gripe Humana/epidemiología , Gripe Humana/genética , Gripe Humana/metabolismo , Masculino , México/epidemiología , Persona de Mediana Edad , Oseltamivir/efectos adversos , Transporte de Proteínas/fisiología , Trastornos Respiratorios/tratamiento farmacológico , Trastornos Respiratorios/epidemiología , Estudios Retrospectivos , Adulto JovenRESUMEN
PURPOSE: Asthenia, myalgia, arthralgia, mucositis, abdominal pain, diarrhea, and neutropenia are adverse reactions commonly reported by women undergoing chemotherapy. Traditional approaches do not take into account the effect that chemotherapeutic changes and variable interactions can cause in adverse reactions. We aimed to identify the impact of the change of a chemotherapy protocol within the same treatment in profiles associated with adverse reactions. METHODS: A total of 166 women admitted to the Brazilian National Institute of Cancer (INCA) were followed. Polymorphisms, clinical variables, and FAC-D protocols (3 cycles of cyclophosphamide, 5-fluorouracil, and doxorubicin followed by 3 cycles of docetaxel) composed the set of independent variables analyzed. Reaction levels were recorded at the end of each chemotherapy cycle via interviews. Marginal models were fitted. RESULTS: The results of marginal models for non-hematological reactions revealed that the docetaxel phase was associated with increased reaction levels compared with the FAC phase. In addition, the set of factors associated with the reactions changed in each protocol. The post-menopausal status was related to high levels of asthenia in docetaxel protocol whereas CYP2B6 polymorphism (rs3745274) was related to high levels in FAC protocol. Regarding the docetaxel phase, high levels of abdominal pain and mucositis were related to CBR3 gene (rs8133052) polymorphism and diabetes respectively. CONCLUSION: The results suggest the need for monitoring non-hematological reactions during the docetaxel phase of FAC-D treatment. The factors related to more severe reactions depend on the chemotherapy protocol used.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Docetaxel/administración & dosificación , Sustitución de Medicamentos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/genética , Dolor Abdominal/inducido químicamente , Dolor Abdominal/epidemiología , Dolor Abdominal/genética , Adulto , Anciano , Oxidorreductasas de Alcohol/genética , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Brasil/epidemiología , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Estudios de Cohortes , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Citocromo P-450 CYP2B6/genética , Diarrea/inducido químicamente , Diarrea/epidemiología , Diarrea/genética , Docetaxel/efectos adversos , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Sustitución de Medicamentos/métodos , Sustitución de Medicamentos/estadística & datos numéricos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/tratamiento farmacológico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Predisposición Genética a la Enfermedad , Humanos , Estudios Longitudinales , Persona de Mediana Edad , Pruebas de Farmacogenómica , Polimorfismo de Nucleótido SimpleRESUMEN
Pharmacogenomics (PGx) has emerged as an encouraging tool in chronic pain therapy. Genetic variations associated with drug effectiveness or adverse reactions (amitriptyline/nortriptyline/codeine/oxycodone/tramadol-CYP2D6, amitriptyline-CYP2C19, carbamazepine-HLA-A, carbamazepine/oxcarbazepine-HLA-B) can be used to guide chronic pain management. Despite this evidence, many obstacles still need to be overcome for the effective clinical implementation of PGx. To translate the pharmacogenetic testing into actionable clinical decisions, the Clinical Pharmacogenetics Implementation Consortium has been developing guidelines for several drug-gene pairs. This review will show the applicability of PGx in chronic pain from disease to treatment; report the drug-gene pairs with strongest evidences in the clinic; and the challenges for the clinical implementation of PGx.
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Analgésicos Opioides/efectos adversos , Analgésicos Opioides/uso terapéutico , Dolor Crónico/tratamiento farmacológico , Dolor Crónico/genética , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/genética , Humanos , Manejo del Dolor/métodos , Farmacogenética/métodos , Polimorfismo Genético/efectos de los fármacos , Polimorfismo Genético/genéticaRESUMEN
Objectives: There are limited data regarding efavirenz pharmacogenetics in admixed populations. The Brazilian population is highly admixed. In a Brazilian cohort, we sought to characterize associations between efavirenz adverse effects (all-cause and CNS) and polymorphisms in seven genes known or suspected to affect efavirenz metabolism and transport. Methods: We studied 225 HIV-positive individuals who had been prescribed efavirenz-containing regimens at a hospital in Rio de Janeiro, Brazil. Eighty-nine cases had efavirenz adverse effects, including 43 with CNS adverse effects, while 136 controls had no adverse effect of any antiretroviral after treatment for at least 6 months. A total of 67 candidate polymorphisms in ABCB1, CYP2A6, CYP2B6, CYP3A4, CYP3A5, NR1I2 and NR1I3 genes were selected for association analysis. Admixture was assessed using 28 ancestry-informative polymorphisms previously validated for the Brazilian population. Associations were evaluated with logistic regression models adjusted for sex and genetic ancestry. Results: There was extensive African, European and Native American admixture in the cohort. Increased all-cause adverse effects were associated with the CYP2B6 genotype combination 15582CC-516TT-983TT (OR = 7.26, P = 0.003) and with the CYP2B6 slow metabolizer group 516TT or 516GT-983CT (OR = 3.10, P = 0.04). CNS adverse effects were nominally associated with CYP3A4 rs4646437 (OR = 4.63, P = 0.014), but not after adjusting for multiple comparisons. Conclusions: In a highly admixed Brazilian cohort, the CYP2B6 slow metabolizer genotype was associated with an increased risk of efavirenz adverse effects.
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Benzoxazinas/efectos adversos , Benzoxazinas/metabolismo , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/genética , Infecciones por VIH/tratamiento farmacológico , Inactivación Metabólica/genética , Inhibidores de la Transcriptasa Inversa/efectos adversos , Inhibidores de la Transcriptasa Inversa/metabolismo , Adulto , Anciano , Alquinos , Benzoxazinas/administración & dosificación , Brasil , Receptor de Androstano Constitutivo , Ciclopropanos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Femenino , Estudios de Asociación Genética , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo Genético , Inhibidores de la Transcriptasa Inversa/administración & dosificaciónRESUMEN
We investigated the effect of pregnane X receptor (PXR) polymorphisms on tacrolimus (FK506) blood trough concentrations and the associated adverse reactions in kidney transplantation recipients (KTRs). Polymerase chain reaction (PCR)-restriction fragment length polymorphism was used to detect the genotypes of single nucleotide polymorphism loci in 336 KTRs. The PXR six-base deletion mutation was classified using specific allele PCR, and the FK506 blood trough concentration in the KTRs was measured by chemiluminescent microparticle immunoassay. There were significant differences in adverse reactions resulting from FK506 in age, weight, body mass index (BMI) and treatment course (P < 0.05). Logistical regression revealed that the FK506 treatment course and BMI were risk factors for hyperlipidemia, and the risk of hyperlipidemia increased 27.534 times when the BMI was less than 18.5. Moreover, age was also a risk factor leading to hyperglycemia. FK506 blood trough concentration and C0/D value had an impact on adverse reactions induced by hyperglycemia. The KTRs' PXR rs3842689, rs6785049, and rs1523127 mutation frequencies were 26.07, 11.79, and 16.07%, respectively. There was no statistically significant difference in the mutation frequency of each locus between the control group and the adverse reaction groups. Therefore, rs3842689, 7635G>A (rs6785049), and 24381C>A (rs1523127) PXR polymorphisms have no obvious impact on FK506; furthermore, the PXR rs3842689 wild-type homozygous WW genotype is a risk factor of FK506 and results in gastrointestinal reactions.
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Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/genética , Trasplante de Riñón/efectos adversos , Receptores de Esteroides/genética , Tacrolimus/sangre , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Índice de Masa Corporal , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/sangre , Genotipo , Humanos , Inmunosupresores/sangre , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Receptor X de Pregnano , Factores de Riesgo , Eliminación de Secuencia , Tacrolimus/uso terapéuticoRESUMEN
BACKGROUND: Many clinical trials have shown the efficacy of aromatase inhibitors (AIs) in the management of breast cancer (BC). There is growing evidence that CYP19A1 single-nucleotide polymorphisms (SNPs) are associated with clinical response (CR) and adverse effects (AEs) among BC patients treated with AIs. The aim of this study was to analyze the association between CYP19A1 polymorphisms and AI treatment in BC patients. METHODS: A systematic review was performed in MEDLINE, EMBASE, and LILACS. A meta-analysis was conducted to compare the association between CYP19A1 variants and treatment response among BC patients. RESULTS: A total of 12 studies were included in the final analysis. There was significant variation among the populations studied and the SNPs and outcomes investigated. A meta-analysis was only possible for the evaluation of SNP rs4646 vs. the wild-type variant with respect to time to progression (TTP) among metastatic BC patients treated with AI. TTP was significantly increased in patients with the rs4646 variant compared with the wild-type gene (hazard ratio (HR) = 0.51 [95 % confidence interval (CI), 0.33-0.78], P = 0.002). Seven studies analyzed the association between AEs with different polymorphisms of CYP19A1. Although there was a statistically significant association with musculoskeletal adverse events (rs934635, rs60271534, rs700518rs, and haplotype M_3_5) and with vasomotor symptoms (rs934635, rs1694189, rs7176005, and haplotype M_5_3) in individual studies, similar associations were not observed in further studies. No statistically significant association between musculoskeletal AEs and SNPs rs4646, rs10046, rs727479, and rs1062033 was found. CONCLUSIONS: These findings suggest that the presence of the rs4646 variant may be a predictive factor of the benefit of AI treatment for BC. The effects of CYP19A1 polymorphisms on clinical outcomes were most often detected in individual studies, suggesting that longer-term studies will better clarify these associations. Additional studies are needed to clarify the predictive value of other SNPs and whether CYP19A1 genotyping should be used to guide AI treatment.
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Inhibidores de la Aromatasa/farmacología , Aromatasa/genética , Neoplasias de la Mama , Resistencia a Antineoplásicos/genética , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/genética , Biomarcadores de Tumor/genética , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Femenino , Pruebas Genéticas , Haplotipos , Humanos , Farmacogenética , Polimorfismo de Nucleótido Simple , Valor Predictivo de las Pruebas , PronósticoRESUMEN
It has been 12 years since the Allele Frequency Net Database (AFND; http://www.allelefrequencies.net) was first launched, providing the scientific community with an online repository for the storage of immune gene frequencies in different populations across the world. There have been a significant number of improvements from the first version, making AFND a primary resource for many clinical and scientific areas including histocompatibility, immunogenetics, pharmacogenetics and anthropology studies, among many others. The most widely used part of AFND stores population frequency data (alleles, genes or haplotypes) related to human leukocyte antigens (HLA), killer-cell immunoglobulin-like receptors (KIR), major histocompatibility complex class I chain-related genes (MIC) and a number of cytokine gene polymorphisms. AFND now contains >1400 populations from more than 10 million healthy individuals. Here, we report how the main features of AFND have been updated to include a new section on 'HLA epitope' frequencies in populations, a new section capturing the results of studies identifying HLA associations with adverse drug reactions (ADRs) and one for the examination of infectious and autoimmune diseases associated with KIR polymorphisms-thus extending AFND to serve a new user base in these growing areas of research. New criteria on data quality have also been included.
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Bases de Datos Genéticas , Epítopos/genética , Frecuencia de los Genes , Antígenos HLA/genética , Receptores KIR/genética , Enfermedad/genética , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/genética , Antígenos HLA/inmunología , Antígenos de Histocompatibilidad Clase I/genética , Humanos , InternetRESUMEN
Hypertension is a leading cause of cardiovascular mortality, but only one third of patients achieve blood pressure goals despite antihypertensive therapy. Genetic polymorphisms may partially account for the interindividual variability and abnormal response to antihypertensive drugs. Candidate gene and genome-wide approaches have identified common genetic variants associated with response to antihypertensive drugs. However, there is no currently available pharmacogenetic test to guide hypertension treatment in clinical practice. In this review, we aimed to summarize the recent findings on pharmacogenetics of the most commonly used antihypertensive drugs in clinical practice, including diuretics, angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers, beta-blockers and calcium channel blockers. Notably, only a small percentage of the genetic variability on response to antihypertensive drugs has been explained, and the vast majority of the genetic variants associated with antihypertensives efficacy and toxicity remains to be identified. Despite some genetic variants with evidence of association with the variable response related to these most commonly used antihypertensive drug classes, further replication is needed to confirm these associations in different populations. Further studies on epigenetics and regulatory pathways involved in the responsiveness to antihypertensive drugs might provide a deeper understanding of the physiology of hypertension, which may favor the identification of new targets for hypertension treatment and genetic predictors of antihypertensive response.
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Antihipertensivos , Resistencia a Medicamentos/genética , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/genética , Hipertensión/tratamiento farmacológico , Antihipertensivos/clasificación , Antihipertensivos/farmacología , Presión Sanguínea/efectos de los fármacos , Estudios de Asociación Genética , Estudio de Asociación del Genoma Completo , Humanos , Farmacogenética , Polimorfismo GenéticoRESUMEN
AIM: Several HLA alleles have been associated with antiepileptic drugs (AEDs)-induced cutaneous adverse drug reactions (cADRs) in different populations; however, this has not been investigated in Mexican Mestizos (MM). Thus, the purpose of this preliminary study was to determine the association of HLA class I alleles with AED-induced cADRs in MM patients. MATERIALS & METHODS: This case-control association study included 21 MM patients with phenytoin (PHT)-, carbamazepine (CBZ)-, or lamotrigine (LTG)-induced maculopapular exanthema (MPE) or Stevens-Johnson syndrome (SJS); 31 MM patients tolerant to the same AEDs; and 225 unrelated, healthy MM volunteers. HLA class I genotyping was performed. Differences in HLA allele frequencies between AED-induced cADR patients and AED-tolerant patients were assessed. Frequencies of alleles possibly associated with AED-induced cADRs in MM patients were compared with those in MM population. RESULTS: The frequency of HLA-C*08:01 allele in PHT-induced MPE was higher than that in the PHT-tolerant group (pc=0.0179) or in the MM population (pc<0.0001). For the first time, HLA-A*02:01:01/-B*35:01:01/-C*04:01:01 haplotype was associated with LTG-induced MPE (pc=0.0048 for LTG-tolerant groups and pc<0.0001 for MM population). CONCLUSION: Our data suggest the HLA-A*02:01:01/-B*35:01:01/-C*04:01:01 haplotype may be a biomarker for LTG-induced MPE and the HLA-C*08:01 allele for PHT-induced MPE. We also identified HLA-A*01:01:01 and -A*31:01:02 as candidates alleles associated with CBZ-induced MPE in MM patients. However, further investigations are necessary to confirm these findings.
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Erupciones por Medicamentos/genética , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Antígenos HLA-C/genética , Triazinas/efectos adversos , Adolescente , Adulto , Anciano , Carbamazepina/administración & dosificación , Carbamazepina/efectos adversos , Erupciones por Medicamentos/patología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/genética , Femenino , Estudios de Asociación Genética , Genotipo , Haplotipos , Humanos , Indígenas Norteamericanos/genética , Lamotrigina , Masculino , Persona de Mediana Edad , Triazinas/administración & dosificaciónRESUMEN
Cancer patients receiving chemotherapy are exposed to high doses of cytotoxic and genotoxic drugs which, in some cases, can lead to treatment related leukemia. Since this only occurs in a minority of patients, however, it is possible some individuals are predisposed due to genetic polymorphisms in genes for enzymes that mediate drug metabolism. To address this possibility we measured the genotoxicity of chemotherapeutic agents in patients receiving treatment for ALL by the frequency of the Vgamma/Jbeta trans-rearrangement in their peripheral blood leukocytes and compared this with CYP3A4 genotype. CYP3A4 is the most abundant of the cytochrome P450 (CYP) enzyme in the liver and intestine which contains a common -392A>G substitution in the promoter region (CYP3A4*1B allele). We found a significant increase in the frequency of rearrangements during chemotherapy only in patients homozygous for the wild type CYP3A4*1A allele. This provides a direct link between CYP3A4 genotype and susceptibility to drug genotoxicity thus strengthening the possibility that predisposition to treatment related leukemia may be measurable by simple genetic testing.