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1.
BMC Med ; 18(1): 288, 2020 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-33109212

RESUMO

BACKGROUND: Advances in antiretroviral therapies have greatly improved the survival of people living with human immunodeficiency virus (HIV) infection (PLWH); yet, PLWH have a higher risk of cardiovascular disease than those without HIV. While numerous genetic loci have been linked to cardiometabolic risk in the general population, genetic predictors of the excessive risk in PLWH are largely unknown. METHODS: We screened for common and HIV-specific genetic variants associated with variation in lipid levels in 6284 PLWH (3095 European Americans [EA] and 3189 African Americans [AA]), from the Centers for AIDS Research Network of Integrated Clinical Systems cohort. Genetic hits found exclusively in the PLWH cohort were tested for association with other traits. We then assessed the predictive value of a series of polygenic risk scores (PRS) recapitulating the genetic burden for lipid levels, type 2 diabetes (T2D), and myocardial infarction (MI) in EA and AA PLWH. RESULTS: We confirmed the impact of previously reported lipid-related susceptibility loci in PLWH. Furthermore, we identified PLWH-specific variants in genes involved in immune cell regulation and previously linked to HIV control, body composition, smoking, and alcohol consumption. Moreover, PLWH at the top of European-based PRS for T2D distribution demonstrated a > 2-fold increased risk of T2D compared to the remaining 95% in EA PLWH but to a much lesser degree in AA. Importantly, while PRS for MI was not predictive of MI risk in AA PLWH, multiethnic PRS significantly improved risk stratification for T2D and MI. CONCLUSIONS: Our findings suggest that genetic loci involved in the regulation of the immune system and predisposition to risky behaviors contribute to dyslipidemia in the presence of HIV infection. Moreover, we demonstrate the utility of the European-based and multiethnic PRS for stratification of PLWH at a high risk of cardiometabolic diseases who may benefit from preventive therapies.

2.
World J Clin Cases ; 8(19): 4550-4557, 2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33083417

RESUMO

BACKGROUND: Gastro-thoracic fistula is a serious complication after radical surgery for esophageal cancer, and a conservative approach or endoscopic intervention is commonly applied to treat most cases. CASE SUMMARY: Here we describe the case of a patient with a gastro-thoracic fistula which could not be closed during gastroscopy after receiving postoperative radiotherapy, together with severe multiple drug-resistant bacterial infection and chest wall fistula. The abscess was drained and local irrigation applied with ozonated water, together with oral ozonated water, which achieved a good effect and highlighted a new way to cure fistula in such patients. CONCLUSION: Patients with gastro-thoracic fistula that cannot be closed and severe infection can be treated by drainage and flushing with ozonated water.

3.
Proc Natl Acad Sci U S A ; 117(45): 28422-28432, 2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33109720

RESUMO

The human cerebral cortex contains many cell types that likely underwent independent functional changes during evolution. However, cell-type-specific regulatory landscapes in the cortex remain largely unexplored. Here we report epigenomic and transcriptomic analyses of the two main cortical neuronal subtypes, glutamatergic projection neurons and GABAergic interneurons, in human, chimpanzee, and rhesus macaque. Using genome-wide profiling of the H3K27ac histone modification, we identify neuron-subtype-specific regulatory elements that previously went undetected in bulk brain tissue samples. Human-specific regulatory changes are uncovered in multiple genes, including those associated with language, autism spectrum disorder, and drug addiction. We observe preferential evolutionary divergence in neuron subtype-specific regulatory elements and show that a substantial fraction of pan-neuronal regulatory elements undergoes subtype-specific evolutionary changes. This study sheds light on the interplay between regulatory evolution and cell-type-dependent gene-expression programs, and provides a resource for further exploration of human brain evolution and function.

4.
Epigenetics ; : 1-13, 2020 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-33016211

RESUMO

MicroRNAs are non-coding RNAs that regulate gene expression post-transcriptionally. In the placenta, the master regulator of foetal growth and development, microRNAs shape the basic processes of trophoblast biology and specific microRNA have been associated with foetal growth. To comprehensively assess the role of microRNAs in placental function and foetal development, we have performed small RNA sequencing to profile placental microRNAs from two independent mother-infant cohorts: the Rhode Island Child Health Study (n = 225) and the New Hampshire Birth Cohort Study (n = 317). We modelled microRNA counts on infant birthweight percentile (BWP) in each cohort, while accounting for race, sex, parity, and technical factors, using negative binomial generalized linear models. We identified microRNAs that were differentially expressed (DEmiRs) with BWP at false discovery rate (FDR) less than 0.05 in both cohorts. hsa-miR-532-5p (miR-532) was positively associated with BWP in both cohorts. By integrating parallel whole transcriptome and small RNA sequencing in the RICHS cohort, we identified putative targets of miR-532. These targets are enriched for pathways involved in adipogenesis, adipocytokine signalling, energy metabolism, and hypoxia response, and included Leptin, which we further demonstrated to have a decreasing expression with increasing BWP, particularly in male infants. Overall, we have shown a robust and reproducible association of miR-532 with BWP, which could influence BWP through regulation of adipocytokines Leptin and Adiponectin.

5.
Atherosclerosis ; 311: 20-29, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32919281

RESUMO

BACKGROUND AND AIMS: Coronary artery disease (CAD) arises from the interaction of genetic and environmental factors. Although genome-wide association studies (GWAS) have identified multiple risk loci and single nucleotide polymorphisms (SNPs) associated with risk of CAD, they are predominantly located in non-coding or intergenic regions and their mechanisms of effect are largely unknown. Accordingly, our objective was to develop a data-driven informatics pipeline to understand complex CAD risk loci, and to apply this to a poorly understood cluster of SNPs in the vicinity of ZEB2. METHODS: We developed a unique informatics pipeline leveraging a multi-tissue CAD genetics-of-gene-expression dataset, GWAS datasets, and other resources. The pipeline first dissected SNP locations and their linkage disequilibrium relationships, and progressed through analyses of tissue-specific expression quantitative trait loci, and then gene-gene, gene-phenotype, SNP-phenotype relationships. The pipeline concluded by exploring CAD-relevant gene regulatory networks (GRNs). RESULTS: We identified three independent CAD risk SNPs in close proximity to the ZEB2 coding region (rs6740731, rs17678683 and rs2252641/rs1830321). Our pipeline determined that these SNPs likely act in concert via the atherosclerotic arterial wall and adipose tissues, by governing metabolic and lipid functions. In addition, ZEB2 is the top key driver of a liver-specific GRN that is related to lipid levels, metabolic and anthropometric measures, and CAD severity. CONCLUSIONS: Using a novel informatics pipeline, we disclosed the multi-faceted mechanisms of action of the ZEB2-associated CAD risk SNPs. This pipeline can serve as a roadmap to dissect complex SNP-gene-tissue-phenotype relationships and to reveal targets for tissue- and gene-specific therapeutic interventions.

6.
Gastroenterology ; 2020 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-32980345

RESUMO

BACKGROUND AND AIMS: The presence of gastrointestinal symptoms and high levels of viral RNA in the stool suggest active Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) replication within enterocytes. METHODS: Here, in multiple, large cohorts of patients with inflammatory bowel disease (IBD), we have studied the intersections between Coronavirus Disease 2019 (COVID-19), intestinal inflammation and IBD treatment. RESULTS: A striking expression of ACE2 on the small bowel enterocyte brush border supports intestinal infectivity by SARS-CoV-2. Commonly used IBD medications, both biologic and non-biologic, do not significantly impact ACE2 and TMPRSS2 receptor expression in the uninflamed intestines. Additionally, we have defined molecular responses to COVID-19 infection that are also enriched in IBD, pointing to shared molecular networks between COVID-19 and IBD. CONCLUSIONS: These data generate a novel appreciation of the confluence of COVID-19- and IBD-associated inflammation and provide mechanistic insights supporting further investigation of specific IBD drugs in the treatment of COVID-19.

7.
J Neurosci Res ; 98(12): 2541-2553, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32918293

RESUMO

Major depressive disorder affects ~20% of the world population and is characterized by strong sexual dimorphism with females being two to three times more likely to develop this disorder. Previously, we demonstrated that a combination therapy with dihydrocaffeic acid and malvidin-glucoside to synergistically target peripheral inflammation and stress-induced synaptic maladaptation in the brain was effective in alleviating chronic social defeat stress (CSDS)-induced depression-like phenotype in male mice. Here, we test the combination therapy in a female CSDS model for depression and compared sex-specific responses to stress in the periphery and the central nervous system. Similar to male mice, the combination treatment is also effective in promoting resilience against the CSDS-induced depression-like behavior in female mice. However, there are sex-specific differences in peripheral immune responses and differential gene regulation in the prefrontal cortex to chronic stress and to the treatment. These data indicate that while therapeutic approaches to combat stress-related disorders may be effective in both sexes, the mechanisms underlying these effects differ, emphasizing the need for inclusion of both sexes in preclinical studies using animal models.

8.
Exp Cell Res ; 396(1): 112237, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32841643

RESUMO

The proliferation and differentiation of myoblast cells are regulated by the fibroblast growth factor receptor (FGFR) signaling pathway. Although the regulation of FGFR signaling cascades has been widely investigated, the inhibitory mechanism that particularly function in skeletal muscle myogenesis remains obscure. In this study, we determined that LRTM1, an inhibitory regulator of the FGFR signaling pathway, negatively modulates the activation of ERK and promotes the differentiation of myoblast cells. LRTM1 is dynamically expressed during myoblast differentiation and skeletal muscle regeneration after injury. In mouse myoblast C2C12 cells, knockout (KO) of Lrtm1 significantly prevents the differentiation of myoblast cells; this effect is associated with the reduction of MyoD transcriptional activity and the overactivation of ERK kinase. Notably, further studies demonstrated that LRTM1 associates with p52Shc and inhibits the recruitment of p52Shc to FGFR1. Taken together, our findings identify a novel negative regulator of FGFR1, which plays an important role in regulating the differentiation of myoblast cells.

9.
Int J Chron Obstruct Pulmon Dis ; 15: 1391-1401, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32606648

RESUMO

Purpose: Circular RNAs (circRNAs) regulate other RNA transcripts by competing for shared microRNAs, which play roles in the pathogenesis of many diseases, including chronic obstructive pulmonary disease (COPD). However, the role of circRNAs in COPD remains unknown. This study aimed to investigate the expression profile and the role of circRNAs in COPD. Patients and Methods: Twenty-one COPD patients and twenty-one normal controls were recruited. Total RNAs were collected from peripheral blood mononuclear cells (PBMCs) of each participant. CircRNAs and protein-coding mRNAs were profiled by microarray and systematically compared between patients with COPD and control subjects. The top differentially expressed circRNAs and mRNAs were validated by quantitative real-time PCR (RT-qPCR). Functional analysis identified pathways relevant to the pathogenesis of COPD. Next, the circRNA target pathway network, the circRNA-miRNA-mRNA network (ceRNA network) and functional ceRNA regulatory modules were constructed. Results: In total, 2132 circRNAs and 2734 protein-coding mRNAs were differentially expressed (|fold change| >1.5 and P-value <0.05) in COPD patients. Six out of nine selected RNAs were confirmed by RT-qPCR validation. Our functional analysis suggested that immune imbalances and inflammatory responses play roles in the pathogenesis of COPD. The ceRNA network highlighted the differentially expressed circRNAs and their related miRNAs and mRNAs in COPD. In the circRNA target pathway network and functional ceRNA regulatory modules, hsa_circRNA_0008672 appeared in the top three KEGG pathways (NOD-like receptor signaling pathway, natural killer cell mediated cytotoxicity and Th17 cell differentiation) and may act as the miRNA sponge regulating the hsa_circRNA_0008672/miR-1265/MAPK1 axis. Conclusion: Our findings demonstrate critical roles of the circRNAs in COPD molecular etiology. The data support a plausible mechanism that circRNAs may be involved in the development of COPD by affecting the immune balance. Moreover, the hsa_circRNA_0008672/miR-1265/MAPK1 axis may contribute to the pathogenesis of COPD, warranting further investigation.

10.
FEBS Lett ; 2020 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-32531799

RESUMO

Regeneration is a unique defense mechanism of liver tissue in response to functional cell loss induced by toxic chemicals or surgical resection. In this study, we found that Islet-cell autoantigen 69 (Ica69) accelerates liver regeneration in mice. Following 70% partial hepatectomy, both Ica69 mRNA and protein are significantly upregulated in mouse hepatocytes at the early stage of liver regeneration. Compared with the wild-type mice, Ica69-deficient mice have more severe liver injury, delayed liver regeneration, and high surgical accidental mortality following hepatectomy. Mechanistically, Ica69 interacts with Pick1 protein to regulate Tgfbr1 protein expression and Tgfß-induced Smad2 phosphorylation. Our findings suggest that Ica69 in liver tissue is a new potential target for promoting liver regeneration.

11.
FASEB J ; 2020 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-32574425

RESUMO

Seasonal exposures influence human health and development. The placenta, as a mediator of the maternal and fetal systems and a regulator of development, is an ideal tissue to understand the biological pathways underlying relationships between season of birth and later life health outcomes. Here, we conducted a differential expression (DE) analysis of season of birth in full-term human placental tissue to evaluate whether the placenta may be influenced by seasonal cues. Of the analyzed transcripts, 583 displayed DE between summer and winter births (False Discovery Rate [FDR] q < .05); among these, BHLHE40, MIR210HG, and HILPDA had increased expression among winter births (Bonferroni P < .05). Enrichment analyses of the seasonally variant genes between summer and winter births indicated overrepresentation of transcription factors HIF1A, VDR, and CLOCK, among others, and of GO term pathways related to ribosomal activity and infection. Additionally, a cosinor analysis found rhythmic expression for approximately 11.9% of all 17 664 analyzed placental transcripts. These results suggest that the placenta responds to seasonal cues and add to the growing body of evidence that the placenta acts as a peripheral clock, which may provide a molecular explanation for the extensive associations between season of birth and health outcomes.

12.
Ecotoxicol Environ Saf ; 201: 110726, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32480160

RESUMO

BACKGROUND: Impaired in utero fetal growth trajectory may have long term health consequences of the newborns and increase risk of adulthood metabolic diseases. Prenatal exposure to air pollution has been linked to fetal development restriction; however, the impact of exposure to ambient air pollutants on the entire course of intrauterine fetal development has not been comprehensively investigated. METHODS: During 2015-2018, two cohorts of mother-infant dyads (N = 678 and 227) were recruited in Shanghai China, from which three categories of data were systematically collected: (1) daily exposure to six air pollutants during pregnancy, (2) fetal biometry in the 2nd (gestational week 24, [GW24]) and 3rd trimester (GW36), and (3) neonatal outcomes at birth. We investigated the impact of prenatal exposure to air pollutant mixture on the trajectory of fetal development during the course of gestation, adjusting for a broad set of potential confounds. RESULTS: Prenatal exposure to PM2.5, PM10, SO2 and O3 significantly reduced fetal biometry at GW24, where SO2 had the most potent effect. For every 10 µg/m3 increment increase of daily SO2 exposure during the 1st trimester shortened femur length by 2.20 mm (p = 6.7E-21) translating to 5.3% reduction from the average of the study cohort. Prenatal air pollution exposure also decreased fetal biometry at GW36 with attenuated effect size. Comparing to the lowest exposed quartile, fetus in the highest exposed quartile had 6.3% (p = 3.5E-5) and 2.1% (p = 2.4E-3) lower estimated intrauterine weight in GW24 and GW36, respectively; however, no difference in birth weight was observed, indicating a rapid catch-up growth in the 3rd trimester. CONCLUSIONS: To our knowledge, for the first time, we demonstrated the impact of prenatal exposure to ambient air pollutants on the course of intrauterine fetal development. The altered growth trajectory and rapid catch-up growth in associated with high prenatal exposure may lead to long-term predisposition for adulthood metabolic disorders.


Assuntos
Poluentes Atmosféricos/toxicidade , Desenvolvimento Fetal/efeitos dos fármacos , Exposição Materna/efeitos adversos , Material Particulado/toxicidade , Adulto , Poluentes Atmosféricos/química , China/epidemiologia , Estudos de Coortes , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Material Particulado/química , Gravidez
13.
Gastroenterology ; 159(2): 549-561.e8, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32371109

RESUMO

BACKGROUND & AIMS: Collagenous colitis (CC) is an inflammatory bowel disorder with unknown etiopathogenesis involving HLA-related immune-mediated responses and environmental and genetic risk factors. We carried out an array-based genetic association study in a cohort of patients with CC and investigated the common genetic basis between CC and Crohn's disease (CD), ulcerative colitis (UC), and celiac disease. METHODS: DNA from 804 CC formalin-fixed, paraffin-embedded tissue samples was genotyped with Illumina Immunochip. Matching genotype data on control samples and CD, UC, and celiac disease cases were provided by the respective consortia. A discovery association study followed by meta-analysis with an independent cohort, polygenic risk score calculation, and cross-phenotype analyses were performed. Enrichment of regulatory expression quantitative trait loci among the CC variants was assessed in hemopoietic and intestinal cells. RESULTS: Three HLA alleles (HLA-B∗08:01, HLA-DRB1∗03:01, and HLA-DQB1∗02:01), related to the ancestral haplotype 8.1, were significantly associated with increased CC risk. We also identified an independent protective effect of HLA-DRB1∗04:01 on CC risk. Polygenic risk score quantifying the risk across multiple susceptibility loci was strongly associated with CC risk. An enrichment of expression quantitative trait loci was detected among the CC-susceptibility variants in various cell types. The cross-phenotype analysis identified a complex pattern of polygenic pleiotropy between CC and other immune-mediated diseases. CONCLUSIONS: In this largest genetic study of CC to date with histologically confirmed diagnosis, we strongly implicated the HLA locus and proposed potential non-HLA mechanisms in disease pathogenesis. We also detected a shared genetic risk between CC, celiac disease, CD, and UC, which supports clinical observations of comorbidity.

14.
Kidney Int ; 98(3): 758-768, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32454123

RESUMO

Donor-recipient (D-R) differences at human leukocyte antigen (HLA) loci are currently incorporated into organ sharing, allocation and immunosuppression decisions. However, while acute rejection episodes have substantially diminished, progressive histologic damage occurs in allografts and improved long-term survival remains an unrealized goal among kidney recipients. Here we tested the hypothesis that non-HLA dependent, genome-wide D-R genetic differences could contribute to unchecked alloimmunity with histologic and functional consequences, culminating in long-term allograft failure. Genome-wide single nucleotide polymorphism (SNP) array data, excluding the HLA region, was utilized from 385 transplants to study the role of D-R differences upon serial histology and allograft survival. ADMIXTURE analysis was performed to quantitatively estimate ancestry in each D-R pair and PLINK was used to estimate the proportion of genome-shared identity-by-descent (pIBD) between D-R pairs. Subsequently, quantitative measures of recipient ancestry based on non-HLA SNPs was associated with death-censored allograft survival in adjusted Cox models. In D-R pairs of similar ancestry, pIBD was significantly associated with allograft survival independent of HLA mismatches in 224 transplants. Surprisingly, pIBD and recipient ancestry were not associated with clinical or subclinical rejection at any time post-transplant. Significantly, in multivariable analysis, pIBD inversely correlated with vascular intimal fibrosis in 160 biopsies obtained less than one year which in turn was significantly associated with allograft survival. Thus, our novel data show that non-HLA D-R differences associate with early vascular intimal fibrosis and allograft survival.

15.
ACS Nano ; 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32003558

RESUMO

A two-dimensional topological insulator features (only) one bulk gap with nontrivial topology, which protects one-dimensional boundary states at the Fermi level. We find a quantum phase of matter beyond this category: a multiple topological insulator. It possesses a ladder of topological gaps; each gap protects a robust edge state. We prove a monolayer of van der Waals material PtBi2 as a two-dimensional multiple topological insulator. By means of scanning tunneling spectroscopy, we directly visualize the one-dimensional hot electron (and hole) channels with nanometer size on the samples. Furthermore, we confirm the topological protection of these channels by directly demonstrating their robustness to variations of crystal orientation, edge geometry, and sample temperature. The discovered topological hot electron materials may be applied as efficient photocatalysts in the future.

16.
Environ Int ; 137: 105508, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32007686

RESUMO

BACKGROUND/AIM: Selenium (Se) levels in pregnancy have been linked to neurobehavioral development of the offspring. DNA methylation is a potential mechanism underlying the impacts of environmental exposures on fetal development; however, very few studies have been done elucidating the role of DNA methylation linking prenatal Se and child neurobehavior. We aimed to investigate the associations between placental Se concentration and epigenome-wide DNA methylation in two U.S. cohorts, and to assess the association between Se-related DNA methylation modifications and newborns' neurobehavior. METHODS: We measured placental Se concentrations in 343 newborns enrolled in the New Hampshire Birth Cohort Study and in 141 newborns in the Rhode Island Child Health Study. Genome-wide placental DNA methylation was measured by HumanMethylation450 BeadChip, and newborn neurobehavioral development was assessed by the NICU Network Neurobehavioral Scales (NNNS). We meta-analyzed the associations between placental Se concentration and DNA methylation in each cohort, adjusting for covariates. We also fit multiple linear regression and ordinal logistic regression for methylation and newborn NNNS summary scores. RESULTS: We identified five Se-related differentially methylated CpG sites. Among them was cg09674502 (GFI1), where selenium concentration was positively associated with methylation (ß-coefficient = 1.11, FDR-adjusted p-value = 0.045), and where we observed that a one percent methylation level increase was associated with a 15% reduced odds of higher muscle tone in the arms, legs and trunk of newborns, (OR [95% Confidence Interval, CI] = 0.85 [0.77, 0.95]). We also observed for each interquartile range (IQR) increase in selenium concentration in the placenta, there was 1.76 times greater odds of higher hypotonicity (OR [95% CI] = 1.76 [1.12, 2.82]). CONCLUSIONS: Placental selenium concentration was inversely associated with muscle tone of newborns, and hypermethylation of GFI1 could be a potential mechanism underlying this association.


Assuntos
Metilação de DNA , Epigênese Genética , Comportamento do Lactente , Sistema Nervoso , Placenta , Selênio , Criança , Estudos de Coortes , Epigenoma , Feminino , Humanos , Comportamento do Lactente/efeitos dos fármacos , Recém-Nascido , Sistema Nervoso/efeitos dos fármacos , New Hampshire , Gravidez , Selênio/toxicidade
17.
Biochem Biophys Res Commun ; 522(4): 924-930, 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-31806371

RESUMO

Lysine-specific demethylase 1 (LSD1) is a well characterized transcriptional regulator functioning on the chromatin to remove mono- and di-methyl groups from lysine 4 or lysine 9 of histone 3 (H3K4 or H3K9). LSD1 also has non-transcriptional activities via targeting non-histone substrates that participate in diverse biological processes. In this report, we determined that LSD1 negatively regulates autophagy in skeletal muscle cells by promoting PTEN degradation in a transcription-independent mechanism. In C2C12 cells, LSD1 inhibition or depletion significantly induced the initiation of autophagy; and autophagy resulted from LSD1 inhibition is associated with AKT/mTORC1 inactivation. Notably, the proteins of PTEN, a prominent repressive AKT modulator, are stabilized by LSD1 inhibition despite a decrease of its mRNA levels. Further data demonstrated that LSD1 interacts with PTEN protein and enhances its ubiquitination and degradation. Together, our findings identify a novel biological function of LSD1 in autophagy, mediated by regulating the stability of PTEN and the activity of AKT/mTORC1.

18.
Cardiovasc Res ; 116(1): 63-77, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31424497

RESUMO

AIMS: Fibromuscular dysplasia (FMD) is a poorly understood disease that predominantly affects women during middle-life, with features that include stenosis, aneurysm, and dissection of medium-large arteries. Recently, plasma proteomics has emerged as an important means to understand cardiovascular diseases. Our objectives were: (i) to characterize plasma proteins and determine if any exhibit differential abundance in FMD subjects vs. matched healthy controls and (ii) to leverage these protein data to conduct systems analyses to provide biologic insights on FMD, and explore if this could be developed into a blood-based FMD test. METHODS AND RESULTS: Females with 'multifocal' FMD and matched healthy controls underwent clinical phenotyping, dermal biopsy, and blood draw. Using dual-capture proximity extension assay and nuclear magnetic resonance-spectroscopy, we evaluated plasma levels of 981 proteins and 31 lipid sub-classes, respectively. In a discovery cohort (Ncases = 90, Ncontrols = 100), we identified 105 proteins and 16 lipid sub-classes (predominantly triglycerides and fatty acids) with differential plasma abundance in FMD cases vs. controls. In an independent cohort (Ncases = 23, Ncontrols = 28), we successfully validated 37 plasma proteins and 10 lipid sub-classes with differential abundance. Among these, 5/37 proteins exhibited genetic control and Bayesian analyses identified 3 of these as potential upstream drivers of FMD. In a 3rd cohort (Ncases = 506, Ncontrols = 876) the genetic locus of one of these upstream disease drivers, CD2-associated protein (CD2AP), was independently validated as being associated with risk of having FMD (odds ratios = 1.36; P = 0.0003). Immune-fluorescence staining identified that CD2AP is expressed by the endothelium of medium-large arteries. Finally, machine learning trained on the discovery cohort was used to develop a test for FMD. When independently applied to the validation cohort, the test showed a c-statistic of 0.73 and sensitivity of 78.3%. CONCLUSION: FMD exhibits a plasma proteogenomic and lipid signature that includes potential causative disease drivers, and which holds promise for developing a blood-based test for this disease.

19.
Epigenetics ; 15(3): 215-230, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31462129

RESUMO

Copper is an essential trace nutrient and an enzymatic cofactor necessary for diverse physiological and biological processes. Copper metabolism is uniquely controlled in the placenta and changes to copper metabolism have been linked with adverse birth outcomes. We investigated associations between patterns of DNA methylation (DNAm; measured at >485 k CpG sites) and copper concentration measured from placentae in two independent mother-infant cohorts: the New Hampshire Birth Cohort Study (NHBCS, n = 306) and the Rhode Island Child Health Study (RICHS, n = 141). We identified nine copper-associated differentially methylated regions (DMRs; adjusted P < 0.05) and 15 suggestive CpGs (raw P < 1e-5). One of the most robust variably methylated CpGs associated with the expression of the antioxidant, GSTP1. Our most robust DMR negatively associates with the expression of the zinc-finger gene, ZNF197 (FDR = 4.5e-11). Genes co-expressed with ZNF197, a transcription factor, are enriched for genes that associate with birth weight in RICHS (OR = 2.9, P = 2.6e-6, N = 194), genes that are near a ZNF197 consensus binding motif (OR = 1.34, P = 0.01, N = 194), and for those classified in GO biological processes growth hormone secretion (P = 3.4e-4), multicellular organism growth (P = 3.8e-4), and molecular functions related to lipid biosynthesis (P = 1.9e-4). Further, putative transcriptional targets for ZNF197 include genes involved in copper metabolism and placentation. Our results suggest that copper metabolism is tied to DNAm in the placenta and that copper-associated patterns in DNAm may mediate normal placentation and foetal development.

20.
Am J Respir Crit Care Med ; 201(5): 564-574, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31710517

RESUMO

Rationale: Idiopathic pulmonary fibrosis (IPF) is a complex lung disease characterized by scarring of the lung that is believed to result from an atypical response to injury of the epithelium. Genome-wide association studies have reported signals of association implicating multiple pathways including host defense, telomere maintenance, signaling, and cell-cell adhesion.Objectives: To improve our understanding of factors that increase IPF susceptibility by identifying previously unreported genetic associations.Methods: We conducted genome-wide analyses across three independent studies and meta-analyzed these results to generate the largest genome-wide association study of IPF to date (2,668 IPF cases and 8,591 controls). We performed replication in two independent studies (1,456 IPF cases and 11,874 controls) and functional analyses (including statistical fine-mapping, investigations into gene expression, and testing for enrichment of IPF susceptibility signals in regulatory regions) to determine putatively causal genes. Polygenic risk scores were used to assess the collective effect of variants not reported as associated with IPF.Measurements and Main Results: We identified and replicated three new genome-wide significant (P < 5 × 10-8) signals of association with IPF susceptibility (associated with altered gene expression of KIF15, MAD1L1, and DEPTOR) and confirmed associations at 11 previously reported loci. Polygenic risk score analyses showed that the combined effect of many thousands of as yet unreported IPF susceptibility variants contribute to IPF susceptibility.Conclusions: The observation that decreased DEPTOR expression associates with increased susceptibility to IPF supports recent studies demonstrating the importance of mTOR signaling in lung fibrosis. New signals of association implicating KIF15 and MAD1L1 suggest a possible role of mitotic spindle-assembly genes in IPF susceptibility.


Assuntos
Fibrose Pulmonar Idiopática/genética , Idoso , Estudos de Casos e Controles , Proteínas de Ciclo Celular/genética , Feminino , Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Cinesina/genética , Masculino , Pessoa de Meia-Idade , Medição de Risco , Transdução de Sinais , Fuso Acromático , Serina-Treonina Quinases TOR/metabolismo
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