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OBJECTIVE: Psoriatic disease remains underdiagnosed and undertreated. We developed and validated a suite of novel, sensor-based smartphone assessments (Psorcast app) that can be self-administered to measure cutaneous and musculoskeletal signs and symptoms of psoriatic disease. METHODS: Participants with psoriasis (PsO) or psoriatic arthritis (PsA) and healthy controls were recruited between June 5, 2019, and November 10, 2021, at 2 academic medical centers. Concordance and accuracy of digital measures and image-based machine learning models were compared to their analogous clinical measures from trained rheumatologists and dermatologists. RESULTS: Of 104 study participants, 51 (49%) were female and 53 (51%) were male, with a mean age of 42.3 years (SD 12.6). Seventy-nine (76%) participants had PsA, 16 (15.4%) had PsO, and 9 (8.7%) were healthy controls. Digital patient assessment of percent body surface area (BSA) affected with PsO demonstrated very strong concordance (Lin concordance correlation coefficient [CCC] 0.94 [95% CI 0.91-0.96]) with physician-assessed BSA. The in-clinic and remote target plaque physician global assessments showed fair-to-moderate concordance (CCCerythema 0.72 [0.59-0.85]; CCCinduration 0.72 [0.62-0.82]; CCCscaling 0.60 [0.48-0.72]). Machine learning models of hand photos taken by patients accurately identified clinically diagnosed nail PsO with an accuracy of 0.76. The Digital Jar Open assessment categorized physician-assessed upper extremity involvement, considering joint tenderness or enthesitis (AUROC 0.68 [0.47-0.85]). CONCLUSION: The Psorcast digital assessments achieved significant clinical validity, although they require further validation in larger cohorts before use in evidence-based medicine or clinical trial settings. The smartphone software and analysis pipelines from the Psorcast suite are open source and freely available.
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Artritis Psoriásica , Aprendizaje Automático , Psoriasis , Teléfono Inteligente , Humanos , Artritis Psoriásica/diagnóstico , Femenino , Masculino , Psoriasis/diagnóstico , Adulto , Persona de Mediana Edad , Prueba de Estudio Conceptual , Aplicaciones Móviles , Reproducibilidad de los ResultadosRESUMEN
Discovering drugs that efficiently treat brain diseases has been challenging. Genetic variants that modulate the expression of potential drug targets can be utilized to assess the efficacy of therapeutic interventions. We therefore employed Mendelian Randomization (MR) on gene expression measured in brain tissue to identify drug targets involved in neurological and psychiatric diseases. We conducted a two-sample MR using cis-acting brain-derived expression quantitative trait loci (eQTLs) from the Accelerating Medicines Partnership for Alzheimer's Disease consortium (AMP-AD) and the CommonMind Consortium (CMC) meta-analysis study (n = 1,286) as genetic instruments to predict the effects of 7,137 genes on 12 neurological and psychiatric disorders. We conducted Bayesian colocalization analysis on the top MR findings (using P<6x10-7 as evidence threshold, Bonferroni-corrected for 80,557 MR tests) to confirm sharing of the same causal variants between gene expression and trait in each genomic region. We then intersected the colocalized genes with known monogenic disease genes recorded in Online Mendelian Inheritance in Man (OMIM) and with genes annotated as drug targets in the Open Targets platform to identify promising drug targets. 80 eQTLs showed MR evidence of a causal effect, from which we prioritised 47 genes based on colocalization with the trait. We causally linked the expression of 23 genes with schizophrenia and a single gene each with anorexia, bipolar disorder and major depressive disorder within the psychiatric diseases and 9 genes with Alzheimer's disease, 6 genes with Parkinson's disease, 4 genes with multiple sclerosis and two genes with amyotrophic lateral sclerosis within the neurological diseases we tested. From these we identified five genes (ACE, GPNMB, KCNQ5, RERE and SUOX) as attractive drug targets that may warrant follow-up in functional studies and clinical trials, demonstrating the value of this study design for discovering drug targets in neuropsychiatric diseases.
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Enfermedad de Alzheimer/genética , Descubrimiento de Drogas , Predisposición Genética a la Enfermedad , Transcriptoma/genética , Enfermedad de Alzheimer/tratamiento farmacológico , Trastorno Bipolar/tratamiento farmacológico , Trastorno Bipolar/genética , Trastorno Bipolar/patología , Encéfalo/metabolismo , Encéfalo/patología , Estudio de Asociación del Genoma Completo , Humanos , Análisis de la Aleatorización Mendeliana , Terapia Molecular Dirigida , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Enfermedades del Sistema Nervioso/genética , Enfermedades del Sistema Nervioso/patología , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo/genética , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/genética , Esquizofrenia/patologíaRESUMEN
MOTIVATION: Late onset Alzheimer's disease is currently a disease with no known effective treatment options. To better understand disease, new multi-omic data-sets have recently been generated with the goal of identifying molecular causes of disease. However, most analytic studies using these datasets focus on uni-modal analysis of the data. Here, we propose a data driven approach to integrate multiple data types and analytic outcomes to aggregate evidences to support the hypothesis that a gene is a genetic driver of the disease. The main algorithmic contributions of our article are: (i) a general machine learning framework to learn the key characteristics of a few known driver genes from multiple feature sets and identifying other potential driver genes which have similar feature representations, and (ii) A flexible ranking scheme with the ability to integrate external validation in the form of Genome Wide Association Study summary statistics. While we currently focus on demonstrating the effectiveness of the approach using different analytic outcomes from RNA-Seq studies, this method is easily generalizable to other data modalities and analysis types. RESULTS: We demonstrate the utility of our machine learning algorithm on two benchmark multiview datasets by significantly outperforming the baseline approaches in predicting missing labels. We then use the algorithm to predict and rank potential drivers of Alzheimer's. We show that our ranked genes show a significant enrichment for single nucleotide polymorphisms associated with Alzheimer's and are enriched in pathways that have been previously associated with the disease. AVAILABILITY AND IMPLEMENTATION: Source code and link to all feature sets is available at https://github.com/Sage-Bionetworks/EvidenceAggregatedDriverRanking.
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Algoritmos , Enfermedad de Alzheimer , Estudio de Asociación del Genoma Completo , Enfermedad de Alzheimer/genética , Humanos , Aprendizaje Automático , Programas InformáticosRESUMEN
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.
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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 fármacosRESUMEN
OBJECTIVES: To find and validate generalizable sepsis subtypes using data-driven clustering. DESIGN: We used advanced informatics techniques to pool data from 14 bacterial sepsis transcriptomic datasets from eight different countries (n = 700). SETTING: Retrospective analysis. SUBJECTS: Persons admitted to the hospital with bacterial sepsis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A unified clustering analysis across 14 discovery datasets revealed three subtypes, which, based on functional analysis, we termed "Inflammopathic, Adaptive, and Coagulopathic." We then validated these subtypes in nine independent datasets from five different countries (n = 600). In both discovery and validation data, the Adaptive subtype is associated with a lower clinical severity and lower mortality rate, and the Coagulopathic subtype is associated with higher mortality and clinical coagulopathy. Further, these clusters are statistically associated with clusters derived by others in independent single sepsis cohorts. CONCLUSIONS: The three sepsis subtypes may represent a unifying framework for understanding the molecular heterogeneity of the sepsis syndrome. Further study could potentially enable a precision medicine approach of matching novel immunomodulatory therapies with septic patients most likely to benefit.
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Perfilación de la Expresión Génica , Sepsis/genética , Inmunidad Adaptativa/genética , Adolescente , Adulto , Anciano , Trastornos de la Coagulación Sanguínea/genética , Análisis por Conglomerados , Conjuntos de Datos como Asunto , Femenino , Humanos , Inmunidad Innata/genética , Inflamación/genética , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Sepsis/microbiología , Adulto JovenRESUMEN
3-hydroxy-3-methylglutaryl-Coenzyme A reductase (HMGCR) encodes the rate-limiting enzyme in the cholesterol biosynthesis pathway and is inhibited by statins, a class of cholesterol-lowering drugs. Expression of an alternatively spliced HMGCR transcript lacking exon 13, HMGCR13(-), has been implicated in the variation of plasma LDL-cholesterol (LDL-C) and is the single most informative molecular marker of LDL-C response to statins. Given the physiological importance of this transcript, our goal was to identify molecules that regulate HMGCR alternative splicing. We recently reported gene expression changes in 480 lymphoblastoid cell lines (LCLs) after in vitro simvastatin treatment, and identified a number of statin-responsive genes involved in mRNA splicing. Heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) was chosen for follow-up since rs3846662, an HMGCR SNP that regulates exon 13 skipping, was predicted to alter an HNRNPA1 binding motif. Here, we not only demonstrate that rs3846662 modulates HNRNPA1 binding, but also that sterol depletion of human hepatoma cell lines reduced HNRNPA1 mRNA levels, an effect that was reversed with sterol add-back. Overexpression of HNRNPA1 increased the ratio of HMGCR13(-) to total HMGCR transcripts by both directly increasing exon 13 skipping in an allele-related manner and specifically stabilizing the HMGCR13(-) transcript. Importantly, HNRNPA1 overexpression also diminished HMGCR enzyme activity, enhanced LDL-C uptake and increased cellular apolipoprotein B (APOB). rs1920045, an SNP associated with HNRNPA1 exon 8 alternative splicing, was also associated with smaller statin-induced reduction in total cholesterol from two independent clinical trials. These results suggest that HNRNPA1 plays a role in the variation of cardiovascular disease risk and statin response.
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Empalme Alternativo , LDL-Colesterol/metabolismo , Ribonucleoproteína Heterogénea-Nuclear Grupo A-B/metabolismo , Hidroximetilglutaril-CoA Reductasas/genética , Alelos , Apolipoproteínas B/metabolismo , Línea Celular Tumoral , Exones , Regulación Neoplásica de la Expresión Génica , Variación Genética , Células Hep G2 , Hepatocitos , Ribonucleoproteína Nuclear Heterogénea A1 , Humanos , Hidroximetilglutaril-CoA Reductasas/metabolismo , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Polimorfismo de Nucleótido Simple , Unión Proteica , Estabilidad del ARNRESUMEN
Genetic variants in cis-regulatory elements or trans-acting regulators frequently influence the quantity and spatiotemporal distribution of gene transcription. Recent interest in expression quantitative trait locus (eQTL) mapping has paralleled the adoption of genome-wide association studies (GWAS) for the analysis of complex traits and disease in humans. Under the hypothesis that many GWAS associations tag non-coding SNPs with small effects, and that these SNPs exert phenotypic control by modifying gene expression, it has become common to interpret GWAS associations using eQTL data. To fully exploit the mechanistic interpretability of eQTL-GWAS comparisons, an improved understanding of the genetic architecture and causal mechanisms of cell type specificity of eQTLs is required. We address this need by performing an eQTL analysis in three parts: first we identified eQTLs from eleven studies on seven cell types; then we integrated eQTL data with cis-regulatory element (CRE) data from the ENCODE project; finally we built a set of classifiers to predict the cell type specificity of eQTLs. The cell type specificity of eQTLs is associated with eQTL SNP overlap with hundreds of cell type specific CRE classes, including enhancer, promoter, and repressive chromatin marks, regions of open chromatin, and many classes of DNA binding proteins. These associations provide insight into the molecular mechanisms generating the cell type specificity of eQTLs and the mode of regulation of corresponding eQTLs. Using a random forest classifier with cell specific CRE-SNP overlap as features, we demonstrate the feasibility of predicting the cell type specificity of eQTLs. We then demonstrate that CREs from a trait-associated cell type can be used to annotate GWAS associations in the absence of eQTL data for that cell type. We anticipate that such integrative, predictive modeling of cell specificity will improve our ability to understand the mechanistic basis of human complex phenotypic variation.
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Cromatina/genética , Expresión Génica , Sitios de Carácter Cuantitativo/genética , Secuencias Reguladoras de Ácidos Nucleicos/genética , Linaje de la Célula/genética , Elementos de Facilitación Genéticos , Estudio de Asociación del Genoma Completo , Humanos , Fenotipo , Polimorfismo de Nucleótido Simple , Regiones Promotoras GenéticasRESUMEN
OBJECTIVE: Interindividual variation in pathways affecting cellular cholesterol metabolism can influence levels of plasma cholesterol, a well-established risk factor for cardiovascular disease. Inherent variation among immortalized lymphoblastoid cell lines from different donors can be leveraged to discover novel genes that modulate cellular cholesterol metabolism. The objective of this study was to identify novel genes that regulate cholesterol metabolism by testing for evidence of correlated gene expression with cellular levels of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) mRNA, a marker for cellular cholesterol homeostasis, in a large panel of lymphoblastoid cell lines. APPROACH AND RESULTS: Expression array profiling was performed on 480 lymphoblastoid cell lines established from participants of the Cholesterol and Pharmacogenetics (CAP) statin clinical trial, and transcripts were tested for evidence of correlated expression with HMGCR as a marker of intracellular cholesterol homeostasis. Of these, transmembrane protein 55b (TMEM55B) showed the strongest correlation (r=0.29; P=4.0E-08) of all genes not previously implicated in cholesterol metabolism and was found to be sterol regulated. TMEM55B knockdown in human hepatoma cell lines promoted the decay rate of the low-density lipoprotein receptor, reduced cell surface low-density lipoprotein receptor protein, impaired low-density lipoprotein uptake, and reduced intracellular cholesterol. CONCLUSIONS: Here, we report identification of TMEM55B as a novel regulator of cellular cholesterol metabolism through the combination of gene expression profiling and functional studies. The findings highlight the value of an integrated genomic approach for identifying genes that influence cholesterol homeostasis.
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Colesterol/metabolismo , Linfocitos/metabolismo , Receptores de LDL/metabolismo , Transporte Biológico , Membrana Celular/metabolismo , Perfilación de la Expresión Génica , Células Hep G2 , Hepatocitos/metabolismo , Homeostasis , Humanos , Hidroximetilglutaril-CoA Reductasas/biosíntesis , Hidroximetilglutaril-CoA Reductasas/genética , Líquido Intracelular/metabolismo , Metabolismo de los Lípidos/genética , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Proteína 2 de Unión a Elementos Reguladores de Esteroles/metabolismoAsunto(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 , HumanosRESUMEN
Although statin drugs are generally efficacious for lowering plasma LDL-cholesterol levels, there is considerable variability in response. To identify candidate genes that may contribute to this variation, we used an unbiased genome-wide filter approach that was applied to 10,149 genes expressed in immortalized lymphoblastoid cell lines (LCLs) derived from 480 participants of the Cholesterol and Pharmacogenomics (CAP) clinical trial of simvastatin. The criteria for identification of candidates included genes whose statin-induced changes in expression were correlated with change in expression of HMGCR, a key regulator of cellular cholesterol metabolism and the target of statin inhibition. This analysis yielded 45 genes, from which RHOA was selected for follow-up because it has been found to participate in mediating the pleiotropic but not the lipid-lowering effects of statin treatment. RHOA knock-down in hepatoma cell lines reduced HMGCR, LDLR, and SREBF2 mRNA expression and increased intracellular cholesterol ester content as well as apolipoprotein B (APOB) concentrations in the conditioned media. Furthermore, inter-individual variation in statin-induced RHOA mRNA expression measured in vitro in CAP LCLs was correlated with the changes in plasma total cholesterol, LDL-cholesterol, and APOB induced by simvastatin treatment (40 mg/d for 6 wk) of the individuals from whom these cell lines were derived. Moreover, the minor allele of rs11716445, a SNP located in a novel cryptic RHOA exon, dramatically increased inclusion of the exon in RHOA transcripts during splicing and was associated with a smaller LDL-cholesterol reduction in response to statin treatment in 1,886 participants from the CAP and Pravastatin Inflamation and CRP Evaluation (PRINCE; pravastatin 40 mg/d) statin clinical trials. Thus, an unbiased filter approach based on transcriptome-wide profiling identified RHOA as a gene contributing to variation in LDL-cholesterol response to statin, illustrating the power of this approach for identifying candidate genes involved in drug response phenotypes.
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Biomarcadores Farmacológicos/metabolismo , Colesterol , Simvastatina/administración & dosificación , Proteína de Unión al GTP rhoA , Alelos , Línea Celular Transformada , Colesterol/genética , Colesterol/metabolismo , Ensayos Clínicos como Asunto , Expresión Génica/efectos de los fármacos , Humanos , Metabolismo de los Lípidos/genética , Polimorfismo de Nucleótido Simple , Pravastatina/administración & dosificación , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteína de Unión al GTP rhoA/genética , Proteína de Unión al GTP rhoA/metabolismoRESUMEN
INTRODUCTION: Alzheimer's disease (AD) is the predominant dementia globally, with heterogeneous presentation and penetrance of clinical symptoms, variable presence of mixed pathologies, potential disease subtypes, and numerous associated endophenotypes. Beyond the difficulty of designing treatments that address the core pathological characteristics of the disease, therapeutic development is challenged by the uncertainty of which endophenotypic areas and specific targets implicated by those endophenotypes to prioritize for further translational research. However, publicly funded consortia driving large-scale open science efforts have produced multiple omic analyses that address both disease risk relevance and biological process involvement of genes across the genome. METHODS: Here we report the development of an informatic pipeline that draws from genetic association studies, predicted variant impact, and linkage with dementia associated phenotypes to create a genetic risk score. This is paired with a multi-omic risk score utilizing extensive sets of both transcriptomic and proteomic studies to identify system-level changes in expression associated with AD. These two elements combined constitute our target risk score that ranks AD risk genome-wide. The ranked genes are organized into endophenotypic space through the development of 19 biological domains associated with AD in the described genetics and genomics studies and accompanying literature. The biological domains are constructed from exhaustive Gene Ontology (GO) term compilations, allowing automated assignment of genes into objectively defined disease-associated biology. This rank-and-organize approach, performed genome-wide, allows the characterization of aggregations of AD risk across biological domains. RESULTS: The top AD-risk-associated biological domains are Synapse, Immune Response, Lipid Metabolism, Mitochondrial Metabolism, Structural Stabilization, and Proteostasis, with slightly lower levels of risk enrichment present within the other 13 biological domains. DISCUSSION: This provides an objective methodology to localize risk within specific biological endophenotypes and drill down into the most significantly associated sets of GO terms and annotated genes for potential therapeutic targets.
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Alzheimer's disease (AD) drug discovery has focused on a set of highly studied therapeutic hypotheses, with limited success. The heterogeneous nature of AD processes suggests that a more diverse, systems-integrated strategy may identify new therapeutic hypotheses. Although many target hypotheses have arisen from systems-level modeling of human disease, in practice and for many reasons, it has proven challenging to translate them into drug discovery pipelines. First, many hypotheses implicate protein targets and/or biological mechanisms that are under-studied, meaning there is a paucity of evidence to inform experimental strategies as well as high-quality reagents to perform them. Second, systems-level targets are predicted to act in concert, requiring adaptations in how we characterize new drug targets. Here we posit that the development and open distribution of high-quality experimental reagents and informatic outputs-termed target enabling packages (TEPs)-will catalyze rapid evaluation of emerging systems-integrated targets in AD by enabling parallel, independent, and unencumbered research.
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OBJECTIVE: Recently, lymphoblastoid cell lines (LCLs) have emerged as an innovative model system for mapping gene variants that predict the dose response to chemotherapy drugs. METHODS: In the current study, this strategy was expanded to the in-vitro genome-wide association approach, using 516 LCLs derived from a White cohort to assess the cytotoxic response to temozolomide. RESULTS: Genome-wide association analysis using â¼2.1 million quality-controlled single-nucleotide polymorphisms (SNPs) identified a statistically significant association (P<10(-8)) with SNPs in the O(6)-methylguanine-DNA methyltransferase (MGMT) gene. We also show that the primary SNP in this region is significantly associated with the differential gene expression of MGMT (P<10(-26)) in LCLs and differential methylation in glioblastoma samples from The Cancer Genome Atlas. CONCLUSION: The previously documented clinical and functional relationships between MGMT and temozolomide response highlight the potential of well-powered genome-wide association studies of the LCL model system to identify meaningful genetic associations.
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Antineoplásicos Alquilantes/farmacología , Metilasas de Modificación del ADN/genética , Enzimas Reparadoras del ADN/genética , Dacarbazina/análogos & derivados , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas Supresoras de Tumor/genética , Línea Celular Tumoral , Metilación de ADN , Dacarbazina/farmacología , Regulación Neoplásica de la Expresión Génica , Genoma Humano , Estudio de Asociación del Genoma Completo , Humanos , Polimorfismo de Nucleótido Simple , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , TemozolomidaRESUMEN
Genetics play an important role in late-onset Alzheimer's Disease (AD) etiology and dozens of genetic variants have been implicated in AD risk through large-scale GWAS meta-analyses. However, the precise mechanistic effects of most of these variants have yet to be determined. Deeply phenotyped cohort data can reveal physiological changes associated with genetic risk for AD across an age spectrum that may provide clues to the biology of the disease. We utilized over 2000 high-quality quantitative measurements obtained from blood of 2831 cognitively normal adult clients of a consumer-based scientific wellness company, each with CLIA-certified whole-genome sequencing data. Measurements included: clinical laboratory blood tests, targeted chip-based proteomics, and metabolomics. We performed a phenome-wide association study utilizing this diverse blood marker data and 25 known AD genetic variants and an AD-specific polygenic risk score (PGRS), adjusting for sex, age, vendor (for clinical labs), and the first four genetic principal components; sex-SNP interactions were also assessed. We observed statistically significant SNP-analyte associations for five genetic variants after correction for multiple testing (for SNPs in or near NYAP1, ABCA7, INPP5D, and APOE), with effects detectable from early adulthood. The ABCA7 SNP and the APOE2 and APOE4 encoding alleles were associated with lipid variability, as seen in previous studies; in addition, six novel proteins were associated with the e2 allele. The most statistically significant finding was between the NYAP1 variant and PILRA and PILRB protein levels, supporting previous functional genomic studies in the identification of a putative causal variant within the PILRA gene. We did not observe associations between the PGRS and any analyte. Sex modified the effects of four genetic variants, with multiple interrelated immune-modulating effects associated with the PICALM variant. In post-hoc analysis, sex-stratified GWAS results from an independent AD case-control meta-analysis supported sex-specific disease effects of the PICALM variant, highlighting the importance of sex as a biological variable. Known AD genetic variation influenced lipid metabolism and immune response systems in a population of non-AD individuals, with associations observed from early adulthood onward. Further research is needed to determine whether and how these effects are implicated in early-stage biological pathways to AD. These analyses aim to complement ongoing work on the functional interpretation of AD-associated genetic variants.
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Enfermedad de Alzheimer , Transportadoras de Casetes de Unión a ATP/genética , Adulto , Enfermedad de Alzheimer/genética , Apolipoproteína E2/genética , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Genómica , Humanos , Masculino , Polimorfismo de Nucleótido SimpleRESUMEN
Remote health assessments that gather real-world data (RWD) outside clinic settings require a clear understanding of appropriate methods for data collection, quality assessment, analysis and interpretation. Here we examine the performance and limitations of smartphones in collecting RWD in the remote mPower observational study of Parkinson's disease (PD). Within the first 6 months of study commencement, 960 participants had enrolled and performed at least five self-administered active PD symptom assessments (speeded tapping, gait/balance, phonation or memory). Task performance, especially speeded tapping, was predictive of self-reported PD status (area under the receiver operating characteristic curve (AUC) = 0.8) and correlated with in-clinic evaluation of disease severity (r = 0.71; P < 1.8 × 10-6) when compared with motor Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS). Although remote assessment requires careful consideration for accurate interpretation of RWD, our results support the use of smartphones and wearables in objective and personalized disease assessments.
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Enfermedad de Parkinson , Teléfono Inteligente , Marcha , Humanos , Movimiento , Enfermedad de Parkinson/diagnóstico , Índice de Severidad de la EnfermedadRESUMEN
[This corrects the article DOI: 10.3389/fnagi.2021.735524.].
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Previous studies have shown that multiple features of atherogenic dyslipidemia are improved by replacement of dietary carbohydrate with mixed sources of protein and that these lipid and lipoprotein changes are independent of dietary saturated fat content. Because epidemiological evidence suggests that red meat intake may adversely affect cardiovascular disease risk, we tested the effects of replacing dietary carbohydrate with beef protein in the context of high- vs. low-saturated fat intake in 40 healthy men. After a 3-wk baseline diet [50% daily energy (E) as carbohydrate, 13% E as protein, 15% E as saturated fat], participants consumed for 3 wk each in a randomized crossover design two high-beef diets in which protein replaced carbohydrate (31% E as carbohydrate, 31% E as protein, with 10% E as beef protein). The high-beef diets differed in saturated fat content (8% E vs. 15% E with exchange of saturated for monounsaturated fat). Two-week washout periods were included following the baseline diet period and between the randomized diets periods. Plasma TG concentrations were reduced after the 2 lower carbohydrate dietary periods relative to after the baseline diet period and these reductions were independent of saturated fat intake. Plasma total, LDL, and non-HDL cholesterol as well as apoB concentrations were lower after the low-carbohydrate, low-saturated fat diet period than after the low-carbohydrate, high-saturated fat diet period. Given our previous observations with mixed protein diets, the present findings raise the possibility that dietary protein source may modify the effects of saturated fat on atherogenic lipoproteins.
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Dieta Aterogénica , Dieta Baja en Carbohidratos , Carbohidratos de la Dieta/administración & dosificación , Proteínas en la Dieta/administración & dosificación , Adolescente , Animales , Apolipoproteínas B/sangre , Bovinos , LDL-Colesterol/sangre , Estudios Cruzados , Dieta con Restricción de Grasas , Grasas de la Dieta , Dislipidemias , Ingestión de Energía , Ácidos Grasos/sangre , Humanos , Lipasa/metabolismo , Masculino , Carne , Periodo Posprandial/efectos de los fármacos , Triglicéridos/sangreRESUMEN
OBJECTIVE: Although statins are efficacious for lowering low-density lipoprotein cholesterol, there is wide interindividual variation in response. We tested the extent to which combined effects of common alleles of LDLR and HMGCR can contribute to this variability. METHODS AND RESULTS: Haplotypes in the LDLR 3'-untranslated region (3-UTR) were tested for association with lipid-lowering response to simvastatin treatment in the Cholesterol and Pharmacogenetics trial (335 blacks and 609 whites). LDLR haplotype 5 (LDLR L5) was associated with smaller simvastatin-induced reductions in low-density lipoprotein cholesterol, total cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B (P=0.0002 to 0.03) in blacks but not whites. The combined presence of LDLR L5 and previously described HMGCR haplotypes in blacks was associated with significantly attenuated apolipoprotein B reduction (-22.4+/-1.5%, N=89) compared with both noncarriers (-30.6+/-1.5%, N=78, P=0.0001) and carriers of either individual haplotype (-28.2+/-1.1%, N=158, P=0.001). We observed similar differences when measuring simvastatin-mediated induction of low-density lipoprotein receptor surface expression using lymphoblast cell lines (P=0.03). CONCLUSIONS: We have identified a common LDLR 3-UTR haplotype that is associated with attenuated lipid-lowering response to simvastatin treatment. Response was further reduced in individuals with both LDLR and previously described HMGCR haplotypes. Previously identified racial differences in statin efficacy were partially explained by the greater prevalence of these combined haplotypes in blacks.
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Dislipidemias/tratamiento farmacológico , Dislipidemias/genética , Hidroximetilglutaril-CoA Reductasas/genética , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Lípidos/sangre , Polimorfismo de Nucleótido Simple , Receptores de LDL/genética , Simvastatina/uso terapéutico , Regiones no Traducidas 3' , Negro o Afroamericano/genética , California/epidemiología , Línea Celular , Dislipidemias/sangre , Dislipidemias/etnología , Haplotipos , Humanos , Linfocitos/efectos de los fármacos , Linfocitos/metabolismo , Resultado del Tratamiento , Población Blanca/genéticaRESUMEN
The endocannabinoid (EC) system regulates food intake and energy metabolism. Cannabinoid receptor type 1 (CB1) antagonists show promise in the treatment of obesity and its metabolic consequences. Although the reduction in adiposity resulting from therapy with CB1 antagonists may not account fully for the concomitant improvements in dyslipidemia, direct effects of overactive EC signaling on plasma lipoprotein metabolism have not been documented. The present study used a chemical approach to evaluate the direct effects of increased EC signaling in mice by inducing acute elevations of endogenously produced cannabinoids through pharmacological inhibition of their enzymatic hydrolysis by isopropyl dodecylfluorophosphonate (IDFP). Acute IDFP treatment increased plasma levels of triglyceride (TG) (2.0- to 3.1-fold) and cholesterol (1.3- to 1.4-fold) in conjunction with an accumulation in plasma of apolipoprotein (apo)E-depleted TG-rich lipoproteins. These changes did not occur in either CB1-null or apoE-null mice, were prevented by pretreatment with CB1 antagonists, and were not associated with reduced hepatic apoE gene expression. Although IDFP treatment increased hepatic mRNA levels of lipogenic genes (Srebp1 and Fas), there was no effect on TG secretion into plasma. Instead, IDFP treatment impaired clearance of an intravenously administered TG emulsion, despite increased postheparin lipoprotein lipase activity. Therefore, overactive EC signaling elicits an increase in plasma triglyceride levels associated with reduced plasma TG clearance and an accumulation in plasma of apoE-depleted TG-rich lipoproteins. These findings suggest a role of CB1 activation in the pathogenesis of obesity-related hypertriglyceridemia and underscore the potential efficacy of CB1 antagonists in treating metabolic disease.
Asunto(s)
Apolipoproteínas E/metabolismo , Moduladores de Receptores de Cannabinoides/metabolismo , Endocannabinoides , Lipoproteínas/metabolismo , Transducción de Señal , Triglicéridos/metabolismo , Animales , Ácidos Araquidónicos/metabolismo , Colesterol/sangre , Inhibidores Enzimáticos/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Glicéridos/metabolismo , Lipasa/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Lípidos/sangre , Lipoproteínas/sangre , Hígado/efectos de los fármacos , Hígado/enzimología , Hígado/metabolismo , Masculino , Ratones , Organofosfonatos/farmacología , Receptor Cannabinoide CB1/metabolismo , Transducción de Señal/efectos de los fármacos , Triglicéridos/sangreRESUMEN
BACKGROUND: Alzheimer's disease (AD) is an incurable neurodegenerative disease currently affecting 1.75% of the US population, with projected growth to 3.46% by 2050. Identifying common genetic variants driving differences in transcript expression that confer AD risk is necessary to elucidate AD mechanism and develop therapeutic interventions. We modify the FUSION transcriptome-wide association study (TWAS) pipeline to ingest gene expression values from multiple neocortical regions. METHODS: A combined dataset of 2003 genotypes clustered to 1000 Genomes individuals from Utah with Northern and Western European ancestry (CEU) was used to construct a training set of 790 genotypes paired to 888 RNASeq profiles from temporal cortex (TCX = 248), prefrontal cortex (FP = 50), inferior frontal gyrus (IFG = 41), superior temporal gyrus (STG = 34), parahippocampal cortex (PHG = 34), and dorsolateral prefrontal cortex (DLPFC = 461). Following within-tissue normalization and covariate adjustment, predictive weights to impute expression components based on a gene's surrounding cis-variants were trained. The FUSION pipeline was modified to support input of pre-scaled expression values and support cross validation with a repeated measure design arising from the presence of multiple transcriptome samples from the same individual across different tissues. RESULTS: Cis-variant architecture alone was informative to train weights and impute expression for 6780 (49.67%) autosomal genes, the majority of which significantly correlated with gene expression; FDR < 5%: N = 6775 (99.92%), Bonferroni: N = 6716 (99.06%). Validation of weights in 515 matched genotype to RNASeq profiles from the CommonMind Consortium (CMC) was (72.14%) in DLPFC profiles. Association of imputed expression components from all 2003 genotype profiles yielded 8 genes significantly associated with AD (FDR < 0.05): APOC1, EED, CD2AP, CEACAM19, CLPTM1, MTCH2, TREM2, and KNOP1. CONCLUSIONS: We provide evidence of cis-genetic variation conferring AD risk through 8 genes across six distinct genomic loci. Moreover, we provide expression weights for 6780 genes as a valuable resource to the community, which can be abstracted across the neocortex and a wide range of neuronal phenotypes.