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4.
Transfus Apher Sci ; 58(4): 386-391, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31307835

RESUMO

Adequate function of the coagulation system is vital for an uncomplicated outcome of surgery. Clinically relevant perioperative bleeding complications may occur when surgical hemostasis is inadequate, but can also be caused by insufficient activity of the hemostatic system. Optimal surgical hemostasis and a satisfactory function of the coagulation system are complementary. In this article current insights on normal function and dysfunction of the coagulation system are reviewed as well as drugs that may affect a proper hemostatic response. We discuss coagulation disorders resulting in increased perioperative blood loss and conditions that may enhance the threat of postoperative thrombosis.

6.
Blood ; 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31217188

RESUMO

To identify novel causes of hereditary thrombocytopenia, we performed a genetic association analysis of whole-genome sequencing (WGS) data from 13,037 individuals enrolled in the NIHR BioResource, including 233 cases with isolated thrombocytopenia. We found an association between rare variants in the transcription factor (TF)-encoding gene IKZF5 and thrombocytopenia. We report five causal missense variants in or near IKZF5 zinc fingers (Znfs), of which two occurred de novo and three co-segregated in three pedigrees. A canonical DNA-Znf binding model predicts that three of the variants alter DNA recognition. Expression studies showed that chromatin binding was disrupted in mutant compared to wild-type (WT) IKZF5 and electron microscopy (EM) revealed a reduced quantity of alpha granules in normally sized platelets. Proplatelet formation (PPF) was reduced in megakaryocytes (MKs) from seven cases relative to six controls. Comparison of RNA-seq data from platelets, monocytes, neutrophils and CD4+ T-cells from three cases and 14 healthy controls showed 1,194 differentially expressed genes (DEGs) in platelets but only four DEGs in each of the other blood cell types. In conclusion, IKZF5 is a novel transcriptional regulator of megakaryopoiesis and the eighth transcription factor associated with dominant thrombocytopenia in humans.

7.
Blood ; 2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31064749

RESUMO

A targeted high-throughput sequencing (HTS) panel test for clinical diagnostics requires careful consideration of the inclusion of appropriate diagnostic-grade genes, the ability to detect multiple types of genomic variation with high levels of analytic sensitivity and reproducibility, and variant interpretation by a multi-disciplinary team (MDT) in the context of the clinical phenotype. We have sequenced 2,396 index patients using the ThromboGenomics HTS panel test of diagnostic-grade genes known to harbour variants associated with rare bleeding, thrombotic or platelet disorders (BTPD). The molecular diagnostic rate was determined by the clinical phenotype, with an overall rate of 49.2% for all thrombotic, coagulation, platelet count and function disorder patients and a rate of 3.2% for patients with unexplained bleeding disorders characterized by normal hemostasis test results. The MDT classified 745 unique variants, including copy number and intronic variants, as Pathogenic, Likely Pathogenic or Variants of Uncertain Significance. Half (50.9%) of these variants are novel and 41 unique variants were identified in 7 genes recently found to be implicated in BTPD. Inspection of canonical hemostasis pathways identified 29 patients with evidence of oligogenic inheritance. A molecular diagnosis has been reported for 894 index patients providing evidence that introducing an HTS genetic test is a valuable addition to laboratory diagnostics in patients with a high likelihood of having an inherited BTPD.

8.
Nat Genet ; 51(3): 452-469, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30778226

RESUMO

Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.


Assuntos
Predisposição Genética para Doença/genética , Variação Genética/genética , Homeostase/genética , Lipídeos/genética , Proteínas/genética , Animais , Distribuição da Gordura Corporal/métodos , Índice de Massa Corporal , Estudos de Casos e Controles , Drosophila/genética , Exoma/genética , Feminino , Frequência do Gene/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Fatores de Risco , Relação Cintura-Quadril/métodos
9.
Br J Haematol ; 185(2): 207-208, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30729496
10.
Haematologica ; 104(6): 1256-1267, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30545925

RESUMO

In combination with microspotting, whole-blood microfluidics can provide high-throughput information on multiple platelet functions in thrombus formation. Based on assessment of the inter- and intra-subject variability in parameters of microspot-based thrombus formation, we aimed to determine the platelet factors contributing to this variation. Blood samples from 94 genotyped healthy subjects were analyzed for conventional platelet phenotyping: i.e. hematologic parameters, platelet glycoprotein (GP) expression levels and activation markers (24 parameters). Furthermore, platelets were activated by ADP, CRP-XL or TRAP. Parallel samples were investigated for whole-blood thrombus formation (6 microspots, providing 48 parameters of adhesion, aggregation and activation). Microspots triggered platelet activation through GP Ib-V-IX, GPVI, CLEC-2 and integrins. For most thrombus parameters, inter-subject variation was 2-4 times higher than the intra-subject variation. Principal component analyses indicated coherence between the majority of parameters for the GPVI-dependent microspots, partly linked to hematologic parameters, and glycoprotein expression levels. Prediction models identified parameters per microspot that were linked to variation in agonist-induced αIIbß3 activation and secretion. Common sequence variation of GP6 and FCER1G, associated with GPVI-induced αIIbß3 activation and secretion, affected parameters of GPVI-and CLEC-2-dependent thrombus formation. Subsequent analysis of blood samples from patients with Glanzmann thrombasthenia or storage pool disease revealed thrombus signatures of aggregation-dependent parameters that were subject-dependent, but not linked to GPVI activity. Taken together, this high-throughput elucidation of thrombus formation revealed patterns of inter-subject differences in platelet function, which were partly related to GPVI-induced activation and common genetic variance linked to GPVI, but also included a distinct platelet aggregation component.

11.
Expert Rev Hematol ; 11(8): 663-672, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29999440

RESUMO

INTRODUCTION: Activation of the hemostatic system can occur in many clinical conditions. However, a systemic and strong activation of coagulation complicating clinical settings such as sepsis, trauma or malignant disease may result in the occurrence disseminated intravascular coagulation (DIC). Areas covered: This article reviews the clinical manifestation and relevance of DIC, the various conditions that may precipitate DIC and the pathogenetic pathways underlying the derangement of the hemostatic system, based on clinical and experimental studies. In addition, the (differential) diagnostic approach to DIC is discussed. Expert commentary: In recent years a lot of precise insights in the pathophysiology of DIC have been uncovered, leading to a better understanding of pathways leading to the hemostatic derangement and providing points of impact for better adjunctive treatment strategies. In addition, simple diagnostic algorithms have been developed and validated to establish a diagnosis of DIC in clinical practice.

13.
Nat Genet ; 50(5): 766-767, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29549330

RESUMO

In the version of this article originally published, one of the two authors with the name Wei Zhao was omitted from the author list and the affiliations for both authors were assigned to the single Wei Zhao in the author list. In addition, the ORCID for Wei Zhao (Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA) was incorrectly assigned to author Wei Zhou. The errors have been corrected in the HTML and PDF versions of the article.

14.
Nat Genet ; 50(1): 26-41, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29273807

RESUMO

Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.

15.
BioData Min ; 10: 25, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28770004

RESUMO

BACKGROUND: The genetic etiology of human lipid quantitative traits is not fully elucidated, and interactions between variants may play a role. We performed a gene-centric interaction study for four different lipid traits: low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglycerides (TG). RESULTS: Our analysis consisted of a discovery phase using a merged dataset of five different cohorts (n = 12,853 to n = 16,849 depending on lipid phenotype) and a replication phase with ten independent cohorts totaling up to 36,938 additional samples. Filters are often applied before interaction testing to correct for the burden of testing all pairwise interactions. We used two different filters: 1. A filter that tested only single nucleotide polymorphisms (SNPs) with a main effect of p < 0.001 in a previous association study. 2. A filter that only tested interactions identified by Biofilter 2.0. Pairwise models that reached an interaction significance level of p < 0.001 in the discovery dataset were tested for replication. We identified thirteen SNP-SNP models that were significant in more than one replication cohort after accounting for multiple testing. CONCLUSIONS: These results may reveal novel insights into the genetic etiology of lipid levels. Furthermore, we developed a pipeline to perform a computationally efficient interaction analysis with multi-cohort replication.

16.
Br J Haematol ; 179(3): 363-376, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28612396

RESUMO

Inherited bleeding disorders affect between 1 in 1000 individuals for the most common disorder, von Willebrand Disease, to only 8 reported cases worldwide of alpha-2-antiplasmin deficiency. Those with an identifiable abnormality can be divided into disorders of coagulation factors (87%), platelet count and function (8%) and the fibrinolytic system (3%). Of the patients registered in the UK with a bleeding disorder, the remaining 2% are unclassifiable. In addition to bleeding symptoms, patients with an inherited bleeding disorder can manifest other abnormalities, making an accurate and complete diagnosis that reflects the underlying molecular pathology important. Although some inherited bleeding disorders can still be easily diagnosed through a combination of careful clinical assessment and laboratory assays of varying degrees of complexity, there are many where conventional approaches are inadequate. Improvements in phenotyping assays have enhanced our diagnostic armoury but genotyping now offers the most accurate and complete diagnosis for some of these conditions. The advent of next generation sequencing technology has meant that many genes can now be analysed routinely in clinical practice. Here, we discuss the different diagnostic tools currently available for inherited bleeding disorders and suggest that genotyping should be incorporated at an early stage in the diagnostic pathway.


Assuntos
Transtornos Herdados da Coagulação Sanguínea/diagnóstico , Genômica/métodos , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Transtornos Herdados da Coagulação Sanguínea/genética , Transtornos Plaquetários/diagnóstico , Transtornos Plaquetários/genética , Diagnóstico Diferencial , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Achados Incidentais , Exame Físico/métodos , Testes de Função Plaquetária/métodos , Doenças de von Willebrand/diagnóstico , Doenças de von Willebrand/genética
17.
Blood ; 129(4): 520-524, 2017 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-28064200

RESUMO

The von Willebrand receptor complex, which is composed of the glycoproteins Ibα, Ibß, GPV, and GPIX, plays an essential role in the earliest steps in hemostasis. During the last 4 decades, it has become apparent that loss of function of any 1 of 3 of the genes encoding these glycoproteins (namely, GP1BA, GP1BB, and GP9) leads to autosomal recessive macrothrombocytopenia complicated by bleeding. A small number of variants in GP1BA have been reported to cause a milder and dominant form of macrothrombocytopenia, but only 2 tentative reports exist of such a variant in GP1BB By analyzing data from a collection of more than 1000 genome-sequenced patients with a rare bleeding and/or platelet disorder, we have identified a significant association between rare monoallelic variants in GP1BB and macrothrombocytopenia. To strengthen our findings, we sought further cases in 2 additional collections in the United Kingdom and Japan. Across 18 families exhibiting phenotypes consistent with autosomal dominant inheritance of macrothrombocytopenia, we report on 27 affected cases carrying 1 of 9 rare variants in GP1BB.


Assuntos
Plaquetas/metabolismo , Hemorragia/genética , Mutação , Complexo Glicoproteico GPIb-IX de Plaquetas/genética , Trombocitopenia/genética , Alelos , Plaquetas/patologia , Estudos de Casos e Controles , Feminino , Expressão Gênica , Genes Dominantes , Genoma Humano , Hemorragia/diagnóstico , Hemorragia/metabolismo , Hemorragia/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Linhagem , Contagem de Plaquetas , Trombocitopenia/diagnóstico , Trombocitopenia/metabolismo , Trombocitopenia/patologia
18.
Cell ; 167(5): 1415-1429.e19, 2016 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-27863252

RESUMO

Many common variants have been associated with hematological traits, but identification of causal genes and pathways has proven challenging. We performed a genome-wide association analysis in the UK Biobank and INTERVAL studies, testing 29.5 million genetic variants for association with 36 red cell, white cell, and platelet properties in 173,480 European-ancestry participants. This effort yielded hundreds of low frequency (<5%) and rare (<1%) variants with a strong impact on blood cell phenotypes. Our data highlight general properties of the allelic architecture of complex traits, including the proportion of the heritable component of each blood trait explained by the polygenic signal across different genome regulatory domains. Finally, through Mendelian randomization, we provide evidence of shared genetic pathways linking blood cell indices with complex pathologies, including autoimmune diseases, schizophrenia, and coronary heart disease and evidence suggesting previously reported population associations between blood cell indices and cardiovascular disease may be non-causal.


Assuntos
Variação Genética , Estudo de Associação Genômica Ampla , Células-Tronco Hematopoéticas/metabolismo , Doenças do Sistema Imunitário/genética , Alelos , Diferenciação Celular , Grupo com Ancestrais do Continente Europeu/genética , Predisposição Genética para Doença , Células-Tronco Hematopoéticas/patologia , Humanos , Doenças do Sistema Imunitário/patologia , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
19.
Atherosclerosis ; 254: 35-41, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27684604

RESUMO

BACKGROUND AND AIMS: Type 2 diabetes (T2D), low-density lipoprotein-cholesterol (LDL-c), body mass index (BMI), blood pressure and smoking are established risk factors that play a causal role in coronary artery disease (CAD). Numerous common genetic variants associating with these and other risk factors have been identified, but their association with CAD has not been comprehensively examined in a single study. Our goal was to comprehensively evaluate the associations of established and emerging risk factors with CAD using genetic variants identified from Genome-wide Association Studies (GWAS). METHODS: We tested the effect of 60 traditional and putative risk factors with CAD, using summary statistics obtained in GWAS. We approximated the regression of a response variable onto an additive multi-SNP genetic risk score in the Coronary Artery DIsease Genomewide Replication And Meta-analysis (CARDIoGRAM) consortium dataset weighted by the effect of the SNP on the risk factors. RESULTS: The strongest association with risk of CAD was for LDL-c SNPs (p = 3.96E-34). For non-established CAD risk factors, we found significant CAD associations for coronary artery calcification (CAC), Lp(a), LP-PLA2 activity, plaque, vWF and FVIII. In an attempt to identify independent associations between risk factors and CAD, only SNPs with an effect on the target trait were included. This identified CAD associations for Lp(a)(p = 1.77E-21), LDL-c (p = 4.16E-06), triglycerides (TG) (p = 1.94E-05), height (p = 2.06E-05), CAC (p = 3.13E-23) and carotid plaque (p = 2.08E-05). CONCLUSIONS: We identified SNPs associated with the emerging risk factors Lp(a), TG, plaque, height and CAC to be independently associated with risk of CAD. This provides further support for-ongoing clinical trials of Lp(a) and TG, and suggests that CAC and plaque could be used as surrogate markers for CAD in clinical trials.


Assuntos
Doença da Artéria Coronariana/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Alelos , Índice de Massa Corporal , Artérias Carótidas/patologia , LDL-Colesterol/sangue , Doença da Artéria Coronariana/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/genética , Testes Genéticos , Variação Genética , Humanos , Lipoproteína(a)/sangue , Modelos Estatísticos , Placa Aterosclerótica/sangue , Placa Aterosclerótica/genética , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Triglicerídeos/sangue
20.
Pharmacogenomics ; 17(6): 583-91, 2016 04.
Artigo em Inglês | MEDLINE | ID: mdl-27045730

RESUMO

AIM: To find new genetic loci associated with statin response, and to investigate the association of a genetic risk score (GRS) with this outcome. PATIENTS & METHODS: In a discovery meta-analysis (five studies, 1991 individuals), we investigated the effects of approximately 50000 single nucleotide polymorphisms on statin response, following up associations with p < 1 × 10(-4) (three independent studies, 5314 individuals). We further assessed the effect of a GRS based on SNPs in ABCG2, LPA and APOE. RESULTS: No new SNPs were found associated with statin response. The GRS was associated with reduced statin response: 0.0394 mmol/l per allele (95% CI: 0.0171-0.0617, p = 5.37 × 10(-4)). CONCLUSION: The GRS was associated with statin response, but the small effect size (˜2% of the average low-density lipoprotein cholesterol reduction) limits applicability.


Assuntos
LDL-Colesterol/sangue , LDL-Colesterol/genética , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Adulto , Idoso , Apolipoproteínas E/genética , Feminino , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
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