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1.
S D Med ; 76(3): 102-110, 2023 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-36898195

RESUMEN

There is wide geographic variability in the prevalence of chronic kidney disease, and much of this variability is unexplained by known clinical risk determinants such as diabetes and hypertension. Additional factors contributing to this geographic variability include social determinants of kidney health, as well as genetic factors (ancestry) and non-genetic factors (the environment). Environmental nephrotoxins can accelerate the progression of kidney disease in some patients at risk. Examples of environmental nephrotoxins that have previously been associated with changes in glomerular filtration rate include chlorotriazine herbicides (e.g., atrazine) and trace metals (e.g., arsenic, cadmium, lead, and mercury). Land management practices influence the concentration of these nephrotoxins in our soil and water. In this review, we explore sustainable approaches to agriculture and the preservation of natural landscapes as land management practices that can optimize kidney health in a variety of communities.


Asunto(s)
Arsénico , Mercurio , Humanos , Conservación de los Recursos Naturales , Riñón , Cadmio
2.
S D Med ; 75(11): 500-502, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-36893027

RESUMEN

Within most electronic medical records, automated decision support helps health care providers reduce the frequency of adverse drug reactions. Historically, this decision support has been used to prevent drug-drug interactions (DDIs). More recently, the clinical and scientific communities have been moving toward the use of this approach to predict and prevent drug-gene interactions (DGIs). Genetic variation in cytochrome P450 2D6 (CYP2D6) is known to impact clinical outcome for many drugs, including opioids. Randomized trials have been initiated to assess the utility of CYP2D6 gene-based dosing versus usual care. We review the use of this approach to guide opioid prescribing in the post-operative setting.


Asunto(s)
Citocromo P-450 CYP2D6 , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Humanos , Citocromo P-450 CYP2D6/genética , Analgésicos Opioides/efectos adversos , Genotipo , Pautas de la Práctica en Medicina
3.
S D Med ; 74(7): 306-309, 2021 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-34449991

RESUMEN

Chronic kidney disease affects nearly 15 percent of the U.S. population. Onset and rate of progression are influenced by a combination of genetic and non-genetic factors. Because health care systems across the U.S. are beginning to deploy automated decision support to stratify patients at risk, we review the relative impact of genetic factors (e.g., APOL1 gene polymorphisms) and non-genetic factors (e.g., clinical comorbidities and exposure to environmental nephrotoxins) contributing to this common disease. Overall, the impact of non-genetic factors appears to exceed the impact of genetic factors.


Asunto(s)
Insuficiencia Renal Crónica , Apolipoproteína L1/genética , Humanos , Insuficiencia Renal Crónica/epidemiología , Insuficiencia Renal Crónica/genética , Factores de Riesgo
4.
Circulation ; 138(17): 1839-1849, 2018 10 23.
Artículo en Inglés | MEDLINE | ID: mdl-29703846

RESUMEN

BACKGROUND: Coronary heart disease (CHD) is a leading cause of death globally. Although therapy with statins decreases circulating levels of low-density lipoprotein cholesterol and the incidence of CHD, additional events occur despite statin therapy in some individuals. The genetic determinants of this residual cardiovascular risk remain unknown. METHODS: We performed a 2-stage genome-wide association study of CHD events during statin therapy. We first identified 3099 cases who experienced CHD events (defined as acute myocardial infarction or the need for coronary revascularization) during statin therapy and 7681 controls without CHD events during comparable intensity and duration of statin therapy from 4 sites in the Electronic Medical Records and Genomics Network. We then sought replication of candidate variants in another 160 cases and 1112 controls from a fifth Electronic Medical Records and Genomics site, which joined the network after the initial genome-wide association study. Finally, we performed a phenome-wide association study for other traits linked to the most significant locus. RESULTS: The meta-analysis identified 7 single nucleotide polymorphisms at a genome-wide level of significance within the LPA/PLG locus associated with CHD events on statin treatment. The most significant association was for an intronic single nucleotide polymorphism within LPA/PLG (rs10455872; minor allele frequency, 0.069; odds ratio, 1.58; 95% confidence interval, 1.35-1.86; P=2.6×10-10). In the replication cohort, rs10455872 was also associated with CHD events (odds ratio, 1.71; 95% confidence interval, 1.14-2.57; P=0.009). The association of this single nucleotide polymorphism with CHD events was independent of statin-induced change in low-density lipoprotein cholesterol (odds ratio, 1.62; 95% confidence interval, 1.17-2.24; P=0.004) and persisted in individuals with low-density lipoprotein cholesterol ≤70 mg/dL (odds ratio, 2.43; 95% confidence interval, 1.18-4.75; P=0.015). A phenome-wide association study supported the effect of this region on coronary heart disease and did not identify noncardiovascular phenotypes. CONCLUSIONS: Genetic variations at the LPA locus are associated with CHD events during statin therapy independently of the extent of low-density lipoprotein cholesterol lowering. This finding provides support for exploring strategies targeting circulating concentrations of lipoprotein(a) to reduce CHD events in patients receiving statins.


Asunto(s)
Enfermedad Coronaria/genética , Enfermedad Coronaria/prevención & control , Dislipidemias/tratamiento farmacológico , Dislipidemias/genética , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Lipoproteína(a)/genética , Polimorfismo de Nucleótido Simple , Estudios de Casos y Controles , Enfermedad Coronaria/sangre , Enfermedad Coronaria/diagnóstico , Bases de Datos Genéticas , Dislipidemias/sangre , Dislipidemias/diagnóstico , Registros Electrónicos de Salud , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Fenotipo , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento
5.
Nature ; 502(7471): 377-80, 2013 Oct 17.
Artículo en Inglés | MEDLINE | ID: mdl-23995691

RESUMEN

Statins are prescribed widely to lower plasma low-density lipoprotein (LDL) concentrations and cardiovascular disease risk and have been shown to have beneficial effects in a broad range of patients. However, statins are associated with an increased risk, albeit small, of clinical myopathy and type 2 diabetes. Despite evidence for substantial genetic influence on LDL concentrations, pharmacogenomic trials have failed to identify genetic variations with large effects on either statin efficacy or toxicity, and have produced little information regarding mechanisms that modulate statin response. Here we identify a downstream target of statin treatment by screening for the effects of in vitro statin exposure on genetic associations with gene expression levels in lymphoblastoid cell lines derived from 480 participants of a clinical trial of simvastatin treatment. This analysis identified six expression quantitative trait loci (eQTLs) that interacted with simvastatin exposure, including rs9806699, a cis-eQTL for the gene glycine amidinotransferase (GATM) that encodes the rate-limiting enzyme in creatine synthesis. We found this locus to be associated with incidence of statin-induced myotoxicity in two separate populations (meta-analysis odds ratio = 0.60). Furthermore, we found that GATM knockdown in hepatocyte-derived cell lines attenuated transcriptional response to sterol depletion, demonstrating that GATM may act as a functional link between statin-mediated lowering of cholesterol and susceptibility to statin-induced myopathy.


Asunto(s)
Amidinotransferasas/genética , Regulación de la Expresión Génica/efectos de los fármacos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Enfermedades Musculares/inducido químicamente , Sitios de Carácter Cuantitativo/genética , Simvastatina/efectos adversos , Amidinotransferasas/deficiencia , Amidinotransferasas/metabolismo , Línea Celular , Colesterol/deficiencia , Colesterol/metabolismo , Colesterol/farmacología , Técnicas de Silenciamiento del Gen , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Linfocitos/citología , Linfocitos/efectos de los fármacos , Linfocitos/metabolismo , Enfermedades Musculares/genética , Enfermedades Musculares/metabolismo , Polimorfismo de Nucleótido Simple/genética , Simvastatina/farmacología , Proteínas de Unión a los Elementos Reguladores de Esteroles/metabolismo , Transcripción Genética/efectos de los fármacos
6.
Am J Hum Genet ; 89(4): 529-42, 2011 Oct 07.
Artículo en Inglés | MEDLINE | ID: mdl-21981779

RESUMEN

We repurposed existing genotypes in DNA biobanks across the Electronic Medical Records and Genomics network to perform a genome-wide association study for primary hypothyroidism, the most common thyroid disease. Electronic selection algorithms incorporating billing codes, laboratory values, text queries, and medication records identified 1317 cases and 5053 controls of European ancestry within five electronic medical records (EMRs); the algorithms' positive predictive values were 92.4% and 98.5% for cases and controls, respectively. Four single-nucleotide polymorphisms (SNPs) in linkage disequilibrium at 9q22 near FOXE1 were associated with hypothyroidism at genome-wide significance, the strongest being rs7850258 (odds ratio [OR] 0.74, p = 3.96 × 10(-9)). This association was replicated in a set of 263 cases and 1616 controls (OR = 0.60, p = 5.7 × 10(-6)). A phenome-wide association study (PheWAS) that was performed on this locus with 13,617 individuals and more than 200,000 patient-years of billing data identified associations with additional phenotypes: thyroiditis (OR = 0.58, p = 1.4 × 10(-5)), nodular (OR = 0.76, p = 3.1 × 10(-5)) and multinodular (OR = 0.69, p = 3.9 × 10(-5)) goiters, and thyrotoxicosis (OR = 0.76, p = 1.5 × 10(-3)), but not Graves disease (OR = 1.03, p = 0.82). Thyroid cancer, previously associated with this locus, was not significantly associated in the PheWAS (OR = 1.29, p = 0.09). The strongest association in the PheWAS was hypothyroidism (OR = 0.76, p = 2.7 × 10(-13)), which had an odds ratio that was nearly identical to that of the curated case-control population in the primary analysis, providing further validation of the PheWAS method. Our findings indicate that EMR-linked genomic data could allow discovery of genes associated with many diseases without additional genotyping cost.


Asunto(s)
Factores de Transcripción Forkhead/genética , Hipotiroidismo/genética , Anciano , Algoritmos , Femenino , Marcadores Genéticos , Variación Genética , Genoma , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , Sistemas de Registros Médicos Computarizados , Persona de Mediana Edad , Fenotipo , Valor Predictivo de las Pruebas
7.
Mol Vis ; 20: 1281-95, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25352737

RESUMEN

PURPOSE: Cataract is the leading cause of blindness in the world, and in the United States accounts for approximately 60% of Medicare costs related to vision. The purpose of this study was to identify genetic markers for age-related cataract through a genome-wide association study (GWAS). METHODS: In the electronic medical records and genomics (eMERGE) network, we ran an electronic phenotyping algorithm on individuals in each of five sites with electronic medical records linked to DNA biobanks. We performed a GWAS using 530,101 SNPs from the Illumina 660W-Quad in a total of 7,397 individuals (5,503 cases and 1,894 controls). We also performed an age-at-diagnosis case-only analysis. RESULTS: We identified several statistically significant associations with age-related cataract (45 SNPs) as well as age at diagnosis (44 SNPs). The 45 SNPs associated with cataract at p<1×10(-5) are in several interesting genes, including ALDOB, MAP3K1, and MEF2C. All have potential biologic relationships with cataracts. CONCLUSIONS: This is the first genome-wide association study of age-related cataract, and several regions of interest have been identified. The eMERGE network has pioneered the exploration of genomic associations in biobanks linked to electronic health records, and this study is another example of the utility of such resources. Explorations of age-related cataract including validation and replication of the association results identified herein are needed in future studies.


Asunto(s)
Catarata/genética , Registros Electrónicos de Salud/estadística & datos numéricos , Fructosa-Bifosfato Aldolasa/genética , Predisposición Genética a la Enfermedad , Quinasa 1 de Quinasa de Quinasa MAP/genética , Polimorfismo de Nucleótido Simple , Factores de Edad , Anciano , Anciano de 80 o más Años , Algoritmos , Catarata/patología , Bases de Datos de Ácidos Nucleicos , Femenino , Marcadores Genéticos , Genoma Humano , Estudio de Asociación del Genoma Completo , Costos de la Atención en Salud , Humanos , Factores de Transcripción MEF2/genética , Masculino , Persona de Mediana Edad , Sitios de Carácter Cuantitativo , Estados Unidos
8.
Hum Genomics ; 7: 16, 2013 Jul 05.
Artículo en Inglés | MEDLINE | ID: mdl-23829686

RESUMEN

BACKGROUND: The standard approach to determine unique or shared genetic factors across populations is to identify risk alleles in one population and investigate replication in others. However, since populations differ in DNA sequence information, allele frequencies, effect sizes, and linkage disequilibrium patterns, SNP association using a uniform stringent threshold on p values may not be reproducible across populations. Here, we developed rank-based methods to investigate shared or population-specific loci and pathways for childhood asthma across individuals of diverse ancestry. We performed genome-wide association studies on 859,790 SNPs genotyped in 527 affected offspring trios of European, African, and Hispanic ancestry using publically available asthma database in the Genotypes and Phenotypes database. RESULTS: Rank-based analyses showed that there are shared genetic factors for asthma across populations, more at the gene and pathway levels than at the SNP level. Although the top 1,000 SNPs were not shared, 11 genes (RYR2, PDE4D, CSMD1, CDH13, ROBO2, RBFOX1, PTPRD, NPAS3, PDE1C, SEMA5A, and CTNNA2) mapped by these SNPs were shared across populations. Ryanodine receptor 2 (RYR2, a statin response-related gene) showed the strongest association in European (p value=2.55×10(-7)) and was replicated in African (2.57×10(-4)) and Hispanic (1.18 × 10(-3)) Americans. Imputation analyses based on the 1000 Genomes Project uncovered additional RYR2 variants associated with asthma. Network and functional ontology analyses revealed that RYR2 is an integral part of dermatological or allergic disorder biological networks, specifically in the functional classes involving inflammatory, eosinophilic, and respiratory diseases. CONCLUSION: Our rank-based genome-wide analysis revealed for the first time an association of RYR2 variants with asthma and replicated previously discovered PDE4D asthma gene across human populations. The replication of top-ranked asthma genes across populations suggests that such loci are less likely to be false positives and could indicate true associations. Variants that are associated with asthma across populations could be used to identify individuals who are at high risk for asthma regardless of genetic ancestry.


Asunto(s)
Asma/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple/genética , Canal Liberador de Calcio Receptor de Rianodina/genética , Alelos , Niño , Frecuencia de los Genes/genética , Redes Reguladoras de Genes/genética , Genética de Población , Humanos , Desequilibrio de Ligamiento/genética , Anotación de Secuencia Molecular , Filogenia , Reproducibilidad de los Resultados , Factores de Riesgo
9.
Am J Med Sci ; 367(1): 14-20, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37838157

RESUMEN

Adverse drug reactions can be either dose-dependent (Type A) or idiosyncratic (Type B). Type B adverse drug reactions tend to be extremely rare and difficult to predict. They are usually immune-mediated. Examples include severe skin reactions and drug-induced liver injury. For many commonly prescribed drugs (such as antibiotics), the risk of developing an idiosyncratic adverse drug reaction is influenced by variability in the human leukocyte antigen (HLA) genes. Because these HLA-mediated adverse drug reactions can be lethal, there is growing interest in defining which specific drug-gene relationships might benefit from pre-emptive HLA genotyping and automated clinical decision support. This review summarizes the literature for HLA-mediated adverse reactions linked to common drugs.


Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Humanos , Antígenos HLA/genética , Antígenos HLA/farmacología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/diagnóstico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/genética , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Piel , Antibacterianos
10.
JACC Adv ; 3(4)2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38737008

RESUMEN

Background: Statins reduce low-density lipoprotein cholesterol (LDL-C) and are efficacious in the prevention of atherosclerotic cardiovascular disease (ASCVD). Dose-response to statins varies among patients and can be modeled using three distinct pharmacological properties: (1) E0 (baseline LDL-C), (2) ED50 (potency: median dose achieving 50% reduction in LDL-C); and (3) Emax (efficacy: maximum LDL-C reduction). However, individualized dose-response and its association with ASCVD events remains unknown. Objective: We analyze the relationship between ED50 and Emax with real-world cardiovascular disease outcomes. Method: We leveraged de-identified electronic health record data to identify individuals exposed to multiple doses of the three most commonly prescribed statins (atorvastatin, simvastatin, or rosuvastatin) within the context of their longitudinal healthcare. We derived ED50 and Emax to quantify the relationship with a composite outcome of ASCVD events and all-cause mortality. Results: We estimated ED50 and Emax for 3,033 unique individuals (atorvastatin: 1,632, simvastatin: 1,089, and rosuvastatin: 312) using a nonlinear, mixed effects dose-response model. Time-to-event analyses revealed that ED50 and Emax are independently associated with the primary endpoint. Hazard ratios were 0.85 (p < 0.01), 0.83 (p < 0.01), and 0.87 (p = 0.10) for ED50 and 1.13 (p < 0.001), 1.06 (p < 0.001), and 1.15 (p = 0.009) for Emax in the atorvastatin, simvastatin, and rosuvastatin cohorts, respectively. Conclusion: The class-wide association of ED50 and Emax with clinical outcomes indicates that these measures influence the risk for ASCVD events in patients on statins.

11.
Clin Transl Sci ; 17(6): e13822, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38860639

RESUMEN

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


Asunto(s)
Citocromo P-450 CYP2C19 , Citocromo P-450 CYP2D6 , Depresión , Pruebas de Farmacogenómica , Inhibidores Selectivos de la Recaptación de Serotonina , Adulto , Femenino , Humanos , Masculino , Antidepresivos/uso terapéutico , Antidepresivos/administración & dosificación , Antidepresivos/efectos adversos , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2D6/genética , Depresión/tratamiento farmacológico , Depresión/genética , Depresión/diagnóstico , Variantes Farmacogenómicas , Ensayos Clínicos Pragmáticos como Asunto , Estudios Prospectivos , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificación , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico
12.
Circ Res ; 109(7): 807-20, 2011 Sep 16.
Artículo en Inglés | MEDLINE | ID: mdl-21921273

RESUMEN

Patients vary in their responses to drug therapy, and some of that variability is genetically determined. This review outlines general approaches used to identify genetic variation that influences drug response. Examples from specific therapeutic areas are presented, such as cholesterol management, arrhythmias, heart failure, hypertension, warfarin anticoagulation, and antiplatelet agents. A brief view of potential pathways to implementation is presented.


Asunto(s)
Fármacos Cardiovasculares/administración & dosificación , Enfermedades Cardiovasculares/tratamiento farmacológico , Variación Genética , Farmacogenética , Transporte Biológico/genética , Biotransformación/genética , Fármacos Cardiovasculares/efectos adversos , Fármacos Cardiovasculares/farmacocinética , Enfermedades Cardiovasculares/genética , Cálculo de Dosificación de Drogas , Humanos , Selección de Paciente , Medicina de Precisión , Medición de Riesgo , Resultado del Tratamiento
13.
JAMA ; 319(14): 1508-1509, 2018 04 10.
Artículo en Inglés | MEDLINE | ID: mdl-29634825
14.
Clin Pharmacol Ther ; 114(2): 404-412, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37150941

RESUMEN

Antibiotics are a known cause of idiosyncratic drug-induced liver injury (DILI). According to the Centers for Disease Control and Prevention, the five most commonly prescribed antibiotics in the United States are azithromycin, ciprofloxacin, cephalexin, amoxicillin, and amoxicillin-clavulanate. We quantified the frequency of acute DILI for these common antibiotics in the All of Us Research Program, one of the largest electronic health record (EHR)-linked research cohorts in the United States. Retrospective analyses were conducted applying a standardized phenotyping algorithm to de-identified clinical data available in the All of Us database for 318,598 study participants. Between February 1984 and December 2022, more than 30% of All of Us participants (n = 119,812 individuals) had been exposed to at least 1 of our 5 study drugs. Initial screening identified 591 potential case patients that met our preselected laboratory-based phenotyping criteria. Because DILI is a diagnosis of exclusion, we then used phenome scanning to narrow the case counts by (i) scanning all EHRs to identify all alternative diagnostic explanations for the laboratory abnormalities, and (ii) leveraging International Classification of Disease 9th revision (ICD)-9 and ICD 10th revision (ICD)-10 codes as exclusion criteria to eliminate misclassification. Our final case counts were 30 DILI cases with amoxicillin-clavulanate, 24 cases with azithromycin, 24 cases with ciprofloxacin, 22 cases with amoxicillin alone, and < 20 cases with cephalexin. These findings demonstrate that data from EHR-linked research cohorts can be efficiently mined to identify DILI cases related to the use of common antibiotics.


Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas , Salud Poblacional , Humanos , Estados Unidos/epidemiología , Antibacterianos/efectos adversos , Azitromicina/efectos adversos , Estudios Retrospectivos , Enfermedad Hepática Inducida por Sustancias y Drogas/diagnóstico , Enfermedad Hepática Inducida por Sustancias y Drogas/epidemiología , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Combinación Amoxicilina-Clavulanato de Potasio/efectos adversos , Amoxicilina , Ciprofloxacina/efectos adversos , Cefalexina
15.
Genet Epidemiol ; 35(8): 887-98, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22125226

RESUMEN

Genome-wide association studies (GWAS) are a useful approach in the study of the genetic components of complex phenotypes. Aside from large cohorts, GWAS have generally been limited to the study of one or a few diseases or traits. The emergence of biobanks linked to electronic medical records (EMRs) allows the efficient reuse of genetic data to yield meaningful genotype-phenotype associations for multiple phenotypes or traits. Phase I of the electronic MEdical Records and GEnomics (eMERGE-I) Network is a National Human Genome Research Institute-supported consortium composed of five sites to perform various genetic association studies using DNA repositories and EMR systems. Each eMERGE site has developed EMR-based algorithms to comprise a core set of 14 phenotypes for extraction of study samples from each site's DNA repository. Each eMERGE site selected samples for a specific phenotype, and these samples were genotyped at either the Broad Institute or at the Center for Inherited Disease Research using the Illumina Infinium BeadChip technology. In all, approximately 17,000 samples from across the five sites were genotyped. A unified quality control (QC) pipeline was developed by the eMERGE Genomics Working Group and used to ensure thorough cleaning of the data. This process includes examination of sample and marker quality and various batch effects. Upon completion of the genotyping and QC analyses for each site's primary study, eMERGE Coordinating Center merged the datasets from all five sites. This larger merged dataset reentered the established eMERGE QC pipeline. Based on lessons learned during the process, additional analyses and QC checkpoints were added to the pipeline to ensure proper merging. Here, we explore the challenges associated with combining datasets from different genotyping centers and describe the expansion to eMERGE QC pipeline for merged datasets. These additional steps will be useful as the eMERGE project expands to include additional sites in eMERGE-II, and also serve as a starting point for investigators merging multiple genotype datasets accessible through the National Center for Biotechnology Information in the database of Genotypes and Phenotypes. Our experience demonstrates that merging multiple datasets after additional QC can be an efficient use of genotype data despite new challenges that appear in the process.


Asunto(s)
Registros Electrónicos de Salud , Estudio de Asociación del Genoma Completo/normas , Control de Calidad , Algoritmos , Genotipo , Humanos , National Human Genome Research Institute (U.S.) , Fenotipo , Estados Unidos
18.
S D Med ; 70(12): 533-534, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-29334439

Asunto(s)
Farmacogenética
19.
Clin Pharmacol Ther ; 111(5): 1075-1083, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35034348

RESUMEN

The SLCO1B1 genotype is known to influence patient adherence to statin therapy, in part by increasing the risk for statin-associated musculoskeletal symptoms (SAMSs). The SLCO1B1*5 allele has previously been associated with simvastatin discontinuation and SAMSs. Prior analyses of the relationship between SLCO1B1*5 and atorvastatin muscle side effects have been inconclusive due to insufficient power. We now quantify the impact of SLCO1B1*5 on atorvastatin discontinuation and SAMSs in a large observational cohort using electronic medical record data from a single health care system. In our study cohort (n = 1,627 patients exposed to atorvastatin during the course of routine clinical care), 56% (n = 912 of 1,627 patients) discontinued atorvastatin and 18% (n = 303 of 1,627 patients) developed SAMSs. A univariate model revealed that SLCO1B1*5 increased the likelihood that patients would stop atorvastatin during routine care (odds ratio 1.2; 95% confidence interval (CI), 1.1-1.5; P = 0.04). A multivariate Cox proportional hazards model further demonstrated that this same variant was associated with time to atorvastatin discontinuation (hazard ratio 1.2; 95% CI, 1.1-1.4; P = 0.004). Additional time-to-event analyses also revealed that SCLO1B1*5 was associated with SAMSs (hazard ratio 1.4; 95% CI, 1.1-1.7; P = 0.02). Atorvastatin discontinuation was associated with SAMSs (odds ratio 1.67; P = 0.0001) in our cohort.


Asunto(s)
Inhibidores de Hidroximetilglutaril-CoA Reductasas , Alelos , Atorvastatina/efectos adversos , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Transportador 1 de Anión Orgánico Específico del Hígado/genética , Músculos , Polimorfismo de Nucleótido Simple , Pirroles/uso terapéutico , Simvastatina/efectos adversos
20.
Clin Pharmacol Ther ; 111(5): 1007-1021, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35152405

RESUMEN

Statins reduce cholesterol, prevent cardiovascular disease, and are among the most commonly prescribed medications in the world. Statin-associated musculoskeletal symptoms (SAMS) impact statin adherence and ultimately can impede the long-term effectiveness of statin therapy. There are several identified pharmacogenetic variants that impact statin disposition and adverse events during statin therapy. SLCO1B1 encodes a transporter (SLCO1B1; alternative names include OATP1B1 or OATP-C) that facilitates the hepatic uptake of all statins. ABCG2 encodes an efflux transporter (BCRP) that modulates the absorption and disposition of rosuvastatin. CYP2C9 encodes a phase I drug metabolizing enzyme responsible for the oxidation of some statins. Genetic variation in each of these genes alters systemic exposure to statins (i.e., simvastatin, rosuvastatin, pravastatin, pitavastatin, atorvastatin, fluvastatin, lovastatin), which can increase the risk for SAMS. We summarize the literature supporting these associations and provide therapeutic recommendations for statins based on SLCO1B1, ABCG2, and CYP2C9 genotype with the goal of improving the overall safety, adherence, and effectiveness of statin therapy. This document replaces the 2012 and 2014 Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for SLCO1B1 and simvastatin-induced myopathy.


Asunto(s)
Inhibidores de Hidroximetilglutaril-CoA Reductasas , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Citocromo P-450 CYP2C9/genética , Genotipo , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Transportador 1 de Anión Orgánico Específico del Hígado/genética , Proteínas de Neoplasias/genética , Farmacogenética , Rosuvastatina Cálcica/efectos adversos , Simvastatina/efectos adversos
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