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1.
Artigo em Inglês | MEDLINE | ID: mdl-33895829

RESUMO

BACKGROUND: A genetic predisposition to lower thyroid stimulating hormone (TSH) levels associates with increased atrial fibrillation (AF) risk through undefined mechanisms. Defining the genetic mediating mechanisms could lead to improved targeted therapies to mitigate AF risk. METHODS: We used two-sample Mendelian randomization (MR) to test associations between TSH-associated single nucleotide polymorphisms (SNPs) and 16 candidate mediators. We then performed multivariable Mendelian randomization (MVMR) to test for a significant attenuation of the genetic association between TSH and AF, after adjusting for each mediator significantly associated with TSH. RESULTS: Four candidate mediators (free T4, systolic blood pressure, heart rate, and height) were significantly inversely associated with genetically predicted TSH after adjusting for multiple testing. In MVMR analyses, adjusting for height significantly decreased the magnitude of the association between TSH and AF from -0.12 (s.e. 0.02) occurrences of AF per standard deviation change in height to -0.06 (0.02) (p=0.005). Adjusting for the other candidate mediators did not significantly attenuate the association. CONCLUSIONS: The genetic association between TSH and increased AF risk is mediated, in part, by taller stature. Thus, some genetic mechanisms underlying TSH variability may contribute to AF risk through mechanisms determining height occurring early in life that differ from those driven by thyroid hormone level elevations in later life.

2.
Eur Heart J ; 42(9): 919-933, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33532862

RESUMO

AIMS: While most patients with myocardial infarction (MI) have underlying coronary atherosclerosis, not all patients with coronary artery disease (CAD) develop MI. We sought to address the hypothesis that some of the genetic factors which establish atherosclerosis may be distinct from those that predispose to vulnerable plaques and thrombus formation. METHODS AND RESULTS: We carried out a genome-wide association study for MI in the UK Biobank (n∼472 000), followed by a meta-analysis with summary statistics from the CARDIoGRAMplusC4D Consortium (n∼167 000). Multiple independent replication analyses and functional approaches were used to prioritize loci and evaluate positional candidate genes. Eight novel regions were identified for MI at the genome wide significance level, of which effect sizes at six loci were more robust for MI than for CAD without the presence of MI. Confirmatory evidence for association of a locus on chromosome 1p21.3 harbouring choline-like transporter 3 (SLC44A3) with MI in the context of CAD, but not with coronary atherosclerosis itself, was obtained in Biobank Japan (n∼165 000) and 16 independent angiography-based cohorts (n∼27 000). Follow-up analyses did not reveal association of the SLC44A3 locus with CAD risk factors, biomarkers of coagulation, other thrombotic diseases, or plasma levels of a broad array of metabolites, including choline, trimethylamine N-oxide, and betaine. However, aortic expression of SLC44A3 was increased in carriers of the MI risk allele at chromosome 1p21.3, increased in ischaemic (vs. non-diseased) coronary arteries, up-regulated in human aortic endothelial cells treated with interleukin-1ß (vs. vehicle), and associated with smooth muscle cell migration in vitro. CONCLUSIONS: A large-scale analysis comprising ∼831 000 subjects revealed novel genetic determinants of MI and implicated SLC44A3 in the pathophysiology of vulnerable plaques.

3.
Curr Hypertens Rep ; 23(2): 8, 2021 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-33537923

RESUMO

PURPOSE OF REVIEW: The purpose of this review is to summarize the evidence supporting a role of short-chain fatty acids (SCFAs) as messengers facilitating cross talk between the host and gut microbiota and discuss the effects of altered SCFA signaling in obesity and hypertension. RECENT FINDINGS: Recent evidence suggests there to be a significant contribution of gut microbiota-derived SCFAs to microbe:host communication and host metabolism. SCFA production within the intestine modulates intestinal pH, microbial composition, and intestinal barrier integrity. SCFA signaling through host receptors, such as PPARγ and GPCRs, modulates host health and disease physiology. Alterations in SCFA signaling and downstream effects on inflammation are implicated in the development of obesity and hypertension. SCFAs are crucial components of the holobiont relationship; in the proper environment, they support normal gut, immune, and metabolic function. Dysregulation of microbial SCFA signaling affects downstream host metabolism, with implications in obesity and hypertension.


Assuntos
Microbioma Gastrointestinal , Hipertensão , Microbiota , Ácidos Graxos Voláteis , Humanos , Obesidade
4.
Circulation ; 143(8): e254-e743, 2021 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-33501848

RESUMO

BACKGROUND: The American Heart Association, in conjunction with the National Institutes of Health, annually reports the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors, including core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure, and glucose control) that contribute to cardiovascular health. The Statistical Update presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, congenital heart disease, rhythm disorders, subclinical atherosclerosis, coronary heart disease, heart failure, valvular disease, venous disease, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs). METHODS: The American Heart Association, through its Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States to provide the most current information available in the annual Statistical Update. The 2021 Statistical Update is the product of a full year's worth of effort by dedicated volunteer clinicians and scientists, committed government professionals, and American Heart Association staff members. This year's edition includes data on the monitoring and benefits of cardiovascular health in the population, an enhanced focus on social determinants of health, adverse pregnancy outcomes, vascular contributions to brain health, the global burden of cardiovascular disease, and further evidence-based approaches to changing behaviors related to cardiovascular disease. RESULTS: Each of the 27 chapters in the Statistical Update focuses on a different topic related to heart disease and stroke statistics. CONCLUSIONS: The Statistical Update represents a critical resource for the lay public, policy makers, media professionals, clinicians, health care administrators, researchers, health advocates, and others seeking the best available data on these factors and conditions.

5.
Clin Sci (Lond) ; 134(17): 2369-2379, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32880388

RESUMO

OBJECTIVE: Type 2 diabetes mellitus (T2DM) reduces exercise capacity, but the mechanisms are incompletely understood. We probed the impact of ischemic stress on skeletal muscle metabolite signatures and T2DM-related vascular dysfunction. METHODS: we recruited 38 subjects (18 healthy, 20 T2DM), placed an antecubital intravenous catheter, and performed ipsilateral brachial artery reactivity testing. Blood samples for plasma metabolite profiling were obtained at baseline and immediately upon cuff release after 5 min of ischemia. Brachial artery diameter was measured at baseline and 1 min after cuff release. RESULTS: as expected, flow-mediated vasodilation was attenuated in subjects with T2DM (P<0.01). We confirmed known T2DM-associated baseline differences in plasma metabolites, including homocysteine, dimethylguanidino valeric acid and ß-alanine (all P<0.05). Ischemia-induced metabolite changes that differed between groups included 5-hydroxyindoleacetic acid (healthy: -27%; DM +14%), orotic acid (healthy: +5%; DM -7%), trimethylamine-N-oxide (healthy: -51%; DM +0.2%), and glyoxylic acid (healthy: +19%; DM -6%) (all P<0.05). Levels of serine, betaine, ß-aminoisobutyric acid and anthranilic acid were associated with vessel diameter at baseline, but only in T2DM (all P<0.05). Metabolite responses to ischemia were significantly associated with vasodilation extent, but primarily observed in T2DM, and included enrichment in phospholipid metabolism (P<0.05). CONCLUSIONS: our study highlights impairments in muscle and vascular signaling at rest and during ischemic stress in T2DM. While metabolites change in both healthy and T2DM subjects in response to ischemia, the relationship between muscle metabolism and vascular function is modified in T2DM, suggesting that dysregulated muscle metabolism in T2DM may have direct effects on vascular function.

6.
Curr Hypertens Rep ; 22(10): 79, 2020 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-32880753

RESUMO

PURPOSE OF REVIEW: Salt sensitivity of blood pressure (SSBP) is an independent predictor of death due to cardiovascular events and affects nearly 50% of the hypertensive and 25% of the normotensive population. Strong evidence indicates that reducing sodium (Na+) intake decreases blood pressure (BP) and cardiovascular events. The precise mechanisms of how dietary Na+ contributes to elevation and cardiovascular disease remain unclear. The goal of this review is to discuss mechanisms of salt-induced cardiovascular disease and how the microbiome may play a role. RECENT FINDINGS: The innate and adaptive immune systems are involved in the genesis of salt-induced hypertension. Mice fed a high-salt diet exhibit increased inflammation with a marked increase in dendritic cell (DC) production of interleukin (IL)-6 and formation of isolevuglandins (IsoLG)-protein adducts, which drive interferon-gamma (IFN-γ) and IL-17A production by T cells. While prior studies have mainly focused on the brain, kidney, and vasculature as playing a role in salt-induced hypertension, the gut is the first and largest location for Na+ absorption. Research from our group and others strongly suggests that the gut microbiome contributes to salt-induced inflammation and hypertension. Recent studies suggest that alterations in the gut microbiome contribute to salt-induced hypertension. However, the contribution of the microbiome to SSBP and its underlying mechanisms are not known. Targeting the microbiota and the associated immune cell activation could conceivably provide the much-needed therapy for SSBP.

7.
Nutr Metab Cardiovasc Dis ; 30(9): 1500-1511, 2020 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-32620337

RESUMO

BACKGROUND AND AIMS: Consumption of soy foods has been associated with protection against cardiometabolic disease, but the mechanisms are incompletely understood. We hypothesized that habitual soy food consumption associates with gut microbiome composition, metabolite production, and the interaction between diet, microbiota and metabolites. METHODS AND RESULTS: We analyzed dietary soy intake, plasma and stool metabolites, and gut microbiome data from two independent cross-sectional samples of healthy US individuals (N = 75 lean or overweight, and N = 29 obese). Habitual soy intake associated with several circulating metabolites. There was a significant interaction between soy intake and gut microbiome composition, as defined by gut enterotype, on metabolites in plasma and stool. Soy consumption associated with reduced systolic blood pressure, but only in a subset of individuals defined by their gut microbiome enterotype, suggesting that responsiveness to soy may be dependent on microbiome composition. Soy intake was associated with differences in specific microbial taxa, including two taxa mapping to genus Dialister and Prevotella which appeared to be suppressed by high soy intake We identified context-dependent effects of these taxa, where presence of Prevotella was associated with higher blood pressure and a worse cardiometabolic profile, but only in the absence of Dialister. CONCLUSIONS: The gut microbiome is an important intermediate in the interplay between dietary soy intake and systemic metabolism. Consumption of soy foods may shape the microbiome by suppressing specific taxa, and may protect against hypertension only in individuals with soy-responsive microbiota. CLINICAL TRIALS REGISTRY: NCT02010359 at clinicaltrials.gov.


Assuntos
Pressão Sanguínea , Metabolismo Energético , Microbioma Gastrointestinal , Intestinos/microbiologia , Obesidade/dietoterapia , Alimentos de Soja , Adolescente , Adulto , Biomarcadores/sangue , Estudos Transversais , Fezes/química , Fezes/microbiologia , Feminino , Interações Hospedeiro-Patógeno , Humanos , Masculino , Metabolômica , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/microbiologia , Obesidade/fisiopatologia , Pennsylvania , Ribotipagem , Fatores de Tempo , Resultado do Tratamento , Estados Unidos , Adulto Jovem
8.
Circ Heart Fail ; 13(7): e006570, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32507024

RESUMO

BACKGROUND: NPs (natriuretic peptides) are cardiac-derived hormones that promote natriuresis, diuresis, and vasodilation. Preclinical evidence suggests that nonhemodynamic triggers for NP release exist, with a few studies implicating inflammatory stimuli. We examined the association between inflammation and NP levels in humans. METHODS: The associations between inflammation and NP levels were examined in 3 independent studies. First, in 5481 MESA (Multi-Ethnic Study of Atherosclerosis) participants, the cross-sectional (exam 1) and longitudinal (exams 1 to 3) associations between circulating IL6 (interleukin-6) and NT-proBNP (N terminal pro B-type natriuretic peptide) levels were examined in multivariable-adjusted models. Second, in a prospective study of 115 healthy individuals, changes in NP levels were quantified following exposure to lipopolysaccharide as an inflammatory stimulus. Third, in 13 435 hospitalized patients, the association between acute inflammatory conditions and circulating NP levels was assessed using multivariable-adjusted models. RESULTS: At the baseline MESA exam, each 1-unit higher natural log IL6 was associated with 16% higher NT-proBNP level ([95% CI, 10%-22%]; P=0.002). Each 1-unit higher baseline natural log IL6 level also associated with 6% higher NT-proBNP level ([95% CI, 1%-11%]; P=0.02) at 4-year follow-up. In the lipopolysaccharide study, median NT-proBNP levels rose from 21 pg/mL pre-lipopolysaccharide to 54 pg/mL post-lipopolysaccharide, P<0.001. In the hospitalized patient study, acute inflammatory conditions were associated with 36% higher NP levels ([95% CI, 17%-60%]; P<0.001). CONCLUSIONS: Inflammation appears to be associated with NP release. Interpretation of NP levels should therefore take into account inflammatory conditions.


Assuntos
Inflamação/sangue , Peptídeos Natriuréticos/sangue , Ensaios Clínicos como Assunto , Humanos , Inflamação/etiologia
9.
Circulation ; 141(9): e139-e596, 2020 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-31992061

RESUMO

BACKGROUND: The American Heart Association, in conjunction with the National Institutes of Health, annually reports on the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors, including core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure, and glucose control) that contribute to cardiovascular health. The Statistical Update presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, congenital heart disease, rhythm disorders, subclinical atherosclerosis, coronary heart disease, heart failure, valvular disease, venous disease, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs). METHODS: The American Heart Association, through its Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States to provide the most current information available in the annual Statistical Update. The 2020 Statistical Update is the product of a full year's worth of effort by dedicated volunteer clinicians and scientists, committed government professionals, and American Heart Association staff members. This year's edition includes data on the monitoring and benefits of cardiovascular health in the population, metrics to assess and monitor healthy diets, an enhanced focus on social determinants of health, a focus on the global burden of cardiovascular disease, and further evidence-based approaches to changing behaviors, implementation strategies, and implications of the American Heart Association's 2020 Impact Goals. RESULTS: Each of the 26 chapters in the Statistical Update focuses on a different topic related to heart disease and stroke statistics. CONCLUSIONS: The Statistical Update represents a critical resource for the lay public, policy makers, media professionals, clinicians, healthcare administrators, researchers, health advocates, and others seeking the best available data on these factors and conditions.


Assuntos
American Heart Association , Cardiopatias/epidemiologia , Cardiopatias/prevenção & controle , Serviços Preventivos de Saúde , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/prevenção & controle , Comorbidade , Nível de Saúde , Cardiopatias/diagnóstico , Cardiopatias/mortalidade , Humanos , Estilo de Vida , Fatores de Proteção , Medição de Risco , Fatores de Risco , Comportamento de Redução do Risco , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/mortalidade , Fatores de Tempo , Estados Unidos/epidemiologia
10.
Diabetes ; 68(12): 2337-2349, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31582408

RESUMO

Novel biomarkers of type 2 diabetes (T2D) and response to preventative treatment in individuals with similar clinical risk may highlight metabolic pathways that are important in disease development. We profiled 331 metabolites in 2,015 baseline plasma samples from the Diabetes Prevention Program (DPP). Cox models were used to determine associations between metabolites and incident T2D, as well as whether associations differed by treatment group (i.e., lifestyle [ILS], metformin [MET], or placebo [PLA]), over an average of 3.2 years of follow-up. We found 69 metabolites associated with incident T2D regardless of treatment randomization. In particular, cytosine was novel and associated with the lowest risk. In an exploratory analysis, 35 baseline metabolite associations with incident T2D differed across the treatment groups. Stratification by baseline levels of several of these metabolites, including specific phospholipids and AMP, modified the effect that ILS or MET had on diabetes development. Our findings highlight novel markers of diabetes risk and preventative treatment effect in individuals who are clinically at high risk and motivate further studies to validate these interactions.


Assuntos
Citosina/sangue , Diabetes Mellitus Tipo 2/sangue , Adulto , Idoso , Biomarcadores/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Humanos , Incidência , Estilo de Vida , Masculino , Metaboloma , Pessoa de Meia-Idade , Fatores de Risco
11.
Circ Genom Precis Med ; 12(9): 421-429, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31462078

RESUMO

The gut microbiome is emerging as an important contributor to both cardiovascular disease risk and metabolism of xenobiotics. Alterations in the intestinal microbiota are associated with atherosclerosis, dyslipidemia, hypertension, and heart failure. The microbiota have the ability to metabolize medications, which can results in altered drug pharmacokinetics and pharmacodynamics or formation of toxic metabolites which can interfere with drug response. Early evidence suggests that the gut microbiome modulates response to statins and antihypertensive medications. In this review, we will highlight mechanisms by which the gut microbiome facilitates the biotransformation of drugs and impacts pharmacological efficacy. A better understanding of the complex interactions of the gut microbiome, host factors, and response to medications will be important for the development of novel precision therapeutics for targeting CVD.


Assuntos
Bactérias/metabolismo , Fármacos Cardiovasculares/administração & dosagem , Microbioma Gastrointestinal , Animais , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Biotransformação , Fármacos Cardiovasculares/metabolismo , Fármacos Cardiovasculares/farmacocinética , Trato Gastrointestinal/metabolismo , Trato Gastrointestinal/microbiologia , Humanos
12.
JCI Insight ; 52019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-31162138

RESUMO

Excess dietary salt contributes to inflammation and hypertension via poorly understood mechanisms. Antigen presenting cells including dendritic cells (DCs) play a key role in regulating intestinal immune homeostasis in part by surveying the gut epithelial surface for pathogens. Previously, we found that highly reactive γ-ketoaldehydes or isolevuglandins (IsoLGs) accumulate in DCs and act as neoantigens, promoting an autoimmune-like state and hypertension. We hypothesized that excess dietary salt alters the gut microbiome leading to hypertension and this is associated with increased immunogenic IsoLG-adduct formation in myeloid antigen presenting cells. To test this hypothesis, we performed fecal microbiome analysis and measured blood pressure of healthy human volunteers with salt intake above or below the American Heart Association recommendations. We also performed 16S rRNA analysis on cecal samples of mice fed normal or high salt diets. In humans and mice, high salt intake was associated with changes in the gut microbiome reflecting an increase in Firmicutes, Proteobacteria and genus Prevotella bacteria. These alterations were associated with higher blood pressure in humans and predisposed mice to vascular inflammation and hypertension in response to a sub-pressor dose of angiotensin II. Mice fed a high salt diet exhibited increased intestinal inflammation including the mesenteric arterial arcade and aorta, with a marked increase in the B7 ligand CD86 and formation of IsoLG-protein adducts in CD11c+ myeloid cells. Adoptive transfer of fecal material from conventionally housed high salt-fed mice to germ-free mice predisposed them to increased intestinal inflammation and hypertension. These findings provide novel insight into the mechanisms underlying inflammation and hypertension associated with excess dietary salt and may lead to interventions targeting the microbiome to prevent and treat this important disease.


Assuntos
Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Disbiose , Hipertensão/metabolismo , Cloreto de Sódio na Dieta/efeitos adversos , Cloreto de Sódio/efeitos adversos , Adolescente , Transferência Adotiva , Adulto , Angiotensina II , Animais , Aorta/metabolismo , Bactérias/classificação , Bactérias/genética , Pressão Sanguínea , Antígeno CD11c/imunologia , Colo/microbiologia , Colo/patologia , Citocinas/metabolismo , Células Dendríticas/patologia , Modelos Animais de Doenças , Feminino , Microbioma Gastrointestinal , Humanos , Inflamação/metabolismo , Lipídeos , Linfonodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Células Mieloides/metabolismo , Nódulos Linfáticos Agregados/microbiologia , Nódulos Linfáticos Agregados/patologia , RNA Ribossômico 16S/genética , Cloreto de Sódio/administração & dosagem , Cloreto de Sódio na Dieta/administração & dosagem , Adulto Jovem
13.
Front Genet ; 10: 454, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31164901

RESUMO

The human microbiome has been associated with health status, and risk of disease development. While the etiology of microbiome-mediated disease remains to be fully elucidated, one mechanism may be through microbial metabolism. Metabolites produced by commensal organisms, including in response to host diet, may affect host metabolic processes, with potentially protective or pathogenic consequences. We conducted multi-omic phenotyping of healthy subjects (N = 136), in order to investigate the interaction between diet, the microbiome, and the metabolome in a cross-sectional sample. We analyzed the nutrient composition of self-reported diet (3-day food records and food frequency questionnaires). We profiled the gut and oral microbiome (16S rRNA) from stool and saliva, and applied metabolomic profiling to plasma and stool samples in a subset of individuals (N = 75). We analyzed these multi-omic data to investigate the relationship between diet, the microbiome, and the gut and circulating metabolome. On a global level, we observed significant relationships, particularly between long-term diet, the gut microbiome and the metabolome. Intake of plant-derived nutrients as well as consumption of artificial sweeteners were associated with significant differences in circulating metabolites, particularly bile acids, which were dependent on gut enterotype, indicating that microbiome composition mediates the effect of diet on host physiology. Our analysis identifies dietary compounds and phytochemicals that may modulate bacterial abundance within the gut and interact with microbiome composition to alter host metabolism.

14.
Circulation ; 139(10): e56-e528, 2019 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-30700139
15.
J Nutr Biochem ; 64: 45-49, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30428424

RESUMO

BACKGROUND: Omega-3 polyunsaturated fatty acids, specifically the fish-oil-derived eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been proposed as inflammation-resolving agents via their effects on adipose tissue. OBJECTIVE: We proposed to determine the effects of EPA and DHA on human adipocyte differentiation and inflammatory activation in vitro. METHODS: Primary human subcutaneous adipocytes from lean and obese subjects were treated with 100 µM EPA and/or DHA throughout differentiation (differentiation studies) or for 72 h postdifferentiation (inflammatory studies). THP-1 monocytes were added to adipocyte wells for co-culture experiments. Subcutaneous and visceral adipose explants from obese subjects were treated for 72 h with EPA and DHA. Oil Red O staining was performed on live cells. Cells were collected for mRNA analysis by quantitative polymerase chain reaction, and media were collected for protein quantification by enzyme-linked immunosorbent assay. RESULTS: Incubation with EPA and/or DHA attenuated inflammatory response to lipopolysaccharide (LPS) and monocyte co-culture with reduction in post-LPS mRNA expression and protein levels of IL6, CCL2 and CX3CL1. Expression of inflammatory genes was also reduced in the endogenous inflammatory response in obese adipose. Both DHA and EPA reduced lipid droplet formation and lipogenic gene expression without alteration in expression of adipogenic genes or adiponectin secretion. CONCLUSIONS: EPA and DHA attenuate inflammatory activation of in vitro human adipocytes and reduce lipogenesis.


Assuntos
Adipócitos/efeitos dos fármacos , Ácidos Graxos Ômega-3/farmacologia , Adipócitos/patologia , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Técnicas de Cocultura , Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico/farmacologia , Humanos , Inflamação/dietoterapia , Leucócitos/metabolismo , Gotículas Lipídicas/efeitos dos fármacos , Lipopolissacarídeos/toxicidade , Macrófagos/citologia , Obesidade/dietoterapia , Obesidade/metabolismo
16.
Circ Genom Precis Med ; 11(11): e001907, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30571184

RESUMO

BACKGROUND: Cytokine responses to activation of innate immunity differ between individuals, yet the genomic and tissue-specific transcriptomic determinants of inflammatory responsiveness are not well understood. We hypothesized that tissue-specific mRNA and long intergenic noncoding RNA (lincRNA) induction differs between individuals with divergent evoked inflammatory responses. METHODS: In the GENE Study (Genetics of Evoked Response to Niacin and Endotoxemia), we performed an inpatient endotoxin challenge (1 ng/kg lipopolysaccharide [LPS]) in healthy humans. We selected individuals in the top (high responders) and bottom (low responders) extremes of inflammatory responses and applied RNA sequencing to CD14 monocytes (N=15) and adipose tissue (N=25) before and after LPS administration. RESULTS: Although only a small number of genes were differentially expressed at baseline, there were clear differences in the magnitude of the transcriptional response post-LPS between high and low responders, with a far greater number of genes differentially expressed by endotoxemia in high responders. Furthermore, tissue responses differed during inflammation, and we found a number of tissue-specific differentially expressed lincRNAs post-LPS, which we validated. Relative to nondifferentially expressed lincRNAs, differentially expressed lincRNAs were equally likely to be nonconserved as conserved between human and mouse, indicating that conservation is not a predictor of lincRNAs associated with human inflammatory pathophysiology. Differentially expressed genes also were enriched for signals with inflammatory and cardiometabolic disease in published genome-wide association studies. CTB-41I6.2 ( AC002091.1), a nonconserved human-specific lincRNA, is one of the top lincRNAs regulated by endotoxemia in monocytes, but not in adipose tissue. Knockdown experiments in THP-1 monocytes suggest that this lincRNA enhances LPS-induced interleukin 6 ( IL6) expression in monocytes, and we now refer to this as monocyte LPS-induced lincRNA regulator of IL6 ( MOLRIL6). CONCLUSIONS: We highlight mRNAs and lincRNAs that represent novel candidates for modulation of innate immune and metabolic responses in humans. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00953667.


Assuntos
Tecido Adiposo/imunologia , Endotoxemia , Regulação da Expressão Gênica/imunologia , Monócitos/imunologia , RNA Longo não Codificante , RNA Mensageiro , Tecido Adiposo/patologia , Animais , Endotoxemia/genética , Endotoxemia/imunologia , Endotoxemia/patologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Imunidade Inata/genética , Inflamação/genética , Inflamação/imunologia , Masculino , Camundongos , Monócitos/patologia , RNA Longo não Codificante/genética , RNA Longo não Codificante/imunologia , RNA Mensageiro/genética , RNA Mensageiro/imunologia , Análise de Sequência de RNA
17.
Circulation ; 138(22): 2469-2481, 2018 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-30571344

RESUMO

BACKGROUND: Proteomic approaches allow measurement of thousands of proteins in a single specimen, which can accelerate biomarker discovery. However, applying these technologies to massive biobanks is not currently feasible because of the practical barriers and costs of implementing such assays at scale. To overcome these challenges, we used a "virtual proteomic" approach, linking genetically predicted protein levels to clinical diagnoses in >40 000 individuals. METHODS: We used genome-wide association data from the Framingham Heart Study (n=759) to construct genetic predictors for 1129 plasma protein levels. We validated the genetic predictors for 268 proteins and used them to compute predicted protein levels in 41 288 genotyped individuals in the Electronic Medical Records and Genomics (eMERGE) cohort. We tested associations for each predicted protein with 1128 clinical phenotypes. Lead associations were validated with directly measured protein levels and either low-density lipoprotein cholesterol or subclinical atherosclerosis in the MDCS (Malmö Diet and Cancer Study; n=651). RESULTS: In the virtual proteomic analysis in eMERGE, 55 proteins were associated with 89 distinct diagnoses at a false discovery rate q<0.1. Among these, 13 associations involved lipid (n=7) or atherosclerosis (n=6) phenotypes. We tested each association for validation in MDCS using directly measured protein levels. At Bonferroni-adjusted significance thresholds, levels of apolipoprotein E isoforms were associated with hyperlipidemia, and circulating C-type lectin domain family 1 member B and platelet-derived growth factor receptor-ß predicted subclinical atherosclerosis. Odds ratios for carotid atherosclerosis were 1.31 (95% CI, 1.08-1.58; P=0.006) per 1-SD increment in C-type lectin domain family 1 member B and 0.79 (0.66-0.94; P=0.008) per 1-SD increment in platelet-derived growth factor receptor-ß. CONCLUSIONS: We demonstrate a biomarker discovery paradigm to identify candidate biomarkers of cardiovascular and other diseases.


Assuntos
Biomarcadores/sangue , Doenças das Artérias Carótidas/diagnóstico , Estudo de Associação Genômica Ampla , Proteoma/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças das Artérias Carótidas/genética , Feminino , Genótipo , Humanos , Lectinas Tipo C/análise , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fenótipo , Polimorfismo de Nucleotídeo Único , Proteômica , Receptor beta de Fator de Crescimento Derivado de Plaquetas/sangue
18.
Children (Basel) ; 5(12)2018 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-30486462

RESUMO

Emerging evidence suggests that microbiome composition and function is associated with development of obesity and metabolic disease. Microbial colonization expands rapidly following birth, and microbiome composition is particularly variable during infancy. Factors that influence the formation of the gut microbiome during infancy and childhood may have a significant impact on development of obesity and metabolic dysfunction, with life-long consequences. In this review, we examine the determinants of gut microbiome composition during infancy and childhood, and evaluate the potential impact on obesity and cardiometabolic risk.

19.
PLoS Med ; 15(8): e1002642, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30153257

RESUMO

BACKGROUND: Observations from statin clinical trials and from Mendelian randomization studies suggest that low low-density lipoprotein cholesterol (LDL-C) concentrations may be associated with increased risk of type 2 diabetes mellitus (T2DM). Despite the findings from statin clinical trials and genetic studies, there is little direct evidence implicating low LDL-C concentrations in increased risk of T2DM. METHODS AND FINDINGS: We used de-identified electronic health records (EHRs) at Vanderbilt University Medical Center to compare the risk of T2DM in a cross-sectional study among individuals with very low (≤60 mg/dl, N = 8,943) and normal (90-130 mg/dl, N = 71,343) LDL-C levels calculated using the Friedewald formula. LDL-C levels associated with statin use, hospitalization, or a serum albumin level < 3 g/dl were excluded. We used a 2-phase approach: in 1/3 of the sample (discovery) we used T2DM phenome-wide association study codes (phecodes) to identify cases and controls, and in the remaining 2/3 (validation) we identified T2DM cases and controls using a validated algorithm. The analysis plan for the validation phase was constructed at the time of the design of that component of the study. The prevalence of T2DM in the very low and normal LDL-C groups was compared using logistic regression with adjustment for age, race, sex, body mass index (BMI), high-density lipoprotein cholesterol, triglycerides, and duration of care. Secondary analyses included prespecified stratification by sex, race, BMI, and LDL-C level. In the discovery cohort, phecodes related to T2DM were significantly more frequent in the very low LDL-C group. In the validation cohort (N = 33,039 after applying the T2DM algorithm to identify cases and controls), the risk of T2DM was increased in the very low compared to normal LDL-C group (odds ratio [OR] 2.06, 95% CI 1.80-2.37; P < 2 × 10-16). The findings remained significant in sensitivity analyses. The association between low LDL-C levels and T2DM was significant in males (OR 2.43, 95% CI 2.00-2.95; P < 2 × 10-16) and females (OR 1.74, 95% CI 1.42-2.12; P = 6.88 × 10-8); in normal weight (OR 2.18, 95% CI 1.59-2.98; P = 1.1× 10-6), overweight (OR 2.17, 95% CI 1.65-2.83; P = 1.73× 10-8), and obese (OR 2.00, 95% CI 1.65-2.41; P = 8 × 10-13) categories; and in individuals with LDL-C < 40 mg/dl (OR 2.31, 95% CI 1.71-3.10; P = 3.01× 10-8) and LDL-C 40-60 mg/dl (OR 1.99, 95% CI 1.71-2.32; P < 2.0× 10-16). The association was significant in individuals of European ancestry (OR 2.67, 95% CI 2.25-3.17; P < 2 × 10-16) but not in those of African ancestry (OR 1.09, 95% CI 0.81-1.46; P = 0.56). A limitation was that we only compared groups with very low and normal LDL-C levels; also, since this was not an inception cohort, we cannot exclude the possibility of reverse causation. CONCLUSIONS: Very low LDL-C concentrations occurring in the absence of statin treatment were significantly associated with T2DM risk in a large EHR population; this increased risk was present in both sexes and all BMI categories, and in individuals of European ancestry but not of African ancestry. Longitudinal cohort studies to assess the relationship between very low LDL-C levels not associated with lipid-lowering therapy and risk of developing T2DM will be important.


Assuntos
LDL-Colesterol/metabolismo , Diabetes Mellitus Tipo 2/epidemiologia , Adulto , Estudos de Casos e Controles , Estudos de Coortes , Estudos Transversais , Diabetes Mellitus Tipo 2/metabolismo , Registros Eletrônicos de Saúde , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fatores de Risco , Estados Unidos/epidemiologia , Adulto Jovem
20.
Sci Transl Med ; 10(446)2018 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-29925637

RESUMO

Long intergenic noncoding RNAs (lincRNAs) have emerged as important modulators of cellular functions. Most lincRNAs are not conserved among mammals, raising the fundamental question of whether nonconserved adipose-expressed lincRNAs are functional. To address this, we performed deep RNA sequencing of gluteal subcutaneous adipose tissue from 25 healthy humans. We identified 1001 putative lincRNAs expressed in all samples through de novo reconstruction of noncoding transcriptomes and integration with existing lincRNA annotations. One hundred twenty lincRNAs had adipose-enriched expression, and 54 of these exhibited peroxisome proliferator-activated receptor γ (PPARγ) or CCAAT/enhancer binding protein α (C/EBPα) binding at their loci. Most of these adipose-enriched lincRNAs (~85%) were not conserved in mice, yet on average, they showed degrees of expression and binding of PPARγ and C/EBPα similar to those displayed by conserved lincRNAs. Most adipose lincRNAs differentially expressed (n = 53) in patients after bariatric surgery were nonconserved. The most abundant adipose-enriched lincRNA in our subcutaneous adipose data set, linc-ADAL, was nonconserved, up-regulated in adipose depots of obese individuals, and markedly induced during in vitro human adipocyte differentiation. We demonstrated that linc-ADAL interacts with heterogeneous nuclear ribonucleoprotein U (hnRNPU) and insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) at distinct subcellular locations to regulate adipocyte differentiation and lipogenesis.


Assuntos
Adipócitos/metabolismo , Tecido Adiposo/metabolismo , RNA Longo não Codificante/metabolismo , Adipócitos/citologia , Diferenciação Celular , Núcleo Celular/metabolismo , Regulação da Expressão Gênica , Ribonucleoproteínas Nucleares Heterogêneas Grupo U/metabolismo , Humanos , Lipídeos/biossíntese , Lipogênese , PPAR gama/metabolismo , RNA Longo não Codificante/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Transcrição Genética
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