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1.
Biomark Med ; 13(16): 1373-1386, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31617736

RESUMO

Aim: Management of patients with infections within the Emergency Department (ED) is challenging for practitioners, as the identification of infectious causes remains difficult with current techniques. A new combination of two biomarkers was tested with a new rapid flow cytometry technique. Materials & methods: Subjects from the ED were tested for their CD64 on neutrophils (nCD64) and CD169 on monocytes (mCD169) levels and results were compared to their clinical records. Results: Among 139 patients, 29% had confirmed bacterial infections and 5% viral infections. nCD64 and mCD169 respectively showed 88 and 86% sensitivity and 90 and 100% specificity for identifying subjects in bacterial or viral conditions. Conclusion: This point-of-care technique could allow better management of patients in the ED.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31630203

RESUMO

OBJECTIVES: Non-conventional aPL have been described in patients presenting clinical manifestations of antiphospholipid syndrome but negative for conventional markers. Among them, detection of autoantibodies against prothrombin has been proposed to improve diagnosis and management of these patients. However autoantibodies against prothrombin are heterogeneous and their use in clinical practice still remains unclear. The aim of this study was to evaluate the interest of IgG and IgM autoantibodies directed against the prothrombin only (aPT). METHODS: We retrospectively studied IgM and IgG aPT results, conventional antiphospholipid syndrome markers and clinical data of a large cohort of 441 patients referred for antiphospholipid syndrome exploration with aPT detection over a period of 5 years. RESULTS: We observed a total prevalence of 17% of aPT-positive patients (75/441). A significant association was found between aPT and thrombosis (P = 0.035), with 70% of patients having unexplained thrombosis, aPT representing the sole aPL detected. aPT positivity was significantly more frequent in venous thrombosis than in arterial thrombosis (P = 0.004). Interestingly, we demonstrated for the first time that aPT IgG levels were higher in recurrent thrombosis than in isolated thrombosis (P = 0.013), leading us to propose a predictive level of recurrence for thrombosis. CONCLUSION: Our results show that aPT are associated with thrombosis and demonstrate the interest of assessing both IgG and IgM aPT, in particular in venous thrombosis when conventional markers are negative. Quantification of aPT could predict recurrence of thrombosis and influence subsequent treatment strategy. Prospective clinical studies are now required to confirm these results.

3.
J Thromb Haemost ; 17(11): 1808-1814, 2019 Nov.
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.

4.
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
5.
Genet Epidemiol ; 43(4): 449-457, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30659681

RESUMO

Although recent Genome-Wide Association Studies have identified novel associations for common variants, there has been no comprehensive exome-wide search for low-frequency variants that affect the risk of venous thromboembolism (VTE). We conducted a meta-analysis of 11 studies comprising 8,332 cases and 16,087 controls of European ancestry and 382 cases and 1,476 controls of African American ancestry genotyped with the Illumina HumanExome BeadChip. We used the seqMeta package in R to conduct single variant and gene-based rare variant tests. In the single variant analysis, we limited our analysis to the 64,794 variants with at least 40 minor alleles across studies (minor allele frequency [MAF] ~0.08%). We confirmed associations with previously identified VTE loci, including ABO, F5, F11, and FGA. After adjusting for multiple testing, we observed no novel significant findings in single variant or gene-based analysis. Given our sample size, we had greater than 80% power to detect minimum odds ratios greater than 1.5 and 1.8 for a single variant with MAF of 0.01 and 0.005, respectively. Larger studies and sequence data may be needed to identify novel low-frequency and rare variants associated with VTE risk.


Assuntos
Exoma/genética , Estudo de Associação Genômica Ampla/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Análise em Microsséries/métodos , Tromboembolia Venosa/genética , Afro-Americanos/genética , Alelos , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Sequenciamento de Nucleotídeos em Larga Escala/estatística & dados numéricos , Humanos , Masculino , Análise em Microsséries/estatística & dados numéricos , Razão de Chances , Polimorfismo de Nucleotídeo Único , Tamanho da Amostra , Tromboembolia Venosa/etnologia
7.
Sci Transl Med ; 10(457)2018 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-30185651

RESUMO

The thymus is the primary lymphoid organ where naïve T cells are generated; however, with the exception of age, the parameters that govern its function in healthy humans remain unknown. We characterized the variability of thymic function among 1000 age- and sex-stratified healthy adults of the Milieu Intérieur cohort, using quantification of T cell receptor excision circles (TRECs) in peripheral blood T cells as a surrogate marker of thymopoiesis. Age and sex were the only nonheritable factors identified that affect thymic function. TREC amounts decreased with age and were higher in women compared to men. In addition, a genome-wide association study revealed a common variant (rs2204985) within the T cell receptor TCRA-TCRD locus, between the DD2 and DD3 gene segments, which associated with TREC amounts. Strikingly, transplantation of human hematopoietic stem cells with the rs2204985 GG genotype into immunodeficient mice led to thymopoiesis with higher TRECs, increased thymocyte counts, and a higher TCR repertoire diversity. Our population immunology approach revealed a genetic locus that influences thymopoiesis in healthy adults, with potentially broad implications in precision medicine.

8.
Blood ; 132(17): 1842-1850, 2018 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-30042098

RESUMO

Many hemostatic factors are associated with age and age-related diseases; however, much remains unknown about the biological mechanisms linking aging and hemostatic factors. DNA methylation is a novel means by which to assess epigenetic aging, which is a measure of age and the aging processes as determined by altered epigenetic states. We used a meta-analysis approach to examine the association between measures of epigenetic aging and hemostatic factors, as well as a clotting time measure. For fibrinogen, we performed European and African ancestry-specific meta-analyses which were then combined via a random effects meta-analysis. For all other measures we could not estimate ancestry-specific effects and used a single fixed effects meta-analysis. We found that 1-year higher extrinsic epigenetic age as compared with chronological age was associated with higher fibrinogen (0.004 g/L/y; 95% confidence interval, 0.001-0.007; P = .01) and plasminogen activator inhibitor 1 (PAI-1; 0.13 U/mL/y; 95% confidence interval, 0.07-0.20; P = 6.6 × 10-5) concentrations, as well as lower activated partial thromboplastin time, a measure of clotting time. We replicated PAI-1 associations using an independent cohort. To further elucidate potential functional mechanisms, we associated epigenetic aging with expression levels of the PAI-1 protein encoding gene (SERPINE1) and the 3 fibrinogen subunit-encoding genes (FGA, FGG, and FGB) in both peripheral blood and aorta intima-media samples. We observed associations between accelerated epigenetic aging and transcription of FGG in both tissues. Collectively, our results indicate that accelerated epigenetic aging is associated with a procoagulation hemostatic profile, and that epigenetic aging may regulate hemostasis in part via gene transcription.

10.
Nat Commun ; 9(1): 554, 2018 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-29396438

RESUMO

The original version of this Article contained an error in the title, which was incorrectly given as 'APRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients'. This has now been corrected in both the PDF and HTML versions of the Article to read 'A PRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients'.

11.
Pharmacol Res ; 131: 211-217, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29452290

RESUMO

Severely obese patients undergoing bariatric surgery (BS) are at increased risk for venous thromboembolism (VTE). How standard low molecular weight heparin (LMWH) regimen should be adapted to provide both sufficient efficacy and safety in this setting is unclear. We aimed to compare the influence of four body size descriptors (BSD) on peak anti-Xa levels in BS obese patients receiving LMWH fixed doses to identify which one had the greatest impact. One hundred and thirteen BS obese patients [median body mass index (BMI), 43.3 kg/m2 (IQR, 40.6-48.7 kg/m2)] receiving subcutaneous dalteparin 5000 IU twice daily were included in this prospective monocenter study. Peak steady-state anti-Xa levels were measured peri-operatively following thromboprophylaxis initiation. Only 48% of patients achieved target anti-Xa levels (0.2-0.5 IU/ml). In univariate analysis, age, gender, total body-weight (TBW), lean body-weight (LBW), ideal body-weight (IBW), BMI and estimated glomerural filtration rate (eGFR) were associated with anti-Xa levels. The strongest negative association was observed with LBW (r = -0.56, p < .0001). Receiver operating characteristic curves indicated that among BSD, LBW (cut-off >55.8 kg) had the highest sensitivity (73%) and specificity (69%) to predict sub-prophylactic anti-Xa levels. In multivariate analysis, LBW and eGFR remained associated with anti-Xa levels (ß = -0.47 ±â€¯0.08, p < .0001 and ß = -0.19 ±â€¯0.08; p = .02, respectively). In BS morbidly obese patients receiving LMWH for thromboprophylaxis after BS, LBW and eGFR are the main determinants of anti-Xa level, and could be proposed in LMWH-based thromboprophylaxis dosing algorithms. The efficacy of a LBW-scale based dosing algorithm for optimal VTE prevention deserves further prospective randomized trials.

12.
Nat Commun ; 9(1): 67, 2018 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-29302025

RESUMO

To date, epimutations reported in man have been somatic and erased in germlines. Here, we identify a cause of the autosomal recessive cblC class of inborn errors of vitamin B12 metabolism that we name "epi-cblC". The subjects are compound heterozygotes for a genetic mutation and for a promoter epimutation, detected in blood, fibroblasts, and sperm, at the MMACHC locus; 5-azacytidine restores the expression of MMACHC in fibroblasts. MMACHC is flanked by CCDC163P and PRDX1, which are in the opposite orientation. The epimutation is present in three generations and results from PRDX1 mutations that force antisense transcription of MMACHC thereby possibly generating a H3K36me3 mark. The silencing of PRDX1 transcription leads to partial hypomethylation of the epiallele and restores the expression of MMACHC. This example of epi-cblC demonstrates the need to search for compound epigenetic-genetic heterozygosity in patients with typical disease manifestation and genetic heterozygosity in disease-causing genes located in other gene trios.


Assuntos
Proteínas de Transporte/genética , Epistasia Genética , Erros Inatos do Metabolismo/genética , Mutação , Peroxirredoxinas/genética , Vitamina B 12/metabolismo , Alelos , Azacitidina/farmacologia , Sequência de Bases , Inibidores Enzimáticos/farmacologia , Saúde da Família , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Heterozigoto , Humanos , Masculino , Erros Inatos do Metabolismo/metabolismo , Linhagem , Sequenciamento Completo do Genoma
13.
Platelets ; 29(1): 95-97, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28960123

RESUMO

BACKGROUND: Light transmission aggregometry (LTA) is considered as the gold standard for testing platelet function in the setting of both platelet disorders suspicion and response to antiplatelet therapy evaluation. LTA requires however specialized equipment, substantial blood sample volumes, is technically challenging and time-consuming. AIM: To evaluate an automated platelet aggregation method performed on a routine coagulation analyzer Sysmex CS-2000i. METHODS: 46 patients presenting a bleeding syndrome and 62 patients with acute coronary syndrome receiving dual antiplatelet therapy were studied in total. Platelet aggregations were performed on CS-2000i equipped with a dedicated software and on APACT-4004 (Elitech, France) as the reference instrument. Aggregation was measured by monitoring the changes in light absorbance occurring in response to ADP 2.5, 5 and 10µM, collagen 3.3 µg/mL, epinephrin 10µM, ristocetin 1.25 mg/mL and arachidonic acid 0.5 mg/mL in platelet rich plasma (PRP). PRP were tested simultaneously on both CS-2000i and APACT-4004 devices. Platelet stirred speed were 800 rpm for both instruments. RESULTS: Significant correlations were observed between CS-2000i and LTA after all stimulations (p< 0.001). Patients presenting a bleeding syndrome had similar aggregation profiles with both methods. A single patient presented a severe platelet disorder (Glanzmann Thrombasthenia) and its PRP showed defective aggregation in response to all agonists except ristocetin with both instruments. Finally, the inter-agreement rates for CS-2000i and APACT-4004 to detect low responders to thienopyridines or aspirine were strong (weighted kappa> 0.70). CONCLUSION: Platelet aggregation on the routine coagulation analyzer CS-2000i is an easily accessible, handy, reliable, standardized, and rapid tool to assess platelet function which allows to skirt most of the LTA limitations.


Assuntos
Testes de Coagulação Sanguínea/métodos , Testes de Função Plaquetária/métodos , Biomarcadores/sangue , Testes de Coagulação Sanguínea/instrumentação , Transtornos Plaquetários/sangue , Transtornos Plaquetários/diagnóstico , Transtornos Plaquetários/tratamento farmacológico , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Humanos , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/farmacologia , Inibidores da Agregação de Plaquetas/uso terapêutico , Testes de Função Plaquetária/instrumentação , Reprodutibilidade dos Testes
14.
Br J Haematol ; 180(3): 335-345, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29082522

RESUMO

Venous thromboembolism (VTE) has a strong genetic component. This review summarizes what is known at the seventeen genes that are now well established to harbour VTE-associated genetic variants. In addition, it discusses additional candidate genes that deserve further validation before being claimed as VTE associated genes. Finally, several research strategies are briefly described to identify other molecular determinants of the disease.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Tromboembolia Venosa/genética , Alelos , Animais , Loci Gênicos , Variação Genética , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos
15.
JACC Cardiovasc Interv ; 10(24): 2560-2570, 2017 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-29268886

RESUMO

OBJECTIVES: This study sought to evaluate the impact of initial platelet reactivity on the benefit of switched strategy. BACKGROUND: TOPIC (Timing Of Platelet Inhibition after acute Coronary Syndrome) study suggested that switched dual antiplatelet therapy (DAPT) could improve net clinical benefit after acute coronary syndrome by preventing bleeding. METHODS: Acute coronary syndrome patients, 1 month after coronary stenting and event free, were randomly assigned to aspirin and clopidogrel (switched DAPT) or continuation of drug regimen (unchanged DAPT). All patients underwent platelet function testing at this time and were classified as low on-treatment platelet reactivity (LTPR) (platelet reactivity index vasodilator-stimulated phosphoprotein ≤20%) or non-LTPR (platelet reactivity index vasodilator-stimulated phosphoprotein >20%). The primary endpoint aimed to evaluate the impact of platelet reactivity on clinical outcomes and benefit of switched DAPT strategy. RESULTS: A total of 645 patients were included, 305 (47%) of whom were classified as LTPR. LTPR patients were less often diabetic (p = 0.01), had lower body mass index (p < 0.01), and were more often on ticagrelor (p < 0.01). Patients defined as LTPR and randomized to unchanged DAPT were at the highest risk of primary endpoint occurrence (31%; p < 0.01). Conversely, in the switched arm, LTPR patients had no significant difference in primary outcome incidence compared with non-LTPR patients (hazard ratio [HR]: 0.78; 95% confidence interval [CI]: 0.40 to 1.49; p = 0.45). The switched strategy was associated with important reduction in primary endpoint incidence in LTPR patients (HR: 0.29; 95% CI: 0.17 to 0.51; p < 0.01) and only numerically lower incidence in non-LTPR patients (HR: 0.79; 95% CI: 0.46 to 1.35; p = 0.39). CONCLUSIONS: Switched DAPT was superior regardless of initial platelet reactivity but the benefit was greater in LTPR patients. Indeed, the switched strategy was highly effective in this group, which had impaired prognosis with unchanged DAPT but similar prognosis after switching.

16.
Platelets ; : 1-7, 2017 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-29172822

RESUMO

Bivalirudin is associated with an increased risk of acute stent thrombosis (AST) compared to unfractionated heparin (UFH) in acute coronary syndrome patients (ACS) during short-duration percutaneous coronary intervention (PCI). The mechanisms involved are unknown. We aimed to investigate the antithrombotic efficacy of bivalirudin compared to UFH during PCI. In a monocenter study, we prospectively enrolled 30 patients undergoing PCI for a non-ST elevation ACS. They were randomly assigned to a single intravenous (IV) bolus of UFH (70 IU/kg) or an IV bolus of bivalirudin 0.75 mg/kg followed by a 1.75 mg/kg/h infusion during PCI. All patients received a loading dose (LD) of 180 mg of ticagrelor at the time of PCI. The VASP index and activated partial thromboplastin time (aPTT) were used to assess the course of platelet reactivity (PR) and antithrombotic activity. The two groups were similar regarding baseline, angiographic, and interventional characteristics. There was no difference between the two groups in the course of PR following ticagrelor LD. An optimal PR inhibition was obtained 4 h after the LD of ticagrelor. The level of antithrombotic activity was significantly lower in the bivalirudin group compared to the UFH group (p < 0.001) during PCI but similar at 2 and 4 h post-PCI. We observed that, in ACS undergoing PCI, the antithrombotic efficacy of an IV bolus of bivalirudin is significantly lower than that of a 70-IU/kg UFH bolus. This could contribute to the excess in thrombotic acute events observed during short-duration PCI.

17.
PLoS One ; 12(10): e0182472, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29084233

RESUMO

BACKGROUND: DNA methylation is affected by the activities of the key enzymes and intermediate metabolites of the one-carbon pathway, one of which involves homocysteine. We investigated the effect of the well-known genetic variant associated with mildly elevated homocysteine: MTHFR 677C>T independently and in combination with other homocysteine-associated variants, on genome-wide leukocyte DNA-methylation. METHODS: Methylation levels were assessed using Illumina 450k arrays on 9,894 individuals of European ancestry from 12 cohort studies. Linear-mixed-models were used to study the association of additive MTHFR 677C>T and genetic-risk score (GRS) based on 18 homocysteine-associated SNPs, with genome-wide methylation. RESULTS: Meta-analysis revealed that the MTHFR 677C>T variant was associated with 35 CpG sites in cis, and the GRS showed association with 113 CpG sites near the homocysteine-associated variants. Genome-wide analysis revealed that the MTHFR 677C>T variant was associated with 1 trans-CpG (nearest gene ZNF184), while the GRS model showed association with 5 significant trans-CpGs annotated to nearest genes PTF1A, MRPL55, CTDSP2, CRYM and FKBP5. CONCLUSIONS: Our results do not show widespread changes in DNA-methylation across the genome, and therefore do not support the hypothesis that mildly elevated homocysteine is associated with widespread methylation changes in leukocytes.


Assuntos
Metilação de DNA , Homocisteína/metabolismo , Leucócitos/metabolismo , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Adulto , Cromossomos Humanos Par 6 , Estudos de Coortes , Ilhas de CpG , Humanos , Polimorfismo de Nucleotídeo Único
18.
Epigenomics ; 9(11): 1403-1422, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28990796

RESUMO

AIM: Homocysteine (Hcy) is a sensitive marker of one-carbon metabolism. Higher Hcy levels have been associated with global DNA hypomethylation. We investigated the association between plasma Hcy and epigenome-wide DNA methylation in leukocytes. METHODS: Methylation was measured using Illumina 450 k arrays in 2035 individuals from six cohorts. Hcy-associated differentially methylated positions and regions were identified using meta-analysis. RESULTS: Three differentially methylated positions cg21607669 (SLC27A1), cg26382848 (AJUBA) and cg10701000 (KCNMA1) at chromosome 19, 14 and 10, respectively, were significantly associated with Hcy. In addition, we identified 68 Hcy-associated differentially methylated regions, the most significant of which was a 1.8-kb spanning domain (TNXB/ATF6B) at chromosome 6. CONCLUSION: We identified novel epigenetic loci associated with Hcy levels, of which specific role needs to be further validated.


Assuntos
Metilação de DNA , Epigênese Genética , Homocisteína/sangue , Leucócitos/metabolismo , Fatores de Transcrição de Zíper de Leucina Básica/genética , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Proteínas de Transporte de Ácido Graxo/genética , Proteínas de Transporte de Ácido Graxo/metabolismo , Feminino , Estudo de Associação Genômica Ampla , Humanos , Proteínas com Domínio LIM/genética , Proteínas com Domínio LIM/metabolismo , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/genética , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/metabolismo , Masculino , Tenascina/genética , Tenascina/metabolismo
19.
Thromb Res ; 158: 102-107, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28866378

RESUMO

OBJECTIVE: The association between impaired kidney function and venous thrombosis has been previously reported but supportive data are still sparse. We here wish to strengthen this association by investigating, by use of a genetic risk score approach, whether single nucleotide polymorphisms (SNPs) known to decrease the estimated glomerular filtration rate (eGFR), a surrogate marker for renal dysfunction, are associated with increased risk of venous thrombosis. APPROACH AND RESULTS: Fifty-one polymorphisms selected from the literature to robustly associate with eGFR were first tested for association with venous thrombosis in a French case-control collection of 1953 patients and 2338 healthy individuals. This led to the identification of a genetic risk score based on 9 polymorphisms that strongly associated with increased risk (odds ratio (OR)=1.09 [1.06-1.15], p=1.44·10-7). This genetic score association replicated (OR=1.18 [1.11-1.26], p=8.86·10-8) in an independent sample of 1289 patients and 1049 healthy controls part of the Dutch MEGA study. We then categorized the genetic score distribution observed in the combined samples into quintiles. Compared with the lowest quintile, the OR for increased risk of disease associated with the second, third, fourth and fifth quintiles were 1.13 [0.94-1.16], 1.47 [1.22-1.77], 1.52 [1.26-1.82] and 1.70 [1.41-2.05], respectively. CONCLUSIONS: Using a genetic risk score analysis, our study provides new elements supporting the association between impaired renal function and the risk of venous thrombosis.


Assuntos
Trombose Venosa/etiologia , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Risco , Fatores de Risco , Trombose Venosa/genética
20.
Sci Rep ; 7(1): 11207, 2017 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-28894120

RESUMO

Efficient interventions to reduce blood triglycerides are few; newer and more tolerable intervention targets are needed. Understanding the molecular mechanisms underlying blood triglyceride levels variation is key to identifying new therapies. To explore the role of epigenetic mechanisms on triglyceride levels, a blood methylome scan was conducted in 199 individuals from 5 French-Canadian families ascertained on venous thromboembolism, and findings were replicated in 324 French unrelated patients with venous thromboembolism. Genetic context and functional relevance were investigated. Two DNA methylation sites associated with triglyceride levels were identified. The first one, located in the ABCG1 gene, was recently reported, whereas the second one, located in the promoter of the PHGDH gene, is novel. The PHGDH methylation site, cg14476101, was found to be associated with variation in triglyceride levels in a threshold manner: cg14476101 was inversely associated with triglyceride levels only when triglyceride levels were above 1.12 mmol/L (discovery P-value = 8.4 × 10-6; replication P-value = 0.0091). Public databases findings supported a functional role of cg14476101 on PHGDH expression. PHGDH catalyses the first step in the serine biosynthesis pathway. These findings highlight the role of epigenetic regulation of the PHGDH gene in triglyceride metabolism, providing novel insights on putative intervention targets.

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