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1.
Hum Mol Genet ; 2021 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-34476477

RESUMO

The etiology of renal artery stenosis (RAS) and abdominal aortic coarctation (AAC) causing the midaortic syndrome (MAS), often resulting in renovascular hypertension (RVH), remains ill-defined. Neurofibromatosis type 1 (NF-1) is frequently observed in children with RVH. Consecutive pediatric patients (N = 102) presenting with RVH secondary to RAS with and without concurrent AAC were prospectively enrolled in a clinical data base, and blood, saliva, and operative tissue when available, were collected. Among the 102 children were 13 having a concurrent clinical diagnosis of NF-1 (12.5%). Whole exome sequencing was performed for germline variant detection and RNASeq analysis of NF1, MAPK pathway genes, and MCP1 levels were undertaken in five NF-1 stenotic renal arteries, as well as control renal and mesenteric arteries from children with no known vasculopathy or NF-1. In 11 unrelated children with sequencing data, 11 NF1 genetic variants were identified, of which 10 had not been reported in gnomAD. Histologic analysis of NF-1 RAS specimens consistently revealed intimal thickening, disruption of the internal elastic lamina, and medial thinning. Analysis of transcript expression in arterial lesions documented an approximately 5-fold reduction in NF1 expression, confirming heterozygosity, MAPK pathway activation, and increased MCP1 expression. In summary, NF-1 related RVH in children is rare but often severe and progressive and as such, important to recognize. It is associated with histologic and molecular features consistent with an aggressive adverse vascular remodeling process. Further research is necessary to define the mechanisms underlying these findings.

3.
FASEB J ; 35(9): e21824, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34370353

RESUMO

Crosstalk between multiple components underlies the formation of mature vessels. Although the players involved in angiogenesis have been identified, mechanisms underlying the crosstalk between them are still unclear. Using the ex vivo aortic ring assay, we set out to dissect the interactions between two key angiogenic signaling pathways, vascular endothelial growth factor (VEGF) and transforming growth factor ß (TGFß), with members of the lysyl oxidase (LOX) family of matrix modifying enzymes. We find an interplay between VEGF, TGFß, and the LOXs is essential for the formation of mature vascular smooth muscle cells (vSMC)-coated vessels. RNA sequencing analysis further identified an interaction with the endothelin-1 pathway. Our work implicates endothelin-1 downstream of TGFß in vascular maturation and demonstrate the complexity of processes involved in generating vSMC-coated vessels.


Assuntos
Endotelina-1/metabolismo , Neovascularização Patológica/metabolismo , Proteína-Lisina 6-Oxidase/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Diferenciação Celular/fisiologia , Células Cultivadas , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Morfogênese/fisiologia , Miócitos de Músculo Liso/metabolismo , Transdução de Sinais/fisiologia , Fator A de Crescimento do Endotélio Vascular/metabolismo
4.
Am J Hum Genet ; 108(9): 1578-1589, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34265237

RESUMO

Thoracic aortic aneurysm (TAA) is characterized by dilation of the aortic root or ascending/descending aorta. TAA is a heritable disease that can be potentially life threatening. While 10%-20% of TAA cases are caused by rare, pathogenic variants in single genes, the origin of the majority of TAA cases remains unknown. A previous study implicated common variants in FBN1 with TAA disease risk. Here, we report a genome-wide scan of 1,351 TAA-affected individuals and 18,295 control individuals from the Cardiovascular Health Improvement Project and Michigan Genomics Initiative at the University of Michigan. We identified a genome-wide significant association with TAA for variants within the third intron of TCF7L2 following replication with meta-analysis of four additional independent cohorts. Common variants in this locus are the strongest known genetic risk factor for type 2 diabetes. Although evidence indicates the presence of different causal variants for TAA and type 2 diabetes at this locus, we observed an opposite direction of effect. The genetic association for TAA colocalizes with an aortic eQTL of TCF7L2, suggesting a functional relationship. These analyses predict an association of higher expression of TCF7L2 with TAA disease risk. In vitro, we show that upregulation of TCF7L2 is associated with BCL2 repression promoting vascular smooth muscle cell apoptosis, a key driver of TAA disease.


Assuntos
Aneurisma da Aorta Torácica/genética , Diabetes Mellitus Tipo 2/genética , Células Endoteliais/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Locos de Características Quantitativas , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética , Aorta/metabolismo , Aorta/patologia , Aneurisma da Aorta Torácica/metabolismo , Aneurisma da Aorta Torácica/patologia , Estudos de Casos e Controles , Caspase 3/genética , Caspase 3/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Células Endoteliais/patologia , Regulação da Expressão Gênica , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , Íntrons , Michigan , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Mutação , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína 2 Semelhante ao Fator 7 de Transcrição/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
5.
Circ Res ; 128(12): 1958-1972, 2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34110898

RESUMO

Multifocal fibromuscular dysplasia (FMD) and spontaneous coronary artery dissection are both sex-biased diseases disproportionately affecting women over men in a 9:1 ratio. Traditionally known in the context of renovascular hypertension, recent advances in knowledge about FMD have demonstrated that FMD is a systemic arteriopathy presenting as arterial stenosis, aneurysm, and dissection in virtually any arterial bed. FMD is also characterized by major cardiovascular presentations including hypertension, stroke, and myocardial infarction. Similar to FMD, spontaneous coronary artery dissection is associated with a high prevalence of extracoronary vascular abnormalities, including FMD, aneurysm, and extracoronary dissection, and recent studies have also found genetic associations between the two diseases. This review will summarize the relationship between FMD and spontaneous coronary artery dissection with a focus on common clinical associations, histopathologic mechanisms, genetic susceptibilities, and the biology of these diseases. The current status of disease models and critical future research directions will also be addressed.

6.
Am J Epidemiol ; 190(10): 1977-1992, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33861317

RESUMO

Genotype-phenotype association studies often combine phenotype data from multiple studies to increase statistical power. Harmonization of the data usually requires substantial effort due to heterogeneity in phenotype definitions, study design, data collection procedures, and data-set organization. Here we describe a centralized system for phenotype harmonization that includes input from phenotype domain and study experts, quality control, documentation, reproducible results, and data-sharing mechanisms. This system was developed for the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine (TOPMed) program, which is generating genomic and other -omics data for more than 80 studies with extensive phenotype data. To date, 63 phenotypes have been harmonized across thousands of participants (recruited in 1948-2012) from up to 17 studies per phenotype. Here we discuss challenges in this undertaking and how they were addressed. The harmonized phenotype data and associated documentation have been submitted to National Institutes of Health data repositories for controlled access by the scientific community. We also provide materials to facilitate future harmonization efforts by the community, which include 1) the software code used to generate the 63 harmonized phenotypes, enabling others to reproduce, modify, or extend these harmonizations to additional studies, and 2) the results of labeling thousands of phenotype variables with controlled vocabulary terms.

7.
Hum Mol Genet ; 30(9): 836-842, 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-33693786

RESUMO

Genomic discovery efforts for hematological traits have been successfully conducted through genome-wide association study on samples of predominantly European ancestry. We sought to conduct unbiased genetic discovery for coding variants that influence hematological traits in a Han Chinese population. A total of 5257 Han Chinese subjects from Beijing, China were included in the discovery cohort and analyzed by an Illumina ExomeChip array. Replication analyses were conducted in 3827 independent Chinese subjects. We analyzed 12 hematological traits and identified 22 exome-wide significant single-nucleotide polymorphisms (SNP)-trait associations with 15 independent SNPs. Our study provides replication for two associations previously reported but not replicated. Further, one association was identified and replicated in the current study, of a coding variant in the myeloproliferative leukemia (MPL) gene, c.793C > T, p.Leu265Phe (L265F) with increased platelet count (ß = 20.6 109 cells/l, Pmeta-analysis = 2.6 × 10-13). This variant is observed at ~2% population frequency in East Asians, whereas it has not been reported in gnomAD European or African populations. Functional analysis demonstrated that expression of MPL L265F in Ba/F3 cells resulted in enhanced phosphorylation of Stat3 and ERK1/2 as compared with the reference MPL allele, supporting altered activation of the JAK-STAT signal transduction pathway as the mechanism underlying the novel association between MPL L265F and platelet count.

8.
Cardiovasc Res ; 2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33739371

RESUMO

Fibromuscular dysplasia (FMD) is a non-atherosclerotic vascular disease that may involve medium-sized muscular arteries throughout the body. The majority of FMD patients are women. Although a variety of genetic, mechanical, and hormonal factors play a role in the pathogenesis of FMD, overall, its cause remains poorly understood. It is probable that the pathogenesis of FMD is linked to a combination of genetic and environmental factors. Extensive studies have correlated the arterial lesions of FMD to histopathological findings of arterial fibrosis, cellular hyperplasia, and distortion of the abnormal architecture of the arterial wall. More recently, the vascular phenotype of lesions associated with FMD has been expanded to include arterial aneurysms, dissections, and tortuosity. However, in the absence of a string of beads or focal stenosis, these lesions do not suffice to establish the diagnosis. While FMD most commonly involves renal and cerebrovascular arteries, involvement of most arteries throughout the body has been reported. Increasing evidence highlights that FMD is a systemic arterial disease and that subclinical alterations can be found in non-affected arterial segments. Recent significant progress in FMD-related research which has led to improved understandings of the disease's clinical manifestations, natural history, epidemiology, and genetics. Ongoing work continues to focus on FMD genetics and proteomics, physiological effects of FMD on cardiovascular structure and function, and novel imaging modalities and blood-based biomarkers that can be used to identify subclinical FMD. It is also hoped that the next decade will bring the development of multi-centred and potentially international clinical trials to provide comparative effectiveness data to inform the optimal management of patients with FMD.

9.
J Hum Hypertens ; 35(3): 265-273, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32265488

RESUMO

The association of blood hemoglobin (Hb) concentration and red blood cell (RBC) count with arterial stiffness is not well-defined. Herein, we examined the associations of brachial-ankle pulse wave velocity (baPWV) and augmentation index (AI) with Hb level and RBC count from a population cohort in and around Beijing, China. A total of 3994 participants (57.1 ± 8.8 years old) were included in our analysis. Blood routine examination, baPWV, and possible covariates were examined. The mean Hb, RBC count, AI corrected for a heart rate of 75 bpm (AIP75), and baPWV were 131.4 ± 17.1 g/l, 4.2 ± 0.5 1012/l, 80.2 ± 12.0%, and 1665.3 ± 377.1 cm/s, respectively, consistent with previously described cohorts. RBC counts and Hb levels were positively associated with baPWV (ß for 1012/l RBC: 50.08 cm/s, 95% confidence interval [CI]: 30.54-69.63, p < 0.001; ß for 10 g/l Hb: 9.05 cm/s, 95% CI: 3.35-14.76, p = 0.002) and AIP75 (ß for 1012/l RBC: 1.33%, 95% CI: 0.55-2.12, p < 0.001; ß for 10 g/l Hb: 0.34%, 95% CI: 0.12-0.57, p = 0.003), despite adjustment for covariates. The average levels of baPWV in the third-fourth quartile RBC groups were higher than in the first quartile (Q1) group (p < 0.001 for all). The average levels of baPWV in the fourth quartile Hb groups were higher than in the Q1 Hb group (p = 0.038). Mean AIP75 levels in the third-fourth RBC and Hb groups were higher than in the Q1 groups (p < 0.05 for all). In conclusion, circulating blood Hb levels and RBC counts are positively associated with arterial stiffness in our community-based study.

10.
J Vasc Surg ; 73(1): 161-171, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32276022

RESUMO

OBJECTIVE: The pathologic nature of pediatric renal artery occlusive lesions causing renovascular hypertension has been the subject of numerous anecdotal reports. This study was undertaken to define the character of childhood renal artery stenoses. A better understanding of this disease is particularly germane, given its unknown etiology and the limited success of certain contemporary treatment options. METHODS: Renal artery specimens obtained during open operations in children being treated for renovascular hypertension from 2004 to 2016 were studied. Excluded from study were arteries subjected to earlier open or endovascular operations. Histologic preparations employing hematoxylin-eosin, Movat, Masson trichrome, and Verhoeff-van Gieson stains allowed characterization of the intima, media, and adventitial tissues. External and luminal diameters were measured. Microscopic data were correlated with preoperative arteriographic images. The histologic and morphologic findings were assessed in regard to coexistent nonrenal arterial and aortic lesions as well as known syndromic diseases. RESULTS: Thirty-three stenotic renal arteries from 28 children were subjected to examination. Stenoses involved the proximal-ostial renal arteries (24), central renal arteries (7), and distal segmental renal arteries (2). Ostial stenoses commonly exhibited preocclusive concentric hyperplasia of intimal tissues, frequent internal elastic lamina disruptions, and diminutive and discontinuous media. Central and distal renal stenoses most often exhibited lesser intimal cellular hyperplasia and more noticeable fibrodysplasia of the media and adventitia. The mean external and luminal diameters of the renal arteries having ostial stenoses were smaller than the expected renal artery size for a given age. Abdominal aortic coarctation or hypoplastic aortas occurred in 14 children. Neurofibromatosis type 1 affected four children with ostial renal artery disease and one child with midrenal artery disease, but there were no distinguishing features unique to their stenoses. CONCLUSIONS: Pediatric renal artery stenotic disease affects exceedingly small arteries. Ostial lesions frequently exhibit extensive luminal encroachments characterized by cellular hyperplasia of intimal tissues and scant medial smooth muscle. Central and distal renal arterial stenoses were characterized most often by extensive fibrodysplasia of the media and adventitia. The early success and durability of catheter-based angioplasty may be compromised by the cellular abnormalities of pediatric renal artery occlusive disease observed in this investigation.


Assuntos
Obstrução da Artéria Renal/diagnóstico , Artéria Renal/diagnóstico por imagem , Biópsia , Criança , Angiografia por Tomografia Computadorizada/métodos , Feminino , Humanos , Masculino , Reprodutibilidade dos Testes , Estudos Retrospectivos
11.
Cardiovasc Res ; 117(4): 1154-1165, 2021 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-32531060

RESUMO

AIMS: Fibromuscular dysplasia (FMD) and spontaneous coronary artery dissection (SCAD) are related, non-atherosclerotic arterial diseases mainly affecting middle-aged women. Little is known about their physiopathological mechanisms. We aimed to identify rare genetic causes to elucidate molecular mechanisms implicated in FMD and SCAD. METHODS AND RESULTS: We analysed 29 exomes that included familial and sporadic FMD. We identified one rare loss-of-function variant (LoF) (frequencygnomAD = 0.000075) shared by two FMD sisters in the prostaglandin I2 receptor gene (PTGIR), a key player in vascular remodelling. Follow-up was conducted by targeted or Sanger sequencing (1071 FMD and 363 SCAD patients) or lookups in exome (264 FMD) or genome sequences (480 SCAD), all independent and unrelated. It revealed four additional LoF allele carriers, in addition to several rare missense variants, among FMD patients, and two LoF allele carriers among SCAD patients, including one carrying a rare splicing mutation (c.768 + 1C>G). We used burden test to test for enrichment in patients compared to gnomAD controls, which detected a putative enrichment in FMD (PTRAPD = 8 × 10-4), but not a significant enrichment (PTRAPD = 0.12) in SCAD. The biological effects of variants on human prostaclycin receptor (hIP) signalling and protein expression were characterized using transient overexpression in human cells. We confirmed the LoFs (Q163X and P17RfsX6) and one missense (L67P), identified in one FMD and one SCAD patient, to severely impair hIP function in vitro. CONCLUSIONS: Our study shows that rare genetic mutations in PTGIR are enriched among FMD patients and found in SCAD patients, suggesting a role for prostacyclin signalling in non-atherosclerotic stenosis and dissection.

12.
Nat Genet ; 52(12): 1333-1345, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33230299

RESUMO

Genome-wide association studies identify genomic variants associated with human traits and diseases. Most trait-associated variants are located within cell-type-specific enhancers, but the molecular mechanisms governing phenotypic variation are less well understood. Here, we show that many enhancer variants associated with red blood cell (RBC) traits map to enhancers that are co-bound by lineage-specific master transcription factors (MTFs) and signaling transcription factors (STFs) responsive to extracellular signals. The majority of enhancer variants reside on STF and not MTF motifs, perturbing DNA binding by various STFs (BMP/TGF-ß-directed SMADs or WNT-induced TCFs) and affecting target gene expression. Analyses of engineered human blood cells and expression quantitative trait loci verify that disrupted STF binding leads to altered gene expression. Our results propose that the majority of the RBC-trait-associated variants that reside on transcription-factor-binding sequences fall in STF target sequences, suggesting that the phenotypic variation of RBC traits could stem from altered responsiveness to extracellular stimuli.


Assuntos
Eritrócitos/fisiologia , Regulação da Expressão Gênica/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Fatores de Transcrição/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Elementos Facilitadores Genéticos/genética , Eritrócitos/citologia , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos , Locos de Características Quantitativas/genética , Proteína Smad1/genética , Proteína Smad1/metabolismo , Fatores de Transcrição/metabolismo , Transcrição Genética/genética
13.
Nat Commun ; 11(1): 4432, 2020 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-32887874

RESUMO

Spontaneous coronary artery dissection (SCAD) is a non-atherosclerotic cause of myocardial infarction (MI), typically in young women. We undertook a genome-wide association study of SCAD (Ncases = 270/Ncontrols = 5,263) and identified and replicated an association of rs12740679 at chromosome 1q21.2 (Pdiscovery+replication = 2.19 × 10-12, OR = 1.8) influencing ADAMTSL4 expression. Meta-analysis of discovery and replication samples identified associations with P < 5 × 10-8 at chromosome 6p24.1 in PHACTR1, chromosome 12q13.3 in LRP1, and in females-only, at chromosome 21q22.11 near LINC00310. A polygenic risk score for SCAD was associated with (1) higher risk of SCAD in individuals with fibromuscular dysplasia (P = 0.021, OR = 1.82 [95% CI: 1.09-3.02]) and (2) lower risk of atherosclerotic coronary artery disease and MI in the UK Biobank (P = 1.28 × 10-17, HR = 0.91 [95% CI :0.89-0.93], for MI) and Million Veteran Program (P = 9.33 × 10-36, OR = 0.95 [95% CI: 0.94-0.96], for CAD; P = 3.35 × 10-6, OR = 0.96 [95% CI: 0.95-0.98] for MI). Here we report that SCAD-related MI and atherosclerotic MI exist at opposite ends of a genetic risk spectrum, inciting MI with disparate underlying vascular biology.


Assuntos
Anomalias dos Vasos Coronários/genética , Genes Neoplásicos , Infarto do Miocárdio/genética , Doenças Vasculares/congênito , Proteínas ADAMTS/genética , Doenças das Artérias Carótidas/complicações , Doenças das Artérias Carótidas/genética , Cromossomos/genética , Estudos de Coortes , Doença da Artéria Coronariana/genética , Feminino , Displasia Fibromuscular/complicações , Displasia Fibromuscular/genética , Estudo de Associação Genômica Ampla , Humanos , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Masculino , Metanálise como Assunto , Proteínas dos Microfilamentos/genética , Fatores de Risco , Doenças Vasculares/genética
14.
Arterioscler Thromb Vasc Biol ; 40(11): 2686-2699, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32938213

RESUMO

OBJECTIVE: While rare variants in the COL5A1 gene have been associated with classical Ehlers-Danlos syndrome and rarely with arterial dissections, recurrent variants in COL5A1 underlying a systemic arteriopathy have not been described. Monogenic forms of multifocal fibromuscular dysplasia (mFMD) have not been previously defined. Approach and Results: We studied 4 independent probands with the COL5A1 pathogenic variant c.1540G>A, p.(Gly514Ser) who presented with arterial aneurysms, dissections, tortuosity, and mFMD affecting multiple arteries. Arterial medial fibroplasia and smooth muscle cell disorganization were confirmed histologically. The COL5A1 c.1540G>A variant is predicted to be pathogenic in silico and absent in gnomAD. The c.1540G>A variant is on a shared 160.1 kb haplotype with 0.4% frequency in Europeans. Furthermore, exome sequencing data from a cohort of 264 individuals with mFMD were examined for COL5A1 variants. In this mFMD cohort, COL5A1 c.1540G>A and 6 additional relatively rare COL5A1 variants predicted to be deleterious in silico were identified and were associated with arterial dissections (P=0.005). CONCLUSIONS: COL5A1 c.1540G>A is the first recurring variant recognized to be associated with arterial dissections and mFMD. This variant presents with a phenotype reminiscent of vascular Ehlers-Danlos syndrome. A shared haplotype among probands supports the existence of a common founder. Relatively rare COL5A1 genetic variants predicted to be deleterious by in silico analysis were identified in ≈2.7% of mFMD cases, and as they were enriched in patients with arterial dissections, may act as disease modifiers. Molecular testing for COL5A1 should be considered in patients with a phenotype overlapping with vascular Ehlers-Danlos syndrome and mFMD.


Assuntos
Aneurisma Dissecante/genética , Artérias/patologia , Colágeno Tipo V/genética , Síndrome de Ehlers-Danlos/genética , Displasia Fibromuscular/genética , Polimorfismo de Nucleotídeo Único , Adulto , Aneurisma Dissecante/diagnóstico por imagem , Aneurisma Dissecante/patologia , Artérias/diagnóstico por imagem , Síndrome de Ehlers-Danlos/diagnóstico por imagem , Síndrome de Ehlers-Danlos/patologia , Feminino , Displasia Fibromuscular/diagnóstico por imagem , Displasia Fibromuscular/patologia , Predisposição Genética para Doença , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Adulto Jovem
15.
Am J Physiol Renal Physiol ; 318(5): F1177-F1187, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32223311

RESUMO

Loss-of-function mutations in phospholipase C-ε1 (PLCE1) have been detected in patients with nephrotic syndrome, but other family members with the same mutation were asymptomatic, suggesting additional stressor are required to cause the full phenotype. Consistent with these observations, we determined that global Plce1-deficient mice have histologically normal glomeruli and no albuminuria at baseline. Angiotensin II (ANG II) is known to induce glomerular damage in genetically susceptible individuals. Therefore, we tested whether ANG II enhances glomerular damage in Plce1-deficient mice. ANG II increased blood pressure equally in Plce1-deficient and wild-type littermates. Additionally, it led to 20-fold increased albuminuria and significantly more sclerotic glomeruli in Plce1-deficient mice compared with wild-type littermates. Furthermore, Plce1-deficient mice demonstrated diffuse mesangial expansion, podocyte loss, and focal podocyte foot process effacement. To determine whether these effects are mediated by hypertension and hyperfiltration, rather than directly through ANG II, we raised blood pressure to a similar level using DOCA + salt + uninephrectomy and norepinephrine. This caused a fivefold increase in albuminuria in Plce1-deficient mice and a significant increase in the number of sclerotic glomeruli. Consistent with previous findings in mice, we detected strong PLCE1 transcript expression in podocytes using single cell sequencing of human kidney tissue. In hemagglutinin-tagged Plce1 transgenic mice, Plce1 was detected in podocytes and also in glomerular arterioles using immunohistochemistry. Our data demonstrate that Plce1 deficiency in mice predisposes to glomerular damage secondary to hypertensive insults.


Assuntos
Pressão Sanguínea , Glomerulonefrite/enzimologia , Hipertensão/enzimologia , Glomérulos Renais/enzimologia , Fosfoinositídeo Fosfolipase C/deficiência , Albuminúria/enzimologia , Albuminúria/genética , Albuminúria/fisiopatologia , Animais , Acetato de Desoxicorticosterona , Modelos Animais de Doenças , Feminino , Glomerulonefrite/genética , Glomerulonefrite/patologia , Glomerulonefrite/fisiopatologia , Hipertensão/genética , Hipertensão/fisiopatologia , Glomérulos Renais/patologia , Glomérulos Renais/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nefrectomia , Fosfoinositídeo Fosfolipase C/genética , Cloreto de Sódio na Dieta
16.
J Vasc Surg ; 72(6): 2035-2046.e1, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32276020

RESUMO

BACKGROUND: Renovascular hypertension (RVH) associated with renal artery and abdominal aortic narrowings is the third most common cause of pediatric hypertension. Untreated children may experience major cardiopulmonary complications, stroke, renal failure, and death. The impetus of this study was to describe the increasingly complex surgical practice for such patients with an emphasis on anatomic phenotype and contemporary outcomes after surgical management as a means of identifying those factors responsible for persistent or recurrent hypertension necessitating reoperation. METHODS: A retrospective analysis was performed of consecutive pediatric patients with RVH undergoing open surgical procedures at the University of Michigan from 1991 to 2017. Anatomic phenotype and patient risk factors were analyzed to predict outcomes of blood pressure control and the need for secondary operations using ordered and binomial logistic multinomial regression models, respectively. RESULTS: There were 169 children (76 girls, 93 boys) who underwent primary index operations at a median age of 8.3 years; 31 children (18%) had neurofibromatosis type 1, 76 (45%) had abdominal aortic coarctations, and 28 (17%) had a single functioning kidney. Before treatment at the University of Michigan, 51 children experienced failed previous open operations (15) or endovascular interventions (36) for RVH at other institutions. Primary surgical interventions (342) included main renal artery (136) and segmental renal artery (10) aortic reimplantation, renal artery bypass (55), segmental renal artery embolization (10), renal artery patch angioplasty (8), resection with reanastomosis (4), and partial or total nephrectomy (25). Non-renal artery procedures included patch aortoplasty (32), aortoaortic bypass (32), and splanchnic arterial revascularization (30). Nine patients required reoperation in the early postoperative period. During a mean follow-up of 49 months, secondary interventions were required in 35 children (21%), including both open surgical (37) and endovascular (14) interventions. Remedial intervention to preserve primary renal artery patency or a nephrectomy if such was impossible was required in 22 children (13%). The remaining secondary procedures were performed to treat previously untreated disease that became clinically evident during follow-up. Age at operation and abdominal aortic coarctation were independent predictors for reoperation. The overall experience revealed hypertension to be cured in 74 children (44%), improved in 78 (46%), and unchanged in 17 (10%). Children undergoing remedial operations were less likely (33%) to be cured of hypertension. There was no perioperative death or renal insufficiency requiring dialysis after either primary or secondary interventions. CONCLUSIONS: Contemporary surgical treatment of pediatric RVH provides a sustainable overall benefit to 90% of children. Interventions in the very young (<3 years) and concurrent abdominal aortic coarctation increase the likelihood of reoperation. Patients undergoing remedial surgery after earlier operative failures are less likely to be cured of hypertension. Judicious postoperative surveillance is imperative in children surgically treated for RVH.


Assuntos
Aorta Abdominal/cirurgia , Coartação Aórtica/cirurgia , Pressão Sanguínea , Hipertensão Renovascular/cirurgia , Obstrução da Artéria Renal/cirurgia , Procedimentos Cirúrgicos Vasculares , Adolescente , Fatores Etários , Anti-Hipertensivos/uso terapêutico , Aorta Abdominal/anormalidades , Aorta Abdominal/diagnóstico por imagem , Aorta Abdominal/fisiopatologia , Coartação Aórtica/complicações , Coartação Aórtica/diagnóstico por imagem , Coartação Aórtica/fisiopatologia , Criança , Pré-Escolar , Feminino , Humanos , Hipertensão Renovascular/diagnóstico , Hipertensão Renovascular/etiologia , Hipertensão Renovascular/fisiopatologia , Masculino , Obstrução da Artéria Renal/complicações , Obstrução da Artéria Renal/diagnóstico por imagem , Obstrução da Artéria Renal/fisiopatologia , Estudos Retrospectivos , Resultado do Tratamento , Procedimentos Cirúrgicos Vasculares/efeitos adversos
17.
PLoS Genet ; 15(12): e1008500, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31869403

RESUMO

Most genome-wide association and fine-mapping studies to date have been conducted in individuals of European descent, and genetic studies of populations of Hispanic/Latino and African ancestry are limited. In addition, these populations have more complex linkage disequilibrium structure. In order to better define the genetic architecture of these understudied populations, we leveraged >100,000 phased sequences available from deep-coverage whole genome sequencing through the multi-ethnic NHLBI Trans-Omics for Precision Medicine (TOPMed) program to impute genotypes into admixed African and Hispanic/Latino samples with genome-wide genotyping array data. We demonstrated that using TOPMed sequencing data as the imputation reference panel improves genotype imputation quality in these populations, which subsequently enhanced gene-mapping power for complex traits. For rare variants with minor allele frequency (MAF) < 0.5%, we observed a 2.3- to 6.1-fold increase in the number of well-imputed variants, with 11-34% improvement in average imputation quality, compared to the state-of-the-art 1000 Genomes Project Phase 3 and Haplotype Reference Consortium reference panels. Impressively, even for extremely rare variants with minor allele count <10 (including singletons) in the imputation target samples, average information content rescued was >86%. Subsequent association analyses of TOPMed reference panel-imputed genotype data with hematological traits (hemoglobin (HGB), hematocrit (HCT), and white blood cell count (WBC)) in ~21,600 African-ancestry and ~21,700 Hispanic/Latino individuals identified associations with two rare variants in the HBB gene (rs33930165 with higher WBC [p = 8.8x10-15] in African populations, rs11549407 with lower HGB [p = 1.5x10-12] and HCT [p = 8.8x10-10] in Hispanics/Latinos). By comparison, neither variant would have been genome-wide significant if either 1000 Genomes Project Phase 3 or Haplotype Reference Consortium reference panels had been used for imputation. Our findings highlight the utility of the TOPMed imputation reference panel for identification of novel rare variant associations not previously detected in similarly sized genome-wide studies of under-represented African and Hispanic/Latino populations.


Assuntos
Afro-Americanos/genética , Hispano-Americanos/genética , Medicina de Precisão/métodos , Sequenciamento Completo do Genoma/métodos , Globinas beta/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biologia Computacional/métodos , Bases de Dados Genéticas , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genética Populacional , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Estados Unidos
18.
Proc Natl Acad Sci U S A ; 116(47): 23618-23624, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31712416

RESUMO

Endothelial cells (ECs) are highly specialized across vascular beds. However, given their interspersed anatomic distribution, comprehensive characterization of the molecular basis for this heterogeneity in vivo has been limited. By applying endothelial-specific translating ribosome affinity purification (EC-TRAP) combined with high-throughput RNA sequencing analysis, we identified pan EC-enriched genes and tissue-specific EC transcripts, which include both established markers and genes previously unappreciated for their presence in ECs. In addition, EC-TRAP limits changes in gene expression after EC isolation and in vitro expansion, as well as rapid vascular bed-specific shifts in EC gene expression profiles as a result of the enzymatic tissue dissociation required to generate single-cell suspensions for fluorescence-activated cell sorting or single-cell RNA sequencing analysis. Comparison of our EC-TRAP with published single-cell RNA sequencing data further demonstrates considerably greater sensitivity of EC-TRAP for the detection of low abundant transcripts. Application of EC-TRAP to examine the in vivo host response to lipopolysaccharide (LPS) revealed the induction of gene expression programs associated with a native defense response, with marked differences across vascular beds. Furthermore, comparative analysis of whole-tissue and TRAP-selected mRNAs identified LPS-induced differences that would not have been detected by whole-tissue analysis alone. Together, these data provide a resource for the analysis of EC-specific gene expression programs across heterogeneous vascular beds under both physiologic and pathologic conditions.


Assuntos
Células Endoteliais/metabolismo , Regulação da Expressão Gênica , Biossíntese de Proteínas , RNA Mensageiro/metabolismo , Animais , Plaquetas/metabolismo , Encéfalo/irrigação sanguínea , Regulação da Expressão Gênica/efeitos dos fármacos , Sequenciamento de Nucleotídeos em Larga Escala , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Especificidade de Órgãos , Isoformas de Proteínas/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas Ribossômicas/metabolismo , Ribossomos/metabolismo , Sensibilidade e Especificidade , Análise de Célula Única , Transgenes , Vísceras/irrigação sanguínea
19.
Ann Vasc Surg ; 60: 147-155.e2, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31200039

RESUMO

BACKGROUND: Renal artery aneurysms (RAAs) may reflect a systemic dysplastic arteriopathy, independent of a recognized connective tissue disease. It is hypothesized that RAAs are associated with an increased risk of intracranial aneurysms (IcAs). The objective of this study was to better define the association of IcAs in women with RAAs. METHODS: Women aged 20 to 60 years who presented with RAAs at the University of Michigan from 2001 to 2016 were included in the study. Their clinical status and radiologic images were retrospectively reviewed, with particular attention directed to the prevalence of IcAs. Phenotypic characteristics predictive of associated cerebrovascular lesions were assessed using various statistical analyses, including binomial logistic regression. RESULTS: Among 83 women with RAAs, the average age at the time of RAA detection was 45.3 ± 9.9 years (range, 20-60 years). Hypertension affected 56 (67.5%) patients and poorly controlled hypertension prompted imaging for suspected renal arterial disease in 12 (14.5%) patients. Multifocal fibromuscular dysplasia occurred in 12 (14.8%) of patients, and unifocal stenosis affected 7 (8.4%) patients. Imaging of the intracranial vasculature (n = 31) documented 12 aneurysms in 9 women, with the cavernous internal carotid artery being the most commonly affected artery. Among the study's patients, 20 (24.1%) had an "at-risk disorder for IcA formation," although the frequency of relevant "at-risk disorders" in those with and without IcAs was not statistically different (P = 0.21). Rupture risk defined by PHASES score was less than 1% for 10 IcAs, but 2 IcAs carried a 2.4% and 7.2% rupture risk, respectively, over a 5-year time period. Surgical management was pursued in 6 (50%) of the study's IcAs. CONCLUSIONS: Coexisting RAAs and IcAs may reflect a systemic arteriopathy. IcAs appear to occur with greater frequency in women with RAAs than the general population. This observation warrants prospective investigation as to the clinical appropriateness and relevance of cerebrovascular imaging in women with RAAs. Furthermore, this study's findings prompt further investigation of the underlying pathogenesis of what appears to be a broader and more complex arterial disease than previously recognized.


Assuntos
Aneurisma/epidemiologia , Aneurisma Intracraniano/epidemiologia , Artéria Renal , Adulto , Aneurisma/diagnóstico por imagem , Feminino , Humanos , Incidência , Aneurisma Intracraniano/diagnóstico por imagem , Michigan/epidemiologia , Pessoa de Meia-Idade , Prevalência , Prognóstico , Artéria Renal/diagnóstico por imagem , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores Sexuais , Fatores de Tempo , Adulto Jovem
20.
Circ Genom Precis Med ; 12(6): e002476, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31211624

RESUMO

BACKGROUND: Thoracic aortic dissection is an emergent life-threatening condition. Routine screening for genetic variants causing thoracic aortic dissection is not currently performed for patients or family members. METHODS: We performed whole exome sequencing of 240 patients with thoracic aortic dissection (n=235) or rupture (n=5) and 258 controls matched for age, sex, and ancestry. Blinded to case-control status, we annotated variants in 11 genes for pathogenicity. RESULTS: Twenty-four pathogenic variants in 6 genes (COL3A1, FBN1, LOX, PRKG1, SMAD3, and TGFBR2) were identified in 26 individuals, representing 10.8% of aortic cases and 0% of controls. Among dissection cases, we compared those with pathogenic variants to those without and found that pathogenic variant carriers had significantly earlier onset of dissection (41 versus 57 years), higher rates of root aneurysm (54% versus 30%), less hypertension (15% versus 57%), lower rates of smoking (19% versus 45%), and greater incidence of aortic disease in family members. Multivariable logistic regression showed that pathogenic variant carrier status was significantly associated with age <50 (odds ratio [OR], 5.5; 95% CI, 1.6-19.7), no history of hypertension (OR, 5.6; 95% CI, 1.4-22.3), and family history of aortic disease (mother: OR, 5.7; 95% CI, 1.4-22.3, siblings: OR, 5.1; 95% CI, 1.1-23.9, children: OR, 6.0; 95% CI, 1.4-26.7). CONCLUSIONS: Clinical genetic testing of known hereditary thoracic aortic dissection genes should be considered in patients with a thoracic aortic dissection, followed by cascade screening of family members, especially in patients with age-of-onset <50 years, family history of thoracic aortic disease, and no history of hypertension.


Assuntos
Aneurisma Dissecante/genética , Aneurisma da Aorta Torácica/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Aneurisma Dissecante/diagnóstico , Aneurisma Dissecante/fisiopatologia , Aneurisma da Aorta Torácica/diagnóstico , Aneurisma da Aorta Torácica/fisiopatologia , Estudos de Casos e Controles , Colágeno Tipo III/genética , Proteína Quinase Dependente de GMP Cíclico Tipo I/genética , Feminino , Fibrilina-1/genética , Testes Genéticos , Humanos , Hipertensão , Masculino , Pessoa de Meia-Idade , Linhagem , Proteína-Lisina 6-Oxidase/genética , Receptor do Fator de Crescimento Transformador beta Tipo II/genética , Fatores de Risco , Proteína Smad3/genética , Sequenciamento Completo do Exoma , Adulto Jovem
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