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Recent years have witnessed substantial progress in cancer immunotherapy, specifically T cell-based therapies. However, the application of T cell therapies has been primarily limited to hematologic malignancies, with limited success in the treatment of solid tumors. The main challenge in treating solid tumor is immune escape, which is characterized by reduced antigenicity, diminished immunogenicity, and the development of suppressive tumor immune microenvironments. To address these obstacles and restore T cell-mediated anti-tumor responses, a novel nanoparticle formulation known as PRA@Oxa-c16 is developed. This innovative approach combines retinoic acid and Pt(IV) to specifically target and overcome immune escape. Notably, the therapeutic efficacy of PRA@Oxa-c16 primarily relies on its ability to induce anti-tumor T cell responses, in contrast to the cytotoxicity associated with conventional chemotherapeutic agents. When combined with an immune checkpoint blockade, anti-programmed death-ligand 1 antibody, PRA@Oxa-c16 effectively eliminates solid tumors and induces immune memory responses, which prevent tumor metastasis and recurrence. This promising approach holds great potential for enhancing the treatment of solid tumors with T cell-based immunotherapy.
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Antígeno B7-H1 , Linfocitos T CD8-positivos , Inmunoterapia , Nanomedicina , Profármacos , Profármacos/química , Profármacos/uso terapéutico , Profármacos/farmacología , Inmunoterapia/métodos , Linfocitos T CD8-positivos/inmunología , Animales , Nanomedicina/métodos , Ratones , Línea Celular Tumoral , Antígeno B7-H1/inmunología , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/metabolismo , Nanopartículas/química , Neoplasias/terapia , Neoplasias/inmunología , Humanos , Platino (Metal)/química , Tretinoina/química , Tretinoina/farmacología , Tretinoina/uso terapéutico , Microambiente Tumoral/efectos de los fármacos , Activación de Linfocitos/efectos de los fármacos , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacologíaRESUMEN
Valproic acid (VPA) is a first-line antiepileptic drug with broad efficacy. Due to significant individual differences in its metabolism, therapeutic drug monitoring is commonly used. However, the recommended therapeutic range (50-100 µg/mL) is inadequate for predicting clinical outcomes. Additionally, the relationship between VPA metabolites and clinical outcomes remains unclear. In this retrospective study, 485 Chinese Southern Han epilepsy patients receiving VPA monotherapy were analyzed after reaching steady-state levels. Plasma concentrations of VPA and its five main metabolites were determined by liquid chromatography-mass spectrometry (LC-MS). We assessed the relevance of the recommended therapeutic VPA range for clinical outcomes and explored the association between VPA/metabolites levels and treatment efficacy/adverse effects. Vitro experiments were conducted to assess 4-ene-VPA hepatotoxicity. The therapeutic range of VPA exhibited no significant correlation with clinical outcomes, and plasma concentrations of VPA failed to serve as predictive indicators for treatment response/adverse effects. Treatment responders had higher 2-PGA concentrations (median, 26.39 ng/mL versus 13.68 ng/mL), with a threshold of 36.5 ng/mL for optimal epilepsy treatment. Patients with abnormal liver function had a higher 4-ene-VPA median concentration (6.41 µg/mL versus 4.83 µg/mL), and the ratio of 4-ene-VPA to VPA better predicted VPA-induced hepatotoxicity (area under the curve, 0.718) than 4-ene-VPA concentration. Vitro experiments revealed that 4-ene-VPA was more hepatotoxic than VPA in HepaRG and L02 cell lines. Total plasma VPA concentration does not serve as a predictor of clinical outcomes. 2-PGA concentrations may be associated with efficacy, whereas the ratio of 4-ene-VPA to VPA may be considered a better biomarker (threshold 10.03%) for VPA-induced hepatotoxicity. SIGNIFICANCE STATEMENT: This was the first and largest observational cohort in China to explore the relationship between patients' parent and metabolites concentrations of VPA and clinical outcomes during the maintenance of VPA monotherapy in epileptic patients. This study provided feasible references of VPA for epilepsy clinical treatment with a larger sample of patients compared with previous studies for a more definitive conclusion based on real-world situations. We found two potential biomarkers in predicting efficacy and liver injury, respectively. This breakthrough has the potential to assist in the rational use of VPA.
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Enfermedad Hepática Inducida por Sustancias y Drogas , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Epilepsia , Humanos , Anticonvulsivantes/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Monitoreo de Drogas , Epilepsia/tratamiento farmacológico , Estudios Retrospectivos , Ácido Valproico/efectos adversosRESUMEN
The impact of microplastic particles of micro- and nanometer sizes on microbial horizontal gene transfer (HGT) remains a controversial topic. Existing studies rely on traditional approaches, which analyze population behavior, leading to conflicting conclusions and a limited understanding. The present study addressed these limitations by employing a novel microfluidic chamber system for in situ visualization and precise quantification of the effects of different concentrations of polystyrene (PS) microbeads on microbial HGT at the single-cell level. The statistical analysis indicated no significant difference in the division times of both the donor and recipient bacteria across different PS microbead concentrations. However, as the concentration of PS microbeads increased from 0 to 2000 mg L-1, the average conjugation frequency of Escherichia coli decreased from 0.028 ± 0.015 to 0.004 ± 0.003. Our observations from the microfluidic experiments revealed that 500 nm PS microbeads created a barrier effect on bacterial conjugative transfer. The presence of microbeads resulted in reduced contact and interaction between the donor and recipient strains, thereby causing a decrease in the conjugation transfer frequency. These findings were validated by an individual-based modeling framework parameterized by the data from the individual-level microfluidic experiments. Overall, this study offers a fresh perspective and strategy for investigating the risks associated with the dissemination of antibiotic resistance genes related to microplastics.
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Escherichia coli , Microplásticos , Escherichia coli/genética , Plásmidos , Plásticos , Poliestirenos , Antibacterianos/farmacología , Transferencia de Gen HorizontalRESUMEN
The paradigm of cancer-targeted therapies has focused largely on inhibition of critical pathways in cancer. Conversely, conditional activation of signaling pathways as a new source of selective cancer vulnerabilities has not been deeply characterized. In this study, we sought to systematically identify context-specific gene-activation-induced lethalities in cancer. To this end, we developed a method for gain-of-function genetic perturbations simultaneously across ~500 barcoded cancer cell lines. Using this approach, we queried the pan-cancer vulnerability landscape upon activating ten key pathway nodes, revealing selective activation dependencies of MAPK and PI3K pathways associated with specific biomarkers. Notably, we discovered new pathway hyperactivation dependencies in subsets of APC-mutant colorectal cancers where further activation of the WNT pathway by APC knockdown or direct ß-catenin overexpression led to robust antitumor effects in xenograft and patient-derived organoid models. Together, this study reveals a new class of conditional gene-activation dependencies in cancer.
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Neoplasias Colorrectales , Humanos , Neoplasias Colorrectales/patología , Fosfatidilinositol 3-Quinasas , beta Catenina/genética , Vía de Señalización Wnt/genética , Proliferación Celular , Línea Celular TumoralRESUMEN
AIMS: To investigate the capability, properties, and molecular mechanism of inulin fermentation by lactic acid bacteria (LAB) from Sichuan pickle. METHODS AND RESULTS: A total of 79 LAB strains were purified from 30 aged Sichuan pickle brine samples, and only 21 Lactiplantibacillus plantarum strains (26.58%, 21/79) derived from 15 samples grew well through utilizing inulin as a carbon source. The fermentation tests through using long-chain inulin (lc-inulin) as a carbon source showed that only 6 L. plantarum strains grew well, while other 15 strains could only utilize short-chain oligofructose (FOS), and thin-layer chromatography analysis evidenced a strain specificity of inulin consumption patterns. Lactiplantibacillus plantarum YT041 is a vigorous inulin fermenter, and whole genome sequencing data revealed that sacPTS1 and fosRABCDXE operons might be associated with the fermentation of FOS and lc-inulin, respectively. CONCLUSIONS: The phenotype of inulin consumption is commonly present in LAB from Sichuan pickle, which is strain-specific and largely depends on their specific ecological niche and degree of polymerization.
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Alimentos Fermentados , Lactobacillales , Lactobacillus plantarum , Inulina/metabolismo , Lactobacillales/metabolismo , Genómica , Fenotipo , Alimentos Fermentados/microbiología , Fermentación , Lactobacillus plantarum/genética , Lactobacillus plantarum/metabolismoRESUMEN
Respiratory syncytial virus (RSV) is a serious respiratory pathogen in infants and young children worldwide. Currently, no licensed RSV vaccines are available. In this study, we explored stable prefusion conformation virus-like particles (Pre-F VLPs) as RSV vaccine candidates. RSV fusion (F) protein mutants were constructed to form stabilized Pre-F or postfusion (Post-F) configurations. VLPs containing Pre-F or Post-F protein were generated using a recombinant baculovirus (rBV)-insect cell expression system. The assembly and immunological properties of Pre-F or Post-F VLPs were investigated. Pre-F and Post-F VLPs contained antigenic sites Ø and I of pre- and postfusion conformations, respectively. Compared with Post-F VLPs, immunization with Pre-F VLPs elicited upregulation of IFN-γ, IL-2 and IL-10 and downregulation of IL-4 and IL-5 cytokine production in mice. A high percentage of CD25+ Foxp3+ cells or a low percentage of IL-17A-producing cells among CD4+ T cells was observed in the lungs of mice vaccinated with Pre-F VLPs. Importantly, immunization with Pre-F VLPs induced a high level of RSV neutralizing antibody and a balanced immune response, which protected mice against RSV infection without evidence of immunopathology. Our results suggested that Pre-F VLPs generated from rBV-insect cells represent promising RSV vaccine candidates.
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Infecciones por Virus Sincitial Respiratorio , Vacunas contra Virus Sincitial Respiratorio , Virus Sincitial Respiratorio Humano , Ratones , Animales , Infecciones por Virus Sincitial Respiratorio/prevención & control , Vacunas contra Virus Sincitial Respiratorio/genética , Anticuerpos Neutralizantes , Virus Sincitial Respiratorio Humano/genética , Anticuerpos Antivirales , InmunidadRESUMEN
BACKGROUND: To minimize drug-related toxicity and monitor dosing regimens, an ultra-sensitive, simple and high-throughput analytical method for therapeutic drug monitoring is required. A novel LC-MS/MS bioassay of levetiracetam, lamotrigine and 10-hydroxycarbazepine in human plasma was established. The analytes were separated on a Hypersil GOLD™ C18 column under a 2.5 min isocratic elution after one-step protein precipitation. MS detection was performed under electrospray ionization positive-mode fitted with selected reaction monitoring. The validated ranges were 0.1-20 µg/ml for LTG, 0.3-60 µg/ml for 10-hydroxycarbazepine and levetiracetam. The intra- and inter-batches of precision and accuracy was within ±15%. The novel method met all other criteria. CONCLUSION: This method can be used to monitor drug concentrations and decision-making in epileptic patients.
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Epilepsia , Espectrometría de Masas en Tándem , Anticonvulsivantes , Carbamazepina/análogos & derivados , Cromatografía Líquida de Alta Presión/métodos , Cromatografía Liquida , Monitoreo de Drogas/métodos , Epilepsia/tratamiento farmacológico , Humanos , Lamotrigina/uso terapéutico , Levetiracetam , Reproducibilidad de los Resultados , Espectrometría de Masas en Tándem/métodosRESUMEN
Combinatorial CRISPR technologies have emerged as a transformative approach to systematically probe genetic interactions and dependencies of redundant gene pairs. However, the performance of different functional genomic tools for multiplexing sgRNAs vary widely. Here, we generate and benchmark ten distinct pooled combinatorial CRISPR libraries targeting paralog pairs to optimize digenic knockout screens. Libraries composed of dual Streptococcus pyogenes Cas9 (spCas9), orthogonal spCas9 and Staphylococcus aureus (saCas9), and enhanced Cas12a from Acidaminococcus were evaluated. We demonstrate a combination of alternative tracrRNA sequences from spCas9 consistently show superior effect size and positional balance between the sgRNAs as a robust combinatorial approach to profile genetic interactions of multiple genes.
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Acidaminococcus , Sistemas CRISPR-Cas , Acidaminococcus/genética , Sistemas CRISPR-Cas/genética , ARN Guía de Kinetoplastida/genética , Staphylococcus aureus/genética , Streptococcus pyogenes/genéticaRESUMEN
Molecular pathologic diagnosis is important in clinical (oncology) practice. Integration of molecular pathology into epidemiological methods (i.e., molecular pathological epidemiology) allows for investigating the distinct etiology of disease subtypes based on biomarker analyses, thereby contributing to precision medicine and prevention. However, existing approaches for investigating etiological heterogeneity deal with categorical subtypes. We aimed to fully leverage continuous measures available in most biomarker readouts (gene/protein expression levels, signaling pathway activation, immune cell counts, microbiome/microbial abundance in tumor microenvironment, etc.). We present a cause-specific Cox proportional hazards regression model for evaluating how the exposure-disease subtype association changes across continuous subtyping biomarker levels. Utilizing two longitudinal observational prospective cohort studies, we investigated how the association of alcohol intake (a risk factor) with colorectal cancer incidence differed across the continuous values of tumor epigenetic DNA methylation at long interspersed nucleotide element-1 (LINE-1). The heterogeneous alcohol effect was modeled using different functions of the LINE-1 marker to demonstrate the method's flexibility. This real-world proof-of-principle computational application demonstrates how the new method enables visualizing the trend of the exposure effect over continuous marker levels. The utilization of continuous biomarker data without categorization for investigating etiological heterogeneity can advance our understanding of biological and pathogenic mechanisms.
RESUMEN
Sichuan pickle is a natural combination of probiotics and dietary fibers, in which a strain Lactiplantibacillus plantarum QS7T was found to be capable of efficiently metabolizing inulin. However, the underlying molecular mechanism of inulin consumption by the strain QS7T is unclear. Therefore, this study firstly investigated the metabolic characteristics of inulin in the strain QS7T, and the results showed it could grow very well on the medium containing inulin as a carbon source (maximum OD600 nm, 1.891 ± 0.028) and degrade both short-chain oligofructose and long-chain fructan components through thin layer chromatography analysis. Genomic sequencing and analysis revealed a high percentage of functional genes associated with carbohydrate transport and metabolism, particularly glycoside hydrolase (GH) genes responsible for hydrolysing carbohydrates, within the genome of the strain QS7T. Furthermore, comparative transcriptomic analysis of L. plantarum QS7T in response to inulin or glucose indicated that functional genes associated with inulin consumption including several genes encoding PTS sugar transporters and two predicted GH32 family genes encoding beta-fructofuranosidase and beta-fructosidase were significantly up-regulated by inulin compared to the gene expression on glucose. In conclusion, we obtained a mechanistic understanding of interplay between probiotic L. plantarum QS7T derived from Sichuan pickle and natural dietary fiber, inulin; totally two operons including a sacPTS1 operon responsible for metabolizing short-chain oligofructose primarily in the cytoplasm and a fos operon responsible for extracellularly degrading all moderate and long-chain fructan components linked to inulin consumption by L. plantarum QS7T.
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Inulina , Probióticos , Operón , Transcriptoma , beta-Fructofuranosidasa/metabolismoRESUMEN
AIM: Previously, we found that diabetes-related liver dysfunction is due to activation of the 5-HT2A receptor (5-HT2AR) and increased synthesis and degradation of 5-HT. Here, we investigated the role of 5-HT in the development of atherosclerosis. METHODS: The study was conducted using high-fat diet-fed male ApoE-/- mice, THP-1 cell-derived macrophages, and HUVECs. Protein expression and biochemical indexes were determined by Western blotting and quantitative analysis kit, respectively. The following staining methods were used: oil red O staining (showing atherosclerotic plaques and intracellular lipid droplets), immunohistochemistry (showing the expression of 5-HT2AR, 5-HT synthase, and CD68 in the aortic wall), and fluorescent probe staining (showing intracellular ROS). RESULTS: In addition to improving hepatic steatosis, insulin resistance, and dyslipidemia, co-treatment with a 5-HT synthesis inhibitor and a 5-HT2AR antagonist significantly suppressed the formation of atherosclerotic plaques and macrophage infiltration in the aorta of ApoE-/- mice in a synergistic manner. Macrophages and HUVECs exposed to oxLDL or palmitic acid in vitro showed that activated 5-HT2AR regulated TG synthesis and oxLDL uptake by activating PKCε, resulting in formation of lipid droplets and even foam cells; ROS production was due to the increase of both intracellular 5-HT synthesis and mitochondrial MAO-A-catalyzed 5-HT degradation, which leads to the activation of NF-κB and the release of the inflammatory cytokines TNF-α and IL-1ß from macrophages and HUVECs as well as MCP-1 release from HUVECs. CONCLUSION: Similar to hepatic steatosis, the pathogenesis of lipid-induced atherosclerosis is associated with activation of intracellular 5-HT2AR, 5-HT synthesis, and 5-HT degradation.
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Aterosclerosis/metabolismo , Células Endoteliales/metabolismo , Células Espumosas/metabolismo , Macrófagos/metabolismo , Placa Aterosclerótica/metabolismo , Receptor de Serotonina 5-HT2A/metabolismo , Serotonina/metabolismo , Animales , Aterosclerosis/patología , Células Cultivadas , Modelos Animales de Enfermedad , Células Endoteliales/patología , Células Espumosas/patología , Macrófagos/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Placa Aterosclerótica/patologíaRESUMEN
Although single-gene perturbation screens have revealed a number of new targets, vulnerabilities specific to frequently altered drivers have not been uncovered. An important question is whether the compensatory relationship between functionally redundant genes masks potential therapeutic targets in single-gene perturbation studies. To identify digenic dependencies, we developed a CRISPR paralog targeting library to investigate the viability effects of disrupting 3,284 genes, 5,065 paralog pairs and 815 paralog families. We identified that dual inactivation of DUSP4 and DUSP6 selectively impairs growth in NRAS and BRAF mutant cells through the hyperactivation of MAPK signaling. Furthermore, cells resistant to MAPK pathway therapeutics become cross-sensitized to DUSP4 and DUSP6 perturbations such that the mechanisms of resistance to the inhibitors reinforce this mechanism of vulnerability. Together, multigene perturbation technologies unveil previously unrecognized digenic vulnerabilities that may be leveraged as new therapeutic targets in cancer.
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Fosfatasa 6 de Especificidad Dual/genética , Fosfatasas de Especificidad Dual/genética , Sistema de Señalización de MAP Quinasas , Fosfatasas de la Proteína Quinasa Activada por Mitógenos/genética , Neoplasias/genética , Línea Celular Tumoral , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Activación Enzimática , GTP Fosfohidrolasas/genética , Técnicas de Inactivación de Genes , Humanos , Melanoma Experimental/genética , Melanoma Experimental/terapia , Proteínas de la Membrana/genética , Neoplasias/enzimología , Neoplasias/metabolismo , Neoplasias/terapia , Proteínas Proto-Oncogénicas B-raf/genéticaRESUMEN
Inulin as a commercial prebiotic could selectively promote the growth of beneficial gut microbes such as lactic acid bacteria (LAB). Whether LAB in rabbit gut possesses the capability to metabolize and utilize inulin is little known. Therefore, this study recovered 94 LAB strains from neonate rabbits and found that only 29% (28/94) could metabolize inulin with both species- and strain-specificity. The most vigorous inulin-degrading strain, Lacticaseibacillus paracasei YT170, could efficiently utilize both short-chain and long-chain components through thin-layer chromatography analysis. From genomic analysis, a predicted fosRABCDXE operon encoding putative cell wall-anchored fructan ß-fructosidase, five fructose-transporting proteins and a pts1BCA operon encoding putative ß-fructofuranosidase and sucrose-specific IIBCA components were linked to long-chain and short-chain inulin utilization respectively. This study provides a mechanistic rationale for effect of inulin administration on rabbits and lays a foundation for synbiotic applications aimed at modulating the intestinal microbiota of young rabbits.
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CDK4/6 inhibitors (CDK4/6i) are effective in metastatic breast cancer, but they have been only modestly effective in most other tumor types. Here we show that tumors expressing low CDK6 rely on CDK4 function, and are exquisitely sensitive to CDK4/6i. In contrast, tumor cells expressing both CDK4 and CDK6 have increased reliance on CDK6 to ensure cell cycle progression. We discovered that CDK4/6i and CDK4/6 degraders potently bind and inhibit CDK6 selectively in tumors in which CDK6 is highly thermo-unstable and strongly associated with the HSP90/CDC37 complex. In contrast, CDK4/6i and CDK4/6 degraders are ineffective in antagonizing tumor cells expressing thermostable CDK6, due to their weaker binding to CDK6 in these cells. Thus, we uncover a general mechanism of intrinsic resistance to CDK4/6i and CDK4/6i-derived degraders and the need for novel inhibitors targeting the CDK4/6i-resistant, thermostable form of CDK6 for application as cancer therapeutics.
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Neoplasias de la Mama , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Quinasa 4 Dependiente de la Ciclina/metabolismo , Quinasa 6 Dependiente de la Ciclina , Femenino , Proteínas HSP90 de Choque Térmico , HumanosRESUMEN
PRMT5 is an essential arginine methyltransferase and a therapeutic target in MTAP-null cancers. PRMT5 uses adaptor proteins for substrate recruitment through a previously undefined mechanism. Here, we identify an evolutionarily conserved peptide sequence shared among the three known substrate adaptors (CLNS1A, RIOK1, and COPR5) and show that it is necessary and sufficient for interaction with PRMT5. We demonstrate that PRMT5 uses modular adaptor proteins containing a common binding motif for substrate recruitment, comparable with other enzyme classes such as kinases and E3 ligases. We structurally resolve the interface with PRMT5 and show via genetic perturbation that it is required for methylation of adaptor-recruited substrates including the spliceosome, histones, and ribosomal complexes. Furthermore, disruption of this site affects Sm spliceosome activity, leading to intron retention. Genetic disruption of the PRMT5-substrate adaptor interface impairs growth of MTAP-null tumor cells and is thus a site for development of therapeutic inhibitors of PRMT5.
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Proteína-Arginina N-Metiltransferasas/metabolismo , Proteína-Arginina N-Metiltransferasas/fisiología , Animales , Línea Celular Tumoral , Citoplasma/metabolismo , Femenino , Células HCT116 , Células HEK293 , Histonas/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Canales Iónicos/metabolismo , Masculino , Metilación , Ratones , Ratones Desnudos , Proteínas Nucleares/metabolismo , Péptidos/genética , Unión Proteica , Procesamiento Proteico-Postraduccional , Proteínas Serina-Treonina Quinasas/metabolismo , Proteína-Arginina N-Metiltransferasas/genética , Empalmosomas/metabolismoRESUMEN
BACKGROUND: Multiple aspects of sleep and Sleep Disordered Breathing (SDB) have been linked to hypertension. However, the standard measure of SDB, the Apnoea Hypopnea Index (AHI), has not identified patients likely to experience large improvements in blood pressure with SDB treatment. METHODS: To use machine learning to select sleep and pulmonary measures associated with hypertension development when considered jointly, we applied feature screening followed by Elastic Net penalized regression in association with incident hypertension using a wide array of polysomnography measures, and lung function, derived for the Sleep Heart Health Study (SHHS). FINDINGS: At baseline, n=860 SHHS individuals with complete data were age 61 years, on average. Of these, 291 developed hypertension ~5 years later. A combination of pulmonary function and 18 sleep phenotypes predicted incident hypertension (OR=1.43, 95% confidence interval [1.14, 1.80] per 1 standard deviation (SD) of the phenotype), while the apnoea-hypopnea index (AHI) had low evidence of association with incident hypertension (OR =1.13, 95% confidence interval [0.97, 1.33] per 1 SD). In a generalization analysis in 923 individuals from the Multi-Ethnic Study of Atherosclerosis, aged 65 on average with 615 individuals with hypertension, the new phenotype was cross-sectionally associated with hypertension (OR=1.26, 95% CI [1.10, 1.45]). INTERPRETATION: A unique combination of sleep and pulmonary function measures better predicts hypertension compared to the AHI. The composite measure included indices capturing apnoea and hypopnea event durations, with shorter event lengths associated with increased risk of hypertension. FUNDING: This research was supported by National Heart, Lung, and Blood Institute (NHLBI) contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169 and by National Center for Advancing Translational Sciences grants UL1-TR- 000040, UL1-TR-001079, and UL1-TR-001420. The MESA Sleep ancillary study was supported by NHLBI grant HL-56984. Pulmonary phenotyping in MESA was funded by NHLBI grants R01-HL077612 and R01-HL093081. This work was supported by NHLBI grant R35HL135818 to Susan Redline.
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Hipertensión/diagnóstico , Síndromes de la Apnea del Sueño/fisiopatología , Anciano , Anciano de 80 o más Años , Estudios Transversales , Femenino , Humanos , Hipertensión/etnología , Aprendizaje Automático , Masculino , Persona de Mediana Edad , Pruebas de Función Respiratoria , Síndromes de la Apnea del Sueño/etnología , EspirometríaRESUMEN
BACKGROUND: Sleep Disordered Breathing (SDB) is associated with a wide range of pathophysiological changes due, in part, to hypoxemia during sleep. We sought to identify gene transcription associations with measures of SDB and hypoxemia during sleep, and study their response to treatment. METHODS: In two discovery cohorts, Framingham Offspring Study (FOS; N = 571) and the Multi-Ethnic Study of Atherosclerosis (MESA; N = 580), we studied gene expression in peripheral blood mononuclear cells in association with three measures of SDB: Apnea Hypopnea Index (AHI); average oxyhemoglobin saturation (avgO2) during sleep; and minimum oxyhemoglobin saturation (minO2) during sleep. Associated genes were used for analysis of gene expression in the blood of 15 participants with moderate or severe obstructive sleep apnea (OSA) from the Heart Biomarkers In Apnea Treatment (HeartBEAT) trial. These genes were studied pre- and post-treatment (three months) with continuous positive airway pressure (CPAP). We also performed Gene Set Enrichment Analysis (GSEA) on all traits and cohort analyses. FINDINGS: Twenty-two genes were associated with SDB traits in both MESA and FOS. Of these, lower expression of CD1D and RAB20 was associated with lower avgO2 in MESA and FOS. CPAP treatment increased the expression of these genes in HeartBEAT participants. Immunity and inflammation pathways were up-regulated in subjects with lower avgO2; i.e., in those with a more severe SDB phenotype (MESA), whereas immuno-inflammatory processes were down-regulated following CPAP treatment (HeartBEAT). INTERPRETATION: Low oxygen saturation during sleep is associated with alterations in gene expression and transcriptional programs that are partially reversed by CPAP treatment.
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Antígenos CD1d/genética , Presión de las Vías Aéreas Positiva Contínua/métodos , Regulación hacia Abajo , Oxihemoglobinas/metabolismo , Síndromes de la Apnea del Sueño/terapia , Proteínas de Unión al GTP rab/genética , Anciano , Femenino , Perfilación de la Expresión Génica , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Síndromes de la Apnea del Sueño/etnología , Síndromes de la Apnea del Sueño/genéticaRESUMEN
Average arterial oxyhemoglobin saturation during sleep (AvSpO2S) is a clinically relevant measure of physiological stress associated with sleep-disordered breathing, and this measure predicts incident cardiovascular disease and mortality. Using high-depth whole-genome sequencing data from the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) project and focusing on genes with linkage evidence on chromosome 8p23,1,2 we observed that six coding and 51 noncoding variants in a gene that encodes the GTPase-activating protein (DLC1) are significantly associated with AvSpO2S and replicated in independent subjects. The combined DLC1 association evidence of discovery and replication cohorts reaches genome-wide significance in European Americans (p = 7.9 × 10-7). A risk score for these variants, built on an independent dataset, explains 0.97% of the AvSpO2S variation and contributes to the linkage evidence. The 51 noncoding variants are enriched in regulatory features in a human lung fibroblast cell line and contribute to DLC1 expression variation. Mendelian randomization analysis using these variants indicates a significant causal effect of DLC1 expression in fibroblasts on AvSpO2S. Multiple sources of information, including genetic variants, gene expression, and methylation, consistently suggest that DLC1 is a gene associated with AvSpO2S.
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Cromosomas Humanos Par 8/genética , Proteínas Activadoras de GTPasa/genética , Oxihemoglobinas/genética , Sueño/genética , Proteínas Supresoras de Tumor/genética , Ligamiento Genético/genética , Estudio de Asociación del Genoma Completo , Humanos , Secuenciación Completa del Genoma/métodosRESUMEN
STUDY OBJECTIVES: Daytime sleepiness is a consequence of inadequate sleep, sleep-wake control disorder, or other medical conditions. Population variability in prevalence of daytime sleepiness is likely due to genetic and biological factors as well as social and environmental influences. DNA methylation (DNAm) potentially influences multiple health outcomes. Here, we explored the association between DNAm and daytime sleepiness quantified by the Epworth Sleepiness Scale (ESS). METHODS: We performed multi-ethnic and ethnic-specific epigenome-wide association studies for DNAm and ESS in the Multi-Ethnic Study of Atherosclerosis (MESA; n = 619) and the Cardiovascular Health Study (n = 483), with cross-study replication and meta-analysis. Genetic variants near ESS-associated DNAm were analyzed for methylation quantitative trait loci and followed with replication of genotype-sleepiness associations in the UK Biobank. RESULTS: In MESA only, we detected four DNAm-ESS associations: one across all race/ethnic groups; three in African-Americans (AA) only. Two of the MESA AA associations, in genes KCTD5 and RXRA, nominally replicated in CHS (p-value < 0.05). In the AA meta-analysis, we detected 14 DNAm-ESS associations (FDR q-value < 0.05, top association p-value = 4.26 × 10-8). Three DNAm sites mapped to genes (CPLX3, GFAP, and C7orf50) with biological relevance. We also found evidence for associations with DNAm sites in RAI1, a gene associated with sleep and circadian phenotypes. UK Biobank follow-up analyses detected SNPs in RAI1, RXRA, and CPLX3 with nominal sleepiness associations. CONCLUSIONS: We identified methylation sites in multiple genes possibly implicated in daytime sleepiness. Most significant DNAm-ESS associations were specific to AA. Future work is needed to identify mechanisms driving ancestry-specific methylation effects.