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Hypertension affects more than one billion people worldwide. Here we identify 113 novel loci, reporting a total of 2,103 independent genetic signals (P < 5 × 10-8) from the largest single-stage blood pressure (BP) genome-wide association study to date (n = 1,028,980 European individuals). These associations explain more than 60% of single nucleotide polymorphism-based BP heritability. Comparing top versus bottom deciles of polygenic risk scores (PRSs) reveals clinically meaningful differences in BP (16.9 mmHg systolic BP, 95% CI, 15.5-18.2 mmHg, P = 2.22 × 10-126) and more than a sevenfold higher odds of hypertension risk (odds ratio, 7.33; 95% CI, 5.54-9.70; P = 4.13 × 10-44) in an independent dataset. Adding PRS into hypertension-prediction models increased the area under the receiver operating characteristic curve (AUROC) from 0.791 (95% CI, 0.781-0.801) to 0.826 (95% CI, 0.817-0.836, ∆AUROC, 0.035, P = 1.98 × 10-34). We compare the 2,103 loci results in non-European ancestries and show significant PRS associations in a large African-American sample. Secondary analyses implicate 500 genes previously unreported for BP. Our study highlights the role of increasingly large genomic studies for precision health research.
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Pressão Sanguínea , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Hipertensão , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Feminino , Humanos , Masculino , Pressão Sanguínea/genética , Estratificação de Risco Genético , Hipertensão/genética , Fatores de RiscoRESUMO
BACKGROUND & AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) affects over 25% of the population and currently has no effective treatments. Plasma proteins with causal evidence may represent promising drug targets. We aimed to identify plasma proteins in the causal pathway of MASLD and explore their interaction with obesity. METHODS: We analysed 2,941 plasma proteins in 43,978 European participants from UK Biobank. We performed genome-wide association study (GWAS) for all MASLD-associated proteins and created the largest MASLD GWAS (109,885 cases/1,014,923 controls). We performed Mendelian Randomization (MR) and integrated proteins and their encoding genes in MASLD ranges to identify candidate causal proteins. We then validated them through independent replication, exome sequencing, liver imaging, bulk and single-cell gene expression, liver biopsies, pathway, and phenome-wide data. We explored the role of obesity by MR and multivariable MR across proteins, body mass index, and MASLD. RESULTS: We found 929 proteins associated with MASLD, reported five novel genetic loci associated with MASLD, and identified 17 candidate MASLD protein targets. We identified four novel targets for MASLD (CD33, GRHPR, HMOX2, and SCG3), provided protein evidence supporting roles of AHCY, FCGR2B, ORM1, and RBKS in MASLD, and validated nine previously known targets. We found that CD33, FCGR2B, ORM1, RBKS, and SCG3 mediated the association of obesity and MASLD, and HMOX2, ORM1, and RBKS had effect on MASLD independent of obesity. CONCLUSIONS: This study identified new protein targets in the causal pathway of MASLD, providing new insights into the multi-omics architecture and pathophysiology of MASLD. These findings advise further therapeutic interventions for MASLD.
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The Pharma Proteomics Project is a precompetitive biopharmaceutical consortium characterizing the plasma proteomic profiles of 54,219 UK Biobank participants. Here we provide a detailed summary of this initiative, including technical and biological validations, insights into proteomic disease signatures, and prediction modelling for various demographic and health indicators. We present comprehensive protein quantitative trait locus (pQTL) mapping of 2,923 proteins that identifies 14,287 primary genetic associations, of which 81% are previously undescribed, alongside ancestry-specific pQTL mapping in non-European individuals. The study provides an updated characterization of the genetic architecture of the plasma proteome, contextualized with projected pQTL discovery rates as sample sizes and proteomic assay coverages increase over time. We offer extensive insights into trans pQTLs across multiple biological domains, highlight genetic influences on ligand-receptor interactions and pathway perturbations across a diverse collection of cytokines and complement networks, and illustrate long-range epistatic effects of ABO blood group and FUT2 secretor status on proteins with gastrointestinal tissue-enriched expression. We demonstrate the utility of these data for drug discovery by extending the genetic proxied effects of protein targets, such as PCSK9, on additional endpoints, and disentangle specific genes and proteins perturbed at loci associated with COVID-19 susceptibility. This public-private partnership provides the scientific community with an open-access proteomics resource of considerable breadth and depth to help to elucidate the biological mechanisms underlying proteo-genomic discoveries and accelerate the development of biomarkers, predictive models and therapeutics1.
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Bancos de Espécimes Biológicos , Proteínas Sanguíneas , Bases de Dados Factuais , Genômica , Saúde , Proteoma , Proteômica , Humanos , Sistema ABO de Grupos Sanguíneos/genética , Proteínas Sanguíneas/análise , Proteínas Sanguíneas/genética , COVID-19/genética , Descoberta de Drogas , Epistasia Genética , Fucosiltransferases/metabolismo , Predisposição Genética para Doença , Plasma/química , Pró-Proteína Convertase 9/metabolismo , Proteoma/análise , Proteoma/genética , Parcerias Público-Privadas , Locos de Características Quantitativas , Reino Unido , Galactosídeo 2-alfa-L-FucosiltransferaseRESUMO
Proteases are an important class of drug targets that continue to drive inhibitor discovery. These enzymes are prone to resistance mutations, yet their promise for treating viral diseases and other disorders continues to grow. This study develops a general approach for detecting microbially synthesized protease inhibitors and uses it to screen terpenoid pathways for inhibitory compounds. The detection scheme relies on a bacterial two-hybrid (B2H) system that links protease inactivation to the transcription of a swappable reporter gene. This system, which can accomodate multiple biochemical outputs (i.e., luminescence and antibiotic resistance), permitted the facile incorporation of four disease-relevant proteases. A B2H designed to detect the inactivation of the main protease of severe acute respiratory syndrome coronavirus 2 enabled the identification of a terpenoid inhibitor of modest potency. An analysis of multiple pathways that make this terpenoid, however, suggested that its production was necessary but not sufficient to confer a survival advantage in growth-coupled assays. This finding highlights an important challenge associated with the use of genetic selection to search for inhibitorsânotably, the influence of pathway toxicityâand underlines the value of including multiple pathways with overlapping product profiles in pathway screens. This study provides a detailed experimental framework for using microbes to screen libraries of biosynthetic pathways for targeted protease inhibitors.
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Proteases 3C de Coronavírus , Inibidores de Proteases , Inibidores de Proteases/química , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/enzimologia , Proteases 3C de Coronavírus/antagonistas & inibidoresRESUMO
Stroke is the second leading cause of death with substantial unmet therapeutic needs. To identify potential stroke therapeutic targets, we estimate the causal effects of 308 plasma proteins on stroke outcomes in a two-sample Mendelian randomization framework and assess mediation effects by stroke risk factors. We find associations between genetically predicted plasma levels of six proteins and stroke (P ≤ 1.62 × 10-4). The genetic associations with stroke colocalize (Posterior Probability >0.7) with the genetic associations of four proteins (TFPI, TMPRSS5, CD6, CD40). Mendelian randomization supports atrial fibrillation, body mass index, smoking, blood pressure, white matter hyperintensities and type 2 diabetes as stroke risk factors (P ≤ 0.0071). Body mass index, white matter hyperintensity and atrial fibrillation appear to mediate the TFPI, IL6RA, TMPRSS5 associations with stroke. Furthermore, thirty-six proteins are associated with one or more of these risk factors using Mendelian randomization. Our results highlight causal pathways and potential therapeutic targets for stroke.
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Fibrilação Atrial , Diabetes Mellitus Tipo 2 , Acidente Vascular Cerebral , Fibrilação Atrial/genética , Proteínas Sanguíneas/genética , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Proteoma/genética , Fatores de Risco , Acidente Vascular Cerebral/genéticaRESUMO
Background and Objectives: Angiotensin-converting enzyme (ACE) inhibitors are a commonly prescribed class of medication used to treat heart failure, hypertension, and chronic kidney disease. However, previous observational studies have shown conflicting directions of associations between ACE inhibitors and risk of Alzheimer disease. Genetic evidence has supported a protective effect of cerebral ACE against Alzheimer disease (AD). However, it is unclear whether this effect is mediated through blood pressure and extends to other neurodegenerative diseases. Methods: We performed genetic colocalization investigating an effect of cortical ACE expression on AD risk in people of European ancestry. We further investigated whether any effect of ACE expression on AD risk is mediated through changes in blood pressure and whether effects extend to Parkinson disease, small-vessel disease, or cognitive function in a Mendelian randomization paradigm. Results: There was genetic evidence supporting a protective effect of cortical ACE expression on AD risk in people of European ancestry. Although higher cortical ACE expression was associated with higher blood pressure, there was no strong evidence to support that its association with AD was mediated through blood pressure nor that ACE expression affected risk of other neurodegenerative traits. Discussion: Genetic evidence supports protective effects of cerebral ACE expression on AD, but not other neurodegenerative outcomes in people of European ancestry. Further work is required to investigate whether therapeutic inhibition of ACE increases risk of Alzheimer disease.
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Terpenoids, the largest and most structurally diverse group of natural products, include a striking variety of biologically active compounds, from flavors to medicines. Despite their well-documented biochemical versatility, the evolutionary processes that generate new functional terpenoids are poorly understood and difficult to recapitulate in engineered systems. This study uses a synthetic biochemical objectiveâa transcriptional system that links the inhibition of protein tyrosine phosphatase 1B (PTP1B), a human drug target, to the expression of a gene for antibiotic resistance in Escherichia coli (E. coli)âto evolve a terpene synthase to produce enzyme inhibitors. Site saturation mutagenesis of poorly conserved residues on γ-humulene synthase (GHS), a promicuous enzyme, yielded mutants that improved fitness (i.e., the antibiotic resistance of E. coli) by reducing GHS toxicity and/or by increasing inhibitor production. Intriguingly, a combination of two mutations enhanced the titer of a minority productâa terpene alcohol that inhibits PTP1Bâby over 50-fold, and a comparison of similar mutants enabled the identification of a site where mutations permit efficient hydroxylation. Findings suggest that the plasticity of terpene synthases enables an efficient sampling of structurally distinct starting points for building new functional molecules and provide an experimental framework for exploiting this plasticity in activity-guided screens.
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Alquil e Aril Transferases , Produtos Biológicos , Alquil e Aril Transferases/genética , Escherichia coli/genética , Humanos , Proteína Tirosina Fosfatase não Receptora Tipo 1 , TerpenosRESUMO
A common variant in the Histone Deacetylase 9 (HDAC9) gene is the strongest genetic risk for large-vessel stroke, and HDAC9 offers a novel target for therapeutic modulation. However, the mechanisms linking the HDAC9 variant with increased stroke risk is still unclear due to the lack of relevant models to study the underlying molecular mechanisms. We generated vascular smooth muscle cells using human induced pluripotent stem cells with the HDAC9 stroke risk variant to assess HDAC9-mediated phenotypic changes in a relevant cells model and test the efficacy of HDAC inhibitors for potential therapeutic strategies. Our human induced pluripotent stem cells derived vascular smooth muscle cells show enhanced HDAC9 expression and allow us to assess HDAC9-mediated effects on promoting smooth muscle cell dysfunction, including proliferation, migration, apoptosis and response to inflammation. These phenotypes could be reverted by treatment with HDAC inhibitors, including sodium valproate and small molecules inhibitors. By demonstrating the relevance of the model and the efficacy of HDAC inhibitors, our model provides a robust phenotypic screening platform, which could be applied to other stroke-associated genetic variants.
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Age-related loss of white matter microstructural integrity is a major determinant of cognitive decline, dementia and gait disorders. However, the mechanisms and molecular pathways that contribute to this loss of integrity remain elusive. We performed a genome-wide association study of white matter microstructural integrity as quantified by diffusion MRI metrics (mean diffusivity and fractional anisotropy) in up to 31 128 individuals from UK Biobank (age 45-81 years) based on a two degrees of freedom (2df) test of single nucleotide polymorphism (SNP) and SNP × Age effects. We identified 18 loci that were associated at genome-wide significance with either mean diffusivity (n = 16) or fractional anisotropy (n = 6). Among the top loci was a region on chromosome 6 encoding the human major histocompatibility complex (MHC). Variants in the MHC region were strongly associated with both mean diffusivity [best SNP: 6:28866209_TTTTG_T, beta (standard error, SE) = -0.069 (0.009); 2df P = 6.5 × 10-15] and fractional anisotropy [best SNP: rs3129787, beta (SE) = -0.056 (0.008); 2df P = 3.5 × 10-12]. Of the imputed human leukocyte antigen (HLA) alleles and complement component 4 (C4) structural haplotype variants in the human MHC, the strongest association was with the C4-BS variant [for mean diffusivity: beta (SE) = -0.070 (0.010); P = 2.7 × 10-11; for fractional anisotropy: beta (SE) = -0.054 (0.011); P = 1.6 × 10-7]. After conditioning on C4-BS no associations with HLA alleles remained significant. The protective influence of C4-BS was stronger in older participants [age ≥ 65; interaction P = 0.0019 (mean diffusivity), P = 0.015 (fractional anisotropy)] and in participants without a history of smoking [interaction P = 0.00093 (mean diffusivity), P = 0.021 (fractional anisotropy)]. Taken together, our findings demonstrate a role of the complement system and of gene-environment interactions in age-related loss of white matter microstructural integrity.
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Complemento C4/metabolismo , Substância Branca , Idoso , Idoso de 80 Anos ou mais , Anisotropia , Imagem de Difusão por Ressonância Magnética , Imagem de Tensor de Difusão , Estudo de Associação Genômica Ampla , Humanos , Pessoa de Meia-Idade , Substância Branca/diagnóstico por imagemRESUMO
OBJECTIVE-: Cardiovascular risk factors have been implicated in the etiology of Cerebral Small Vessel Disease (CSVD), however whether the associations are causal remains unclear in part due to the susceptibility of observational studies to reverse causation and confounding. Here we use Mendelian randomization (MR) to determine which cardiovascular risk factors are likely to be involved in the etiology of CSVD. METHODS-: We used data from large scale genome-wide association studies (GWAS) of European ancestry to identify genetic proxies for blood pressure, blood lipids, body mass index (BMI), type-II diabetes, smoking initiation, cigarettes per day and alcohol consumption. MR was performed to assess their association with three neuroimaging features which are altered in CSVD (white matter hyperintensities (WMH), fractional anisotropy (FA) and mean diffusivity (MD)) using genetic summary data from UK Biobank (N=31,855). Our primary analysis used inverse-weighted median (IVW) MR, with validation using weighted median, MR-Egger and a pleiotropy-minimizing approach. Finally, multivariable MR was performed to study the effects of multiple risk factors jointly. RESULTS-: MR analysis showed consistent associations across all methods for higher genetically proxied systolic and diastolic blood pressure with WMH, FA, and MD; and for higher genetically proxied BMI with WMH. There was weaker evidence for associations between total cholesterol, LDL, smoking initiation, pulse pressure and type-II diabetes liability and at least one CSVD imaging feature, but these associations were not reproducible across all validation methods used. Multivariable MR analysis for blood pressure traits found that the effect was primarily through genetically proxied diastolic blood pressure across all CSVD traits. CONCLUSION-: Genetic predisposition to higher blood pressure, primarily diastolic blood pressure, and higher BMI is associated with a higher burden of CSVD, suggesting a causal role. Improved management and treatment of these risk factors could reduce the burden of CSVD.
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BACKGROUND: Cardiorespiratory fitness (CRF) and physical activity (PA) are well-established predictors of morbidity and all-cause mortality. However, CRF is not routinely measured and PA not routinely prescribed as part of standard healthcare. The American Heart Association (AHA) recently presented a scientific case for the inclusion of CRF as a clinical vital sign based on epidemiological and clinical observation. Here, we leverage genetic data in the UK Biobank (UKB) to strengthen the case for CRF as a vital sign and make a case for the prescription of PA. METHODS: We derived two CRF measures from the heart rate data collected during a submaximal cycle ramp test: CRF-vo2max, an estimate of the participants' maximum volume of oxygen uptake, per kilogram of body weight, per minute; and CRF-slope, an estimate of the rate of increase of heart rate during exercise. Average PA over a 7-day period was derived from a wrist-worn activity tracker. After quality control, 70,783 participants had data on the two derived CRF measures, and 89,683 had PA data. We performed genome-wide association study (GWAS) analyses by sex, and post-GWAS techniques to understand genetic architecture of the traits and prioritise functional genes for follow-up. RESULTS: We found strong evidence that genetic variants associated with CRF and PA influenced genetic expression in a relatively small set of genes in the heart, artery, lung, skeletal muscle and adipose tissue. These functionally relevant genes were enriched among genes known to be associated with coronary artery disease (CAD), type 2 diabetes (T2D) and Alzheimer's disease (three of the top 10 causes of death in high-income countries) as well as Parkinson's disease, pulmonary fibrosis, and blood pressure, heart rate, and respiratory phenotypes. Genetic variation associated with lower CRF and PA was also correlated with several disease risk factors (including greater body mass index, body fat and multiple obesity phenotypes); a typical T2D profile (including higher insulin resistance, higher fasting glucose, impaired beta-cell function, hyperglycaemia, hypertriglyceridemia); increased risk for CAD and T2D; and a shorter lifespan. CONCLUSIONS: Genetics supports three decades of evidence for the inclusion of CRF as a clinical vital sign. Given the genetic, clinical and epidemiological evidence linking CRF and PA to increased morbidity and mortality, regular measurement of CRF as a marker of health and routine prescription of PA could be a prudent strategy to support public health.
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Aptidão Cardiorrespiratória/fisiologia , Atenção à Saúde , Exercício Físico/fisiologia , Estudo de Associação Genômica Ampla , Prescrições , Sinais Vitais/genética , Tecido Adiposo , Doença de Alzheimer , Índice de Massa Corporal , Peso Corporal , Diabetes Mellitus Tipo 2 , Feminino , Humanos , Resistência à Insulina , Masculino , Obesidade , Fenótipo , Fatores de RiscoRESUMO
White matter hyperintensities (WMH) are among the most common radiological abnormalities in the ageing population and an established risk factor for stroke and dementia. While common variant association studies have revealed multiple genetic loci with an influence on their volume, the contribution of rare variants to the WMH burden in the general population remains largely unexplored. We conducted a comprehensive analysis of this burden in the UK Biobank using publicly available whole-exome sequencing data (n up to 17 830) and found a splice-site variant in GBE1, encoding 1,4-alpha-glucan branching enzyme 1, to be associated with lower white matter burden on an exome-wide level [c.691+2T>C, ß = -0.74, standard error (SE) = 0.13, P = 9.7 × 10-9]. Applying whole-exome gene-based burden tests, we found damaging missense and loss-of-function variants in HTRA1 (frequency of 1 in 275 in the UK Biobank population) to associate with an increased WMH volume (P = 5.5 × 10-6, false discovery rate = 0.04). HTRA1 encodes a secreted serine protease implicated in familial forms of small vessel disease. Domain-specific burden tests revealed that the association with WMH volume was restricted to rare variants in the protease domain (amino acids 204-364; ß = 0.79, SE = 0.14, P = 9.4 × 10-8). The frequency of such variants in the UK Biobank population was 1 in 450. The WMH volume was brought forward by â¼11 years in carriers of a rare protease domain variant. A comparison with the effect size of established risk factors for WMH burden revealed that the presence of a rare variant in the HTRA1 protease domain corresponded to a larger effect than meeting the criteria for hypertension (ß = 0.26, SE = 0.02, P = 2.9 × 10-59) or being in the upper 99.8% percentile of the distribution of a polygenic risk score based on common genetic variants (ß = 0.44, SE = 0.14, P = 0.002). In biochemical experiments, most (6/9) of the identified protease domain variants resulted in markedly reduced protease activity. We further found EGFL8, which showed suggestive evidence for association with WMH volume (P = 1.5 × 10-4, false discovery rate = 0.22) in gene burden tests, to be a direct substrate of HTRA1 and to be preferentially expressed in cerebral arterioles and arteries. In a phenome-wide association study mapping ICD-10 diagnoses to 741 standardized Phecodes, rare variants in the HTRA1 protease domain were associated with multiple neurological and non-neurological conditions including migraine with aura (odds ratio = 12.24, 95%CI: 2.54-35.25; P = 8.3 × 10-5]. Collectively, these findings highlight an important role of rare genetic variation and the HTRA1 protease in determining WMH burden in the general population.
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Encéfalo/diagnóstico por imagem , Proteínas de Ligação ao Cálcio/genética , Família de Proteínas EGF/genética , Sequenciamento do Exoma/métodos , Serina Peptidase 1 de Requerimento de Alta Temperatura A/genética , Substância Branca/diagnóstico por imagem , Feminino , Células HEK293 , Humanos , Masculino , Pessoa de Meia-Idade , Reino Unido/epidemiologiaRESUMO
Essential hypertension is a complex trait where the underlying aetiology is not completely understood. Left untreated it increases the risk of severe health complications including cardiovascular and renal disease. It is almost 15 years since the first genome-wide association study for hypertension, and after a slow start there are now over 1000 blood pressure (BP) loci explaining â¼6% of the single nucleotide polymorphism-based heritability. Success in discovery of hypertension genes has provided new pathological insights and drug discovery opportunities and translated to the development of BP genetic risk scores (GRSs), facilitating population disease risk stratification. Comparing highest and lowest risk groups shows differences of 12.9 mm Hg in systolic-BP with significant differences in risk of hypertension, stroke, cardiovascular disease and myocardial infarction. GRSs are also being trialled in antihypertensive drug responses. Drug targets identified include NPR1, for which an agonist drug is currently in clinical trials. Identification of variants at the PHACTR1 locus provided insights into regulation of EDN1 in the endothelin pathway, which is aiding the development of endothelin receptor EDNRA antagonists. Drug re-purposing opportunities, including SLC5A1 and canagliflozin (a type-2 diabetes drug), are also being identified. In this review, we present key studies from the past, highlight current avenues of research and look to the future focusing on gene discovery, epigenetics, gene-environment interactions, GRSs and drug discovery. We evaluate limitations affecting BP genetics, including ancestry bias and discuss streamlining of drug target discovery and applications for treating and preventing hypertension, which will contribute to tailored precision medicine for patients.
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Hipertensão , Infarto do Miocárdio , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Estudo de Associação Genômica Ampla , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/genética , Infarto do Miocárdio/tratamento farmacológico , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Duchenne muscular dystrophy is characterized by structural degeneration of muscle, which is exacerbated by localized functional ischemia due to loss of nitric oxide synthase-induced vasodilation. Treatment strategies aimed at increasing vascular perfusion have been proposed. Toward this end, we have developed monoclonal antibodies (mAbs) that bind to the vascular endothelial growth factor (VEGF) receptor VEGFR-1 (Flt-1) and its soluble splice variant isoform (sFlt-1) leading to increased levels of free VEGF and proangiogenic signaling. The lead chimeric mAb, 21B3, had high affinity and specificity for both human and mouse sFlt-1 and inhibited VEGF binding to sFlt-1 in a competitive manner. Proof-of-concept studies in the mdx mouse model of Duchenne muscular dystrophy showed that intravenous administration of 21B3 led to elevated VEGF levels, increased vascularization and blood flow to muscles, and decreased fibrosis after 6-12 weeks of treatment. Greater muscle strength was also observed after 4 weeks of treatment. A humanized form of the mAb, 27H6, was engineered and demonstrated a comparable pharmacologic effect. Overall, administration of anti-Flt-1 mAbs in mdx mice inhibited the VEGF:Flt-1 interaction, promoted angiogenesis, and improved muscle function. These studies suggest a potential therapeutic benefit of Flt-1 inhibition for patients with Duchenne muscular dystrophy.
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BACKGROUND: The genetic basis of lacunar stroke is poorly understood, with a single locus on 16q24 identified to date. We sought to identify novel associations and provide mechanistic insights into the disease. METHODS: We did a pooled analysis of data from newly recruited patients with an MRI-confirmed diagnosis of lacunar stroke and existing genome-wide association studies (GWAS). Patients were recruited from hospitals in the UK as part of the UK DNA Lacunar Stroke studies 1 and 2 and from collaborators within the International Stroke Genetics Consortium. Cases and controls were stratified by ancestry and two meta-analyses were done: a European ancestry analysis, and a transethnic analysis that included all ancestry groups. We also did a multi-trait analysis of GWAS, in a joint analysis with a study of cerebral white matter hyperintensities (an aetiologically related radiological trait), to find additional genetic associations. We did a transcriptome-wide association study (TWAS) to detect genes for which expression is associated with lacunar stroke; identified significantly enriched pathways using multi-marker analysis of genomic annotation; and evaluated cardiovascular risk factors causally associated with the disease using mendelian randomisation. FINDINGS: Our meta-analysis comprised studies from Europe, the USA, and Australia, including 7338 cases and 254 798 controls, of which 2987 cases (matched with 29 540 controls) were confirmed using MRI. Five loci (ICA1L-WDR12-CARF-NBEAL1, ULK4, SPI1-SLC39A13-PSMC3-RAPSN, ZCCHC14, ZBTB14-EPB41L3) were found to be associated with lacunar stroke in the European or transethnic meta-analyses. A further seven loci (SLC25A44-PMF1-BGLAP, LOX-ZNF474-LOC100505841, FOXF2-FOXQ1, VTA1-GPR126, SH3PXD2A, HTRA1-ARMS2, COL4A2) were found to be associated in the multi-trait analysis with cerebral white matter hyperintensities (n=42 310). Two of the identified loci contain genes (COL4A2 and HTRA1) that are involved in monogenic lacunar stroke. The TWAS identified associations between the expression of six genes (SCL25A44, ULK4, CARF, FAM117B, ICA1L, NBEAL1) and lacunar stroke. Pathway analyses implicated disruption of the extracellular matrix, phosphatidylinositol 5 phosphate binding, and roundabout binding (false discovery rate <0·05). Mendelian randomisation analyses identified positive associations of elevated blood pressure, history of smoking, and type 2 diabetes with lacunar stroke. INTERPRETATION: Lacunar stroke has a substantial heritable component, with 12 loci now identified that could represent future treatment targets. These loci provide insights into lacunar stroke pathogenesis, highlighting disruption of the vascular extracellular matrix (COL4A2, LOX, SH3PXD2A, GPR126, HTRA1), pericyte differentiation (FOXF2, GPR126), TGF-ß signalling (HTRA1), and myelination (ULK4, GPR126) in disease risk. FUNDING: British Heart Foundation.
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Predisposição Genética para Doença/epidemiologia , Estudo de Associação Genômica Ampla , Acidente Vascular Cerebral Lacunar/epidemiologia , Acidente Vascular Cerebral Lacunar/genética , Austrália , Europa (Continente) , Predisposição Genética para Doença/genética , Humanos , Imageamento por Ressonância Magnética , Acidente Vascular Cerebral Lacunar/diagnóstico , Estados UnidosRESUMO
OBJECTIVE: To identify common genetic variants associated with the presence of brain microbleeds (BMBs). METHODS: We performed genome-wide association studies in 11 population-based cohort studies and 3 case-control or case-only stroke cohorts. Genotypes were imputed to the Haplotype Reference Consortium or 1000 Genomes reference panel. BMBs were rated on susceptibility-weighted or T2*-weighted gradient echo MRI sequences, and further classified as lobar or mixed (including strictly deep and infratentorial, possibly with lobar BMB). In a subset, we assessed the effects of APOE ε2 and ε4 alleles on BMB counts. We also related previously identified cerebral small vessel disease variants to BMBs. RESULTS: BMBs were detected in 3,556 of the 25,862 participants, of which 2,179 were strictly lobar and 1,293 mixed. One locus in the APOE region reached genome-wide significance for its association with BMB (lead single nucleotide polymorphism rs769449; odds ratio [OR]any BMB [95% confidence interval (CI)] 1.33 [1.21-1.45]; p = 2.5 × 10-10). APOE ε4 alleles were associated with strictly lobar (OR [95% CI] 1.34 [1.19-1.50]; p = 1.0 × 10-6) but not with mixed BMB counts (OR [95% CI] 1.04 [0.86-1.25]; p = 0.68). APOE ε2 alleles did not show associations with BMB counts. Variants previously related to deep intracerebral hemorrhage and lacunar stroke, and a risk score of cerebral white matter hyperintensity variants, were associated with BMB. CONCLUSIONS: Genetic variants in the APOE region are associated with the presence of BMB, most likely due to the APOE ε4 allele count related to a higher number of strictly lobar BMBs. Genetic predisposition to small vessel disease confers risk of BMB, indicating genetic overlap with other cerebral small vessel disease markers.
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Apolipoproteína E4/genética , Apolipoproteínas E/genética , Hemorragia Cerebral/genética , Hemorragia Cerebral/patologia , Doenças de Pequenos Vasos Cerebrais/genética , Estudo de Associação Genômica Ampla , Substância Branca/patologia , Idoso , Idoso de 80 Anos ou mais , Alelos , Apolipoproteína E2/genética , Estudos de Casos e Controles , Hemorragia Cerebral/diagnóstico por imagem , Hemorragia Cerebral/epidemiologia , Doenças de Pequenos Vasos Cerebrais/epidemiologia , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Risco , Substância Branca/diagnóstico por imagemRESUMO
BACKGROUND AND PURPOSE: Stroke is a complex disease with multiple genetic and environmental risk factors. Blacks endure a nearly 2-fold greater risk of stroke and are 2× to 3× more likely to die from stroke than European Americans. METHODS: The COMPASS (Consortium of Minority Population Genome-Wide Association Studies of Stroke) has conducted a genome-wide association meta-analysis of stroke in >22 000 individuals of African ancestry (3734 cases, 18 317 controls) from 13 cohorts. RESULTS: In meta-analyses, we identified one single nucleotide polymorphism (rs55931441) near the HNF1A gene that reached genome-wide significance (P=4.62×10-8) and an additional 29 variants with suggestive evidence of association (P<1×10-6), representing 24 unique loci. For validation, a look-up analysis for a 100 kb region flanking the COMPASS single nucleotide polymorphism was performed in SiGN (Stroke Genetics Network) Europeans, SiGN Hispanics, and METASTROKE (Europeans). Using a stringent Bonferroni correction P value of 2.08×10-3 (0.05/24 unique loci), we were able to validate associations at the HNF1A locus in both SiGN (P=8.18×10-4) and METASTROKE (P=1.72×10-3) European populations. Overall, 16 of 24 loci showed evidence for validation across multiple populations. Previous studies have reported associations between variants in the HNF1A gene and lipids, C-reactive protein, and risk of coronary artery disease and stroke. Suggestive associations with variants in the SFXN4 and TMEM108 genes represent potential novel ischemic stroke loci. CONCLUSIONS: These findings represent the most thorough investigation of genetic determinants of stroke in individuals of African descent, to date.
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Negro ou Afro-Americano/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único/genética , Acidente Vascular Cerebral/genética , Negro ou Afro-Americano/etnologia , Estudos de Coortes , Predisposição Genética para Doença/etnologia , Humanos , Acidente Vascular Cerebral/etnologiaRESUMO
It is imperative to understand the specific and shared etiologies of major depression and cardio-metabolic disease, as both traits are frequently comorbid and each represents a major burden to society. This study examined whether there is a genetic association between major depression and cardio-metabolic traits and if this association is stratified by age at onset for major depression. Polygenic risk scores analysis and linkage disequilibrium score regression was performed to examine whether differences in shared genetic etiology exist between depression case control status (N cases = 40,940, N controls = 67,532), earlier (N = 15,844), and later onset depression (N = 15,800) with body mass index, coronary artery disease, stroke, and type 2 diabetes in 11 data sets from the Psychiatric Genomics Consortium, Generation Scotland, and UK Biobank. All cardio-metabolic polygenic risk scores were associated with depression status. Significant genetic correlations were found between depression and body mass index, coronary artery disease, and type 2 diabetes. Higher polygenic risk for body mass index, coronary artery disease, and type 2 diabetes was associated with both early and later onset depression, while higher polygenic risk for stroke was associated with later onset depression only. Significant genetic correlations were found between body mass index and later onset depression, and between coronary artery disease and both early and late onset depression. The phenotypic associations between major depression and cardio-metabolic traits may partly reflect their overlapping genetic etiology irrespective of the age depression first presents.
Assuntos
Transtorno Depressivo Maior/genética , Síndrome Metabólica/genética , Fatores Etários , Idade de Início , Índice de Massa Corporal , Fatores de Risco Cardiometabólico , Estudos de Casos e Controles , Comorbidade , Doença da Artéria Coronariana/genética , Bases de Dados Genéticas , Depressão/genética , Depressão/fisiopatologia , Transtorno Depressivo Maior/fisiopatologia , Diabetes Mellitus Tipo 2/genética , Feminino , Estudos de Associação Genética/métodos , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Desequilíbrio de Ligação/genética , Masculino , Síndrome Metabólica/fisiopatologia , Herança Multifatorial/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Acidente Vascular Cerebral/genéticaRESUMO
Cerebral small vessel disease is a major cause of stroke and dementia, but its genetic basis is incompletely understood. We perform a genetic study of three MRI markers of the disease in UK Biobank imaging data and other sources: white matter hyperintensities (N = 42,310), fractional anisotropy (N = 17,663) and mean diffusivity (N = 17,467). Our aim is to better understand the disease pathophysiology. Across the three traits, we identify 31 loci, of which 21 were previously unreported. We perform a transcriptome-wide association study to identify associations with gene expression in relevant tissues, identifying 66 associated genes across the three traits. This genetic study provides insights into the understanding of the biological mechanisms underlying small vessel disease.
Assuntos
Doenças de Pequenos Vasos Cerebrais/diagnóstico por imagem , Doenças de Pequenos Vasos Cerebrais/genética , Acidente Vascular Cerebral/genética , Adulto , Idoso , Biomarcadores , Doenças de Pequenos Vasos Cerebrais/complicações , Feminino , Regulação da Expressão Gênica/genética , Ontologia Genética , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/genética , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Especificidade de Órgãos , Polimorfismo de Nucleotídeo Único , Transcriptoma/genéticaRESUMO
We aimed to characterize the genetics of endothelial function and how this influences risk for cardiovascular diseases such as ischemic stroke. We integrated genetic data from a study of ultrasound flow-mediated dilatation of brachial artery in adolescents from ALSPAC (Avon Longitudinal Study of Parents and Children; n=5214) with a study of ischemic stroke (MEGASTROKE: n=60 341 cases and 452 969 controls) to identify variants that confer risk of ischemic stroke through altered endothelial function. We identified a variant in PDE3A (Phosphodiesterase 3A), encoding phosphodiesterase 3A, which was associated with flow-mediated dilatation in adolescents (9-12 years of age; ß[SE], 0.38 [0.070]; P=3.8×10-8) and confers risk of ischemic stroke (odds ratio, 1.04 [95% CI, 1.02-1.06]; P=5.2×10-6). Bayesian colocalization analyses showed the same underlying variation is likely to lead to both associations (posterior probability, 97%). The same variant was associated with flow-mediated dilatation in a second study in young adults (age, 24-27 years; ß[SE], 0.47 [0.23]; P=0.047) but not in older adults (ß[SE], -0.012 [0.13]; P=0.89). We conclude that a genetic variant in PDE3A influences endothelial function in early life and leads to increased risk of ischemic stroke. Subtle, measurable changes to the vasculature that are influenced by genetics also influence risk of ischemic stroke.