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1.
Artigo em Inglês | MEDLINE | ID: mdl-33021809

RESUMO

RATIONALE: The cellular and molecular landscape and translational value of commonly used models of pulmonary arterial hypertension (PAH) are poorly understood. Single-cell transcriptomics can enhance molecular understanding of preclinical models and facilitate their rational use and interpretation. OBJECTIVES: We aim to determine and prioritize dysregulated genes, pathways, and cell types in lungs of PAH rat models to assess relevance to human PAH and identify drug repositioning candidates. METHODS: Single-cell RNA-seq was performed on the lungs of monocrotaline, Sugen-hypoxia, and control rats to identify altered genes and cell types, followed by validation using flow-sorted cells, RNA in situ hybridization, and immunofluorescence. Relevance to human PAH was assessed by histology of lungs from patients and via integration with human PAH genetic loci and known disease genes. Candidate drugs were predicted using Connectivity Map. MEASUREMENTS AND MAIN RESULTS: Distinct changes in genes and pathways in numerous cell types were identified in Sugen-hypoxia and monocrotaline lungs. Widespread upregulation of NF-κB signaling and downregulation of interferon signaling was observed across cell types. Sugen-hypoxia non-classical monocytes and monocrotaline conventional dendritic cells showed particularly strong NF-κB pathway activation. Genes altered in Sugen-hypoxia non-classical monocytes were significantly enriched for PAH-associated genes and genetic variants, and candidate drugs predicted to reverse the changes were identified. An open-access online platform was developed to share single-cell data and drug candidates (http://mergeomics. RESEARCH: idre.ucla.edu/PVDSingleCell/). CONCLUSIONS: Our study revealed the distinct and shared dysregulation of genes and pathways in two commonly used PAH models for the first time at single-cell resolution and demonstrated their relevance to human PAH and utility for drug repositioning.

2.
Arterioscler Thromb Vasc Biol ; 40(10): 2527-2538, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32757649

RESUMO

OBJECTIVE: Deep vein thrombosis and pulmonary embolism referred as venous thromboembolism (VTE) are a common cause of morbidity and mortality. Plasma from healthy controls or individuals who have experienced a VTE were analyzed using metabolomics to characterize biomarkers and metabolic systems of patients with VTE. Approach and Results: Polar metabolite and lipidomic profiles from plasma collected 3 months after an incident VTE were obtained using liquid chromatography mass spectrometry. Fasting-state plasma samples from 42 patients with VTE and 42 healthy controls were measured. Plasma metabolomic profiling identified 512 metabolites forming 62 biological clusters. Multivariate analysis revealed a panel of 21 metabolites altogether capable of predicting VTE status with an area under the curve of 0.92 (P=0.00174, selectivity=0.857, sensitivity=0.971). Multiblock systems analysis revealed 25 of the 62 functional biological groups as significantly affected in the VTE group (P<0.05 to control). Complementary correlation network analysis of the dysregulated functions highlighted a subset of the lipidome composed mainly of n-3 long-chain polyunsaturated fatty acids within the predominant triglycerides as a potential regulator of the post-VTE event biological response, possibly controlling oxidative and inflammatory defence systems, and metabolic disorder associated dysregulations. Of interest was microbiota metabolites including trimethylamine N-oxide that remained associated to post incident VTE patients, highlighting a possible involvement of gut microbiota on VTE risk and relapse. CONCLUSIONS: These findings show promise for the elucidation of underlying mechanisms and the design of a diagnostic test to assess the likely efficacy of clinical care in patients with VTE.


Assuntos
Metabolismo Energético , Lipídeos/sangue , Metabolômica , Embolia Pulmonar/sangue , Biologia de Sistemas , Tromboembolia Venosa/sangue , Trombose Venosa/sangue , Adulto , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Microbioma Gastrointestinal , Humanos , Incidência , Lipidômica , Masculino , Pessoa de Meia-Idade , Embolia Pulmonar/diagnóstico por imagem , Embolia Pulmonar/epidemiologia , Recidiva , Fatores de Tempo , Tromboembolia Venosa/diagnóstico por imagem , Tromboembolia Venosa/epidemiologia , Trombose Venosa/diagnóstico por imagem , Trombose Venosa/epidemiologia
3.
Sci Rep ; 10(1): 11404, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32647159

RESUMO

There is currently no therapy to limit the development of cardiac fibrosis and consequent heart failure. We have recently shown that cardiac fibrosis post-myocardial infarction (MI) can be regulated by resident cardiac cells with a fibrogenic signature and identified by the expression of PW1 (Peg3). Here we identify αV-integrin (CD51) as an essential regulator of cardiac PW1+ cells fibrogenic behavior. We used transcriptomic and proteomic approaches to identify specific cell-surface markers for cardiac PW1+ cells and found that αV-integrin (CD51) was expressed in almost all cardiac PW1+ cells (93% ± 1%), predominantly as the αVß1 complex. αV-integrin is a subunit member of the integrin family of cell adhesion receptors and was found to activate complex of latent transforming growth factor beta (TGFß at the surface of cardiac PW1+ cells. Pharmacological inhibition of αV-integrin reduced the profibrotic action of cardiac PW1+CD51+ cells and was associated with improved cardiac function and animal survival following MI coupled with a reduced infarct size and fibrotic lesion. These data identify a targetable pathway that regulates cardiac fibrosis in response to an ischemic injury and demonstrate that pharmacological inhibition of αV-integrin could reduce pathological outcomes following cardiac ischemia.


Assuntos
Integrina alfaV/efeitos dos fármacos , Infarto do Miocárdio/tratamento farmacológico , Venenos de Serpentes/uso terapêutico , Células Estromais/efeitos dos fármacos , Animais , Células Cultivadas , Avaliação Pré-Clínica de Medicamentos , Fibrose , Integrina alfaV/fisiologia , Fatores de Transcrição Kruppel-Like/análise , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , RNA Mensageiro/biossíntese , Análise de Célula Única , Venenos de Serpentes/farmacologia , Células Estromais/química , Fator de Crescimento Transformador beta1/farmacologia
4.
Am J Hum Genet ; 107(2): 211-221, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32649856

RESUMO

Dual antiplatelet therapy reduces ischemic events in cardiovascular disease, but it increases bleeding risk. Thrombin receptors PAR1 and PAR4 are drug targets, but the role of thrombin in platelet aggregation remains largely unexplored in large populations. We performed a genome-wide association study (GWAS) of platelet aggregation in response to full-length thrombin, followed by clinical association analyses, Mendelian randomization, and functional characterization including iPSC-derived megakaryocyte and platelet experiments. We identified a single sentinel variant in the GRK5 locus (rs10886430-G, p = 3.0 × 10-42) associated with increased thrombin-induced platelet aggregation (ß = 0.70, SE = 0.05). We show that disruption of platelet GRK5 expression by rs10886430-G is associated with enhanced platelet reactivity. The proposed mechanism of a GATA1-driven megakaryocyte enhancer is confirmed in allele-specific experiments. Utilizing further data, we demonstrate that the allelic effect is highly platelet- and thrombin-specific and not likely due to effects on thrombin levels. The variant is associated with increased risk of cardiovascular disease outcomes in UK BioBank, most strongly with pulmonary embolism. The variant associates with increased risk of stroke in the MEGASTROKE, UK BioBank, and FinnGen studies. Mendelian randomization analyses in independent samples support a causal role for rs10886430-G in increasing risk for stroke, pulmonary embolism, and venous thromboembolism through its effect on thrombin-induced platelet reactivity. We demonstrate that G protein-coupled receptor kinase 5 (GRK5) promotes platelet activation specifically via PAR4 receptor signaling. GRK5 inhibitors in development for the treatment of heart failure and cancer could have platelet off-target deleterious effects. Common variants in GRK5 may modify clinical outcomes with PAR4 inhibitors, and upregulation of GRK5 activity or signaling in platelets may have therapeutic benefits.


Assuntos
Plaquetas/fisiologia , Doenças Cardiovasculares/genética , Receptores de Trombina/genética , Transdução de Sinais/genética , Trombina/genética , Alelos , Embolia/genética , Feminino , Estudo de Associação Genômica Ampla/métodos , Insuficiência Cardíaca/genética , Humanos , Pulmão/fisiologia , Masculino , Pessoa de Meia-Idade , Neoplasias/genética , Ativação Plaquetária/genética , Agregação Plaquetária/genética , Receptor PAR-1/genética , Acidente Vascular Cerebral/genética
5.
Thromb Res ; 193: 31-35, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32505996

RESUMO

INTRODUCTION: ABO blood group influence the risk of venous thromboembolism (VTE) by modifying A and B glycosyltransferases (AGT and BGT) activities that further modulates Factor VIII (FVIII) and von Willebrand Factor (VWF) plasma levels. The aim of this work was to evaluate the association of plasma GTs activities with VWF/FVIII plasma levels and VTE risk in a case-control study. MATERIALS AND METHODS: 420 cases were matched with 420 controls for age and ABO blood group. GT activities in plasma were measured using the quantitative transfer of tritiated N-acetylgalactosamine or galactose to the 2'-fucosyl-lactose and expressed in disintegration per minute/30 µL of plasma and 2 h of reaction (dpm/30 µL/2H). FVIII and VWF plasma levels were respectively measured using human FVIII-deficient plasma in a 1-stage factor assay and STA LIATEST VWF (Diagnostica Stago). RESULTS: A and B GT activities were significantly lower in cases than in controls (8119 ± 4027 vs 9682 ± 4177 dpm/30 µL/2H, p = 2.03 × 10-5, and 4931 ± 2305 vs 5524 ± 2096 dpm/30 µL/2H, p=0.043 respectively). This association was observed whatever the ABO blood groups. The ABO A1 blood group was found to explain~80% of AGT activity. After adjusting for ABO blood groups, AGT activity was not correlated to VWF/FVIII plasma levels. Conversely, there was a moderate correlation (ρ ~ 0.30) between BGT activity and VWF/ FVIII plasma levels in B blood group carriers. CONCLUSION: Work showed, for the first time, that GT activities were decreased in VTE patients in comparison to controls with the same ABO blood group. The biological mechanisms responsible for this association remained to be determined.

6.
Am J Respir Crit Care Med ; 202(4): 586-594, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32352834

RESUMO

Rationale: Idiopathic and heritable pulmonary arterial hypertension (PAH) are rare but comprise a genetically heterogeneous patient group. RNA sequencing linked to the underlying genetic architecture can be used to better understand the underlying pathology by identifying key signaling pathways and stratify patients more robustly according to clinical risk.Objectives: To use a three-stage design of RNA discovery, RNA validation and model construction, and model validation to define a set of PAH-associated RNAs and a single summarizing RNA model score. To define genes most likely to be involved in disease development, we performed Mendelian randomization (MR) analysis.Methods: RNA sequencing was performed on whole-blood samples from 359 patients with idiopathic, heritable, and drug-induced PAH and 72 age- and sex-matched healthy volunteers. The score was evaluated against disease severity markers including survival analysis using all-cause mortality from diagnosis. MR used known expression quantitative trait loci and summary statistics from a PAH genome-wide association study.Measurements and Main Results: We identified 507 genes with differential RNA expression in patients with PAH compared with control subjects. A model of 25 RNAs distinguished PAH with 87% accuracy (area under the curve 95% confidence interval: 0.791-0.945) in model validation. The RNA model score was associated with disease severity and long-term survival (P = 4.66 × 10-6) in PAH. MR detected an association between SMAD5 levels and PAH disease susceptibility (odds ratio, 0.317; 95% confidence interval, 0.129-0.776; P = 0.012).Conclusions: A whole-blood RNA signature of PAH, which includes RNAs relevant to disease pathogenesis, associates with disease severity and identifies patients with poor clinical outcomes. Genetic variants associated with lower SMAD5 expression may increase susceptibility to PAH.


Assuntos
Hipertensão Pulmonar Primária Familiar/sangue , Hipertensão Pulmonar Primária Familiar/genética , RNA/sangue , Adulto , Estudos de Coortes , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade
7.
Clin Sci (Lond) ; 134(10): 1181-1190, 2020 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-32426810

RESUMO

Autosomal dominant inherited Protein S deficiency (PSD) (MIM 612336) is a rare disorder caused by rare mutations, mainly located in the coding sequence of the structural PROS1 gene, and associated with an increased risk of venous thromboembolism. To identify the molecular defect underlying PSD observed in an extended French pedigree with seven PSD affected members in whom no candidate deleterious PROS1 mutation was detected by Sanger sequencing of PROS1 exons and their flanking intronic regions or via an multiplex ligation-dependent probe amplification (MLPA) approach, a whole genome sequencing strategy was adopted. This led to the identification of a never reported C to T substitution at c.-39 from the natural ATG codon of the PROS1 gene that completely segregates with PSD in the whole family. This substitution ACG→ATG creates a new start codon upstream of the main ATG. We experimentally demonstrated in HeLa cells that the variant generates a novel overlapping upstream open reading frame (uORF) and inhibits the translation of the wild-type PS. This work describes the first example of 5'UTR PROS1 mutation causing PSD through the creation of an uORF, a mutation that is not predicted to be deleterious by standard annotation softwares, and emphasizes the need for better exploration of such type of non-coding variations in clinical genomics.


Assuntos
Regiões 5' não Traduzidas/genética , Códon de Iniciação/genética , Mutação/genética , Biossíntese de Proteínas , Deficiência de Proteína S/genética , Proteína S/genética , Sequência de Bases , Feminino , Células HeLa , Humanos , Masculino , Linhagem , Adulto Jovem
8.
Blood ; 136(5): 533-541, 2020 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-32457982

RESUMO

Deep vein thrombosis and pulmonary embolism, collectively defined as venous thromboembolism (VTE), are the third leading cause of cardiovascular death in the United States. Common genetic variants conferring increased varying degrees of VTE risk have been identified by genome-wide association studies (GWAS). Rare mutations in the anticoagulant genes PROC, PROS1 and SERPINC1 result in perinatal lethal thrombosis in homozygotes and markedly increased VTE risk in heterozygotes. However, currently described VTE variants account for an insufficient portion of risk to be routinely used for clinical decision making. To identify new rare VTE risk variants, we performed a whole-exome study of 393 individuals with unprovoked VTE and 6114 controls. This study identified 4 genes harboring an excess number of rare damaging variants in patients with VTE: PROS1, STAB2, PROC, and SERPINC1. At STAB2, 7.8% of VTE cases and 2.4% of controls had a qualifying rare variant. In cell culture, VTE-associated variants of STAB2 had a reduced surface expression compared with reference STAB2. Common variants in STAB2 have been previously associated with plasma von Willebrand factor and coagulation factor VIII levels in GWAS, suggesting that haploinsufficiency of stabilin-2 may increase VTE risk through elevated levels of these procoagulants. In an independent cohort, we found higher von Willebrand factor levels and equivalent propeptide levels in individuals with rare STAB2 variants compared with controls. Taken together, this study demonstrates the utility of gene-based collapsing analyses to identify loci harboring an excess of rare variants with functional connections to a complex thrombotic disease.

10.
Cardiovasc Res ; 2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-32077919

RESUMO

AIMS: Diabetes is a known risk factor for coronary artery disease. There is accumulating evidence that coronary artery disease pathogenesis differs for individuals with type 1 diabetes. However, the genetic background has not been extensively studied. We aimed to discover genetic loci increasing coronary artery disease susceptibility especially in type 1 diabetes, to examine the function of these discoveries and to study the role of the known risk loci in type 1 diabetes. METHODS AND RESULTS: We performed the largest genome-wide association study to date for coronary artery disease in type 1 diabetes, comprising 4869 individuals with type 1 diabetes (cases/controls: 941/3928). Two loci reached genome-wide significance, rs1970112 in CDKN2B-AS1 (OR = 1.32, p=1.50 × 10-8), and rs6055069 on DEFB127 promoter (OR = 4.17, p=2.35 × 10-9), with consistent results in survival analysis. The CDKN2B-AS1 variant replicated (p=0.04) when adjusted for diabetic kidney disease in three additional type 1 diabetes cohorts (cases/controls: 434/3123). Furthermore, we explored the function of the lead discoveries with a cardio-phenome-wide analysis. Among the eight suggestive loci (p<1 × 10-6), rs70962766 near B3GNT2 associated with central blood pressure, rs1344228 near CNTNAP5 with intima media thickness, and rs2112481 on GRAMD2B promoter with serum leucocyte concentration. Finally, we calculated genetic risk scores for individuals with type 1 diabetes with the known susceptibility loci. General population risk variants were modestly but significantly associated with coronary artery disease also in type 1 diabetes (p=4.21 × 10-7). CONCLUSIONS: While general population coronary artery disease risk loci had limited effect on the risk in type 1 diabetes, for the first time, variants at the CDKN2B-AS1 locus were robustly associated with coronary artery disease in individuals with type 1 diabetes. The novel finding on ß-defensin DEFB127 promoter provides a link between diabetes, infection susceptibility and coronary artery disease, although pending on future confirmation. TRANSLATIONAL PERSPECTIVE: Genetic association studies enable the discovery of novel genes and genetic pathways associated with the disease. Thus, this study provides an insight into coronary artery disease mechanisms specific to type 1 diabetes. The DEFB127 discovery may lead to a therapeutic target and improve patient care, if replicated in the future. Furthermore, genetic studies on coronary artery disease in type 1 diabetes are required for accurate personalized treatment plans achieved through genetic data for those with type 1 diabetes.

11.
Biomolecules ; 10(1)2020 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-31940748

RESUMO

Cardiovascular diseases (CVDs) comprise 45% of all deaths in Europe and causes 3.9 million deaths annually. Coronary artery disease (CAD) which includes myocardial infarction (MI) represents the most common form of CVD. A relevant proportion of MI cases seems preventable since reports claim that up to two-thirds of these patients exhibit symptoms suggestive for MI within 12 months prior to the acute MI event. An early identification of these at-risk subjects is necessary to manage an early and efficient treatment during the ischemic phase. The aim of the PRecision MEDicine in Coronary Artery Disease (PREMED-CAD) consortium is to apply a system medicine approach towards studying and identifying an ischemia specific 'biomarker signature' that improves the identification of individuals 'at-risk' for acute MI. The consortium will take an interdisciplinary and translational approach integrating knowledge from CAD epidemiology, imaging, bioinformatics, statistics and molecular biology, as well as existing phenotypic, blood-based and clinical biomarker data of distinct CAD and subclinical MI phenotypes. This biomarker signature will be validated through atherosclerosis-prone mouse models and human cohorts. The validated signature will be translated in a real-world clinical setting using an ongoing clinical trial comprising patients with subclinical ischemia. The aim of the knowledge obtained from this project is to aid in early MI detection and reduce the mortality and morbidity rate in these at-risk MI individuals.

12.
Eur Respir J ; 55(2)2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31744833

RESUMO

Pulmonary arterial hypertension (PAH) is a rare disease that leads to premature death from right heart failure. It is strongly associated with elevated red cell distribution width (RDW), a correlate of several iron status biomarkers. High RDW values can signal early-stage iron deficiency or iron deficiency anaemia. This study investigated whether elevated RDW is causally associated with PAH.A two-sample Mendelian randomisation (MR) approach was applied to investigate whether genetic predisposition to higher levels of RDW increases the odds of developing PAH. Primary and secondary MR analyses were performed using all available genome-wide significant RDW variants (n=179) and five genome-wide significant RDW variants that act via systemic iron status, respectively.We confirmed the observed association between RDW and PAH (OR 1.90, 95% CI 1.80-2.01) in a multicentre case-control study (cases n=642, disease controls n=15 889). The primary MR analysis was adequately powered to detect a causal effect (odds ratio) between 1.25 and 1.52 or greater based on estimates reported in the RDW genome-wide association study or from our own data. There was no evidence for a causal association between RDW and PAH in either the primary (ORcausal 1.07, 95% CI 0.92-1.24) or the secondary (ORcausal 1.09, 95% CI 0.77-1.54) MR analysis.The results suggest that at least some of the observed association of RDW with PAH is secondary to disease progression. Results of iron therapeutic trials in PAH should be interpreted with caution, as any improvements observed may not be mechanistically linked to the development of PAH.

13.
J Neurosurg ; : 1-5, 2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31783362

RESUMO

OBJECTIVE: The authors sought to identify mRNA biomarkers of cerebral vasospasm in whole blood of patients suffering from aneurysmal subarachnoid hemorrhage (aSAH). METHODS: A prospective transcriptomic study for vasospasm was conducted in whole blood samples of 44 aSAH patients who developed (VSP+ group, n = 22) or did not develop (VSP- group, n = 22) vasospasm. Samples from all patients were profiled for 21,460 mRNA probes using the Illumina Human HT12v4.0 array. Differential statistical analysis was performed using a linear mixed model. RESULTS: Levels of sphingosine-1-phosphate receptor 4 (S1PR4) mRNA were significantly higher (p = 8.03 × 10-6) at presentation in patients who developed vasospasm after aSAH than in patients who did not. CONCLUSIONS: The results, which are consistent with findings of previous experimental investigations conducted in animal models, support the role of S1PR4 and its ligand, sphingosine-1-phosphate (S1P), in arterial-associated vasoconstriction, which suggests that S1PR4 could be used as a biomarker for cerebral vasospasm in aSAH patients.

14.
Nat Genet ; 51(11): 1574-1579, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31676865

RESUMO

Venous thromboembolism is a significant cause of mortality1, yet its genetic determinants are incompletely defined. We performed a discovery genome-wide association study in the Million Veteran Program and UK Biobank, with testing of approximately 13 million DNA sequence variants for association with venous thromboembolism (26,066 cases and 624,053 controls) and meta-analyzed both studies, followed by independent replication with up to 17,672 venous thromboembolism cases and 167,295 controls. We identified 22 previously unknown loci, bringing the total number of venous thromboembolism-associated loci to 33, and subsequently fine-mapped these associations. We developed a genome-wide polygenic risk score for venous thromboembolism that identifies 5% of the population at an equivalent incident venous thromboembolism risk to carriers of the established factor V Leiden p.R506Q and prothrombin G20210A mutations. Our data provide mechanistic insights into the genetic epidemiology of venous thromboembolism and suggest a greater overlap among venous and arterial cardiovascular disease than previously thought.


Assuntos
Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Doenças Vasculares/genética , Tromboembolia Venosa/genética , Idoso , Animais , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Inibidor 1 de Ativador de Plasminogênio/genética , Fatores de Risco , Reino Unido/epidemiologia , Doenças Vasculares/epidemiologia , Doenças Vasculares/patologia , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/patologia
15.
J Thromb Haemost ; 17(11): 1808-1814, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31271701

RESUMO

BACKGROUND: Factor V (FV) is a circulating protein primarily synthesized in the liver, and mainly present in plasma. It is a major component of the coagulation process. OBJECTIVE: To detect novel genetic loci participating to the regulation of FV plasma levels. METHODS: We conducted the first Genome Wide Association Study on FV plasma levels in a sample of 510 individuals and replicated the main findings in an independent sample of 1156 individuals. RESULTS: In addition to genetic variations at the F5 locus, we identified novel associations at the PLXDC2 locus, with the lead PLXDC2 rs927826 polymorphism explaining ~3.7% (P = 7.5 × 10-15 in the combined discovery and replication samples) of the variability of FV plasma levels. In silico transcriptomic analyses in various cell types confirmed that PLXDC2 expression is positively correlated to F5 expression. SiRNA experiments in human hepatocellular carcinoma cell line confirmed the role of PLXDC2 in modulating factor F5 gene expression, and revealed further influences on F2 and F10 expressions. CONCLUSION: Our study identified PLXDC2 as a new molecular player of the coagulation process.

16.
J Am Heart Assoc ; 8(15): e012994, 2019 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-31310728

RESUMO

Background Systemic iron status has been implicated in atherosclerosis and thrombosis. The aim of this study was to investigate the effect of genetically determined iron status on carotid intima-media thickness, carotid plaque, and venous thromboembolism using Mendelian randomization. Methods and Results Genetic instrumental variables for iron status were selected from a genome-wide meta-analysis of 48 972 subjects. Genetic association estimates for carotid intima-media thickness and carotid plaque were obtained using data from 71 128 and 48 434 participants, respectively, and estimates for venous thromboembolism were obtained using data from a study incorporating 7507 cases and 52 632 controls. Conventional 2-sample summary data Mendelian randomization was performed for the main analysis. Higher genetically determined iron status was associated with increased risk of venous thromboembolism. Odds ratios per SD increase in biomarker levels were 1.37 (95% CI 1.14-1.66) for serum iron, 1.25 (1.09-1.43) for transferrin saturation, 1.92 (1.28-2.88) for ferritin, and 0.76 (0.63-0.92) for serum transferrin (with higher transferrin levels representing lower iron status). In contrast, higher iron status was associated with lower risk of carotid plaque. Corresponding odds ratios were 0.85 (0.73-0.99) for serum iron and 0.89 (0.80-1.00) for transferrin saturation, with concordant trends for serum transferrin and ferritin that did not reach statistical significance. There was no Mendelian randomization evidence of an effect of iron status on carotid intima-media thickness. Conclusions These findings support previous work to suggest that higher genetically determined iron status is protective against some forms of atherosclerotic disease but increases the risk of thrombosis related to stasis of blood.

17.
RNA ; 25(6): 657-668, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30819774

RESUMO

Next-generation sequencing is an increasingly popular and efficient approach to characterize the full set of microRNAs (miRNAs) present in human biosamples. MiRNAs' detection and quantification still remain a challenge as they can undergo different posttranscriptional modifications and might harbor genetic variations (polymiRs) that may impact on the alignment step. We present a novel algorithm, OPTIMIR, that incorporates biological knowledge on miRNA editing and genome-wide genotype data available in the processed samples to improve alignment accuracy. OPTIMIR was applied to 391 human plasma samples that had been typed with genome-wide genotyping arrays. OPTIMIR was able to detect genotyping errors, suggested the existence of novel miRNAs and highlighted the allelic imbalance expression of polymiRs in heterozygous carriers. OPTIMIR is written in python, and freely available on the GENMED website (http://www.genmed.fr/index.php/fr/) and on Github (github.com/FlorianThibord/OptimiR).


Assuntos
Algoritmos , Genoma Humano , MicroRNAs/genética , Alinhamento de Sequência/métodos , Trombose Venosa/genética , Sequência de Bases , Biologia Computacional/métodos , Bases de Dados Genéticas , Estudo de Associação Genômica Ampla , Genótipo , Heterozigoto , Humanos , MicroRNAs/sangue , MicroRNAs/classificação , Análise de Sequência com Séries de Oligonucleotídeos , Software , Trombose Venosa/sangue , Trombose Venosa/patologia
18.
Diabetes Care ; 42(1): 93-101, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30455333

RESUMO

OBJECTIVE: Patients with type 1 diabetes and diabetic nephropathy are targets for intervention to reduce high risk of end-stage renal disease (ESRD) and deaths. This study compares risks of these outcomes in four international cohorts. RESEARCH DESIGN AND METHODS: In the 1990s and early 2000s, Caucasian patients with type 1 diabetes with persistent macroalbuminuria in chronic kidney disease stages 1-3 were identified in the Joslin Clinic (U.S., 432), Finnish Diabetic Nephropathy Study (FinnDiane) (Finland, 486), Steno Diabetes Center Copenhagen (Denmark, 368), and INSERM (France, 232) and were followed for 3-18 years with annual creatinine measurements to ascertain ESRD and deaths unrelated to ESRD. RESULTS: During 15,685 patient-years, 505 ESRD cases (rate 32/1,000 patient-years) and 228 deaths unrelated to ESRD (rate 14/1,000 patient-years) occurred. Risk of ESRD was associated with male sex; younger age; lower estimated glomerular filtration rate (eGFR); higher albumin/creatinine ratio, HbA1c, and systolic blood pressure; and smoking. Risk of death unrelated to ESRD was associated with older age, smoking, and higher baseline eGFR. In adjusted analysis, ESRD risk was highest in Joslin versus reference FinnDiane (hazard ratio [HR] 1.44, P = 0.003) and lowest in Steno (HR 0.54, P < 0.001). Differences in eGFR slopes paralleled risk of ESRD. Mortality unrelated to ESRD was lowest in Joslin (HR 0.68, P = 0.003 vs. the other cohorts). Competing risk did not explain international differences in the outcomes. CONCLUSIONS: Despite almost universal renoprotective treatment, progression to ESRD and mortality in patients with type 1 diabetes with advanced nephropathy are still very high and differ among countries. Finding causes of these differences may help reduce risk of these outcomes.


Assuntos
Diabetes Mellitus Tipo 1/mortalidade , Nefropatias Diabéticas/mortalidade , Falência Renal Crônica/mortalidade , Adulto , Albuminúria/urina , Pressão Sanguínea , Colesterol/sangue , Creatinina/sangue , Dinamarca , Diabetes Mellitus Tipo 1/sangue , Nefropatias Diabéticas/sangue , Progressão da Doença , Feminino , Finlândia , Seguimentos , França , Taxa de Filtração Glomerular , Hemoglobina A Glicada/metabolismo , Humanos , Falência Renal Crônica/sangue , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco
19.
Clin Genet ; 95(3): 356-367, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30471092

RESUMO

Left ventricular non-compaction (LVNC) is a cardiomyopathy that may be of genetic origin; however, few data are available about the yield of mutation, the spectrum of genes and allelic variations. The aim of this study was to better characterize the genetic spectrum of isolated LVNC in a prospective cohort of 95 unrelated adult patients through the molecular investigation of 107 genes involved in cardiomyopathies and arrhythmias. Fifty-two pathogenic or probably pathogenic variants were identified in 40 patients (42%) including 31 patients (32.5%) with single variant and 9 patients with complex genotypes (9.5%). Mutated patients tended to have younger age at diagnosis than patients with no identified mutation. The most prevalent genes were TTN, then HCN4, MYH7, and RYR2. The distribution includes 13 genes previously reported in LVNC and 10 additional candidate genes. Our results show that LVNC is basically a genetic disease and support genetic counseling and cardiac screening in relatives. There is a large genetic heterogeneity, with predominant TTN null mutations and frequent complex genotypes. The gene spectrum is close to the one observed in dilated cardiomyopathy but with specific genes such as HCN4. We also identified new candidate genes that could be involved in this sub-phenotype of cardiomyopathy.

20.
Diabetes ; 68(2): 441-456, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30487263

RESUMO

To identify genetic variants associated with diabetic retinopathy (DR), we performed a large multiethnic genome-wide association study. Discovery included eight European cohorts (n = 3,246) and seven African American cohorts (n = 2,611). We meta-analyzed across cohorts using inverse-variance weighting, with and without liability threshold modeling of glycemic control and duration of diabetes. Variants with a P value <1 × 10-5 were investigated in replication cohorts that included 18,545 European, 16,453 Asian, and 2,710 Hispanic subjects. After correction for multiple testing, the C allele of rs142293996 in an intron of nuclear VCP-like (NVL) was associated with DR in European discovery cohorts (P = 2.1 × 10-9), but did not reach genome-wide significance after meta-analysis with replication cohorts. We applied the Disease Association Protein-Protein Link Evaluator (DAPPLE) to our discovery results to test for evidence of risk being spread across underlying molecular pathways. One protein-protein interaction network built from genes in regions associated with proliferative DR was found to have significant connectivity (P = 0.0009) and corroborated with gene set enrichment analyses. These findings suggest that genetic variation in NVL, as well as variation within a protein-protein interaction network that includes genes implicated in inflammation, may influence risk for DR.


Assuntos
Diabetes Mellitus Tipo 2/genética , Estudo de Associação Genômica Ampla/métodos , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Retinopatia Diabética , Predisposição Genética para Doença , Genótipo , Hemoglobina A Glicada/metabolismo , Humanos , Metanálise como Assunto , Polimorfismo de Nucleotídeo Único/genética , Ligação Proteica
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