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  • Ovid Technologies (Wolters Kluwer Health)  (7)
  • 1
    Online-Ressource
    Online-Ressource
    Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension
    Ovid Technologies (Wolters Kluwer Health) ; 2017
    In:  Circulation Vol. 136, No. 21 ( 2017-11-21), p. 2022-2033
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 136, No. 21 ( 2017-11-21), p. 2022-2033
    Kurzfassung: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 ( BMPR2 ) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene ( EIF2AK4 ) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. Methods: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource–Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of 〈 1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. Results: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (K co ; 33% [interquartile range, 30%–35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23–38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival. Conclusions: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low K co and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation.
    Materialart: Online-Ressource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/CIRCULATIONAHA.117.028351
    Sprache: Englisch
    Verlag: Ovid Technologies (Wolters Kluwer Health)
    Publikationsdatum: 2017
    ZDB Id: 1466401-X
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 2
    Online-Ressource
    Online-Ressource
    Bayesian Inference Associates Rare KDR Variants With Specific Phenotypes in Pulmonary Arterial Hypertension
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Circulation: Genomic and Precision Medicine Vol. 14, No. 1 ( 2021-02)
    Details
    In: Circulation: Genomic and Precision Medicine, Ovid Technologies (Wolters Kluwer Health), Vol. 14, No. 1 ( 2021-02)
    Kurzfassung: Approximately 25% of patients with pulmonary arterial hypertension (PAH) have been found to harbor rare mutations in disease-causing genes. To identify missing heritability in PAH, we integrated deep phenotyping with whole-genome sequencing data using Bayesian statistics. Methods: We analyzed 13 037 participants enrolled in the NBR study (NIHR BioResource—Rare Diseases), of which 1148 were recruited to the PAH domain. To test for genetic associations between genes and selected phenotypes of pulmonary hypertension, we used the Bayesian rare variant association method BeviMed. Results: Heterozygous, high impact, likely loss-of-function variants in the kinase insert domain receptor ( KDR ) gene were strongly associated with significantly reduced transfer coefficient for carbon monoxide (posterior probability=0.989) and older age at diagnosis (posterior probability=0.912). We also provide evidence for familial segregation of a rare nonsense KDR variant with these phenotypes. On computed tomographic imaging of the lungs, a range of parenchymal abnormalities were observed in the 5 patients harboring these predicted deleterious variants in KDR . Four additional PAH cases with rare likely loss-of-function variants in KDR were independently identified in the US PAH Biobank cohort with similar phenotypic characteristics. Conclusions: The Bayesian inference approach allowed us to independently validate KDR , which encodes for the VEGFR2 (vascular endothelial growth factor receptor 2), as a novel PAH candidate gene. Furthermore, this approach specifically associated high impact likely loss-of-function variants in the genetically constrained gene with distinct phenotypes. These findings provide evidence for KDR being a clinically actionable PAH gene and further support the central role of the vascular endothelium in the pathobiology of PAH.
    Materialart: Online-Ressource
    ISSN: 2574-8300
    URL: Article
    DOI: 10.1161/CIRCGEN.120.003155
    Sprache: Englisch
    Verlag: Ovid Technologies (Wolters Kluwer Health)
    Publikationsdatum: 2021
    ZDB Id: 2927603-2
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 3
    Online-Ressource
    Online-Ressource
    Four Genetic Loci Influencing Electrocardiographic Indices of Left Ventricular Hypertrophy
    Ovid Technologies (Wolters Kluwer Health) ; 2011
    In:  Circulation: Cardiovascular Genetics Vol. 4, No. 6 ( 2011-12), p. 626-635
    Details
    In: Circulation: Cardiovascular Genetics, Ovid Technologies (Wolters Kluwer Health), Vol. 4, No. 6 ( 2011-12), p. 626-635
    Kurzfassung: Presence of left ventricular hypertrophy on an ECG (ECG-LVH) is widely assessed clinically and provides prognostic information in some settings. There is evidence for significant heritability of ECG-LVH. We conducted a large-scale gene-centric association analysis of 4 commonly measured indices of ECG-LVH. Methods and Results— We calculated the Sokolow-Lyon index, Cornell product, 12-lead QRS voltage sum, and 12-lead QRS voltage product in 10 256 individuals from 3 population-based cohorts and typed their DNA using a customized gene array (the Illumina HumanCVD BeadChip 50K array), containing 49 094 genetic variants in ≈2100 genes of cardiovascular relevance. We followed-up promising associations in 11 777 additional individuals. We identified and replicated 4 loci associated with ECG-LVH indices: 3p22.2 ( SCN5A , rs6797133, P =1.22×10 −7 ) with Cornell product and 12q13.3 ( PTGES3 , rs2290893, P =3.74×10 −8 ), 15q25.2 ( NMB , rs2292462, P =3.23×10 −9 ), and 15q26.3 ( IGF1R , rs4966014, P =1.26×10 -7 ) with the 12-lead QRS voltage sum. The odds ratio of being in the top decile for the 12-lead QRS voltage sum for those carrying 6 trait-raising alleles at the 12q13.3, 15q25.2, and 15q26.3 loci versus those carrying 0 to 1 alleles was 1.60 (95% CI: 1.20 to 2.29). Lead single-nucleotide polymorphisms at the 12q13.3 and 15q25.2 loci showed significant expression quantitative trait loci effects in monocytes. Conclusions— These findings provide novel insights into the genetic determination of ECG-LVH. The findings could help to improve our understanding of the mechanisms determining this prognostically important trait.
    Materialart: Online-Ressource
    ISSN: 1942-325X , 1942-3268
    URL: Article
    DOI: 10.1161/CIRCGENETICS.111.960203
    Sprache: Englisch
    Verlag: Ovid Technologies (Wolters Kluwer Health)
    Publikationsdatum: 2011
    ZDB Id: 2927603-2
    ZDB Id: 2457085-0
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 4
    Online-Ressource
    Online-Ressource
    How common are single gene mutations as a cause for lacunar stroke? : A targeted gene panel study
    Ovid Technologies (Wolters Kluwer Health) ; 2019
    In:  Neurology Vol. 93, No. 22 ( 2019-11-26), p. e2007-e2020
    Details
    In: Neurology, Ovid Technologies (Wolters Kluwer Health), Vol. 93, No. 22 ( 2019-11-26), p. e2007-e2020
    Kurzfassung: To determine the frequency of rare and pertinent disease-causing variants in small vessel disease (SVD)-associated genes (such as NOTCH3 , HTRA1 , COL4A1 , COL4A2 , FOXC1 , TREX1 , and GLA ) in cerebral SVD, we performed targeted gene sequencing in 950 patients with younger-onset apparently sporadic SVD stroke using a targeted sequencing panel. Methods We designed a high-throughput sequencing panel to identify variants in 15 genes (7 known SVD genes, 8 SVD-related disorder genes). The panel was used to screen a population of 950 patients with younger-onset (≤70 years) MRI-confirmed SVD stroke, recruited from stroke centers across the United Kingdom. Variants were filtered according to their frequency in control databases, predicted effect, presence in curated variant lists, and combined annotation dependent depletion scores. Whole genome sequencing and genotyping were performed on a subset of patients to provide a direct comparison of techniques. The frequency of known disease-causing and pertinent variants of uncertain significance was calculated. Results We identified previously reported variants in 14 patients (8 cysteine-changing NOTCH3 variants in 11 patients, 2 HTRA1 variants in 2 patients, and 1 missense COL4A1 variant in 1 patient). In addition, we identified 29 variants of uncertain significance in 32 patients. Conclusion Rare monogenic variants account for about 1.5% of younger onset lacunar stroke. Most are cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy variants, but the second most common gene affected is HTRA1. A high-throughput sequencing technology platform is an efficient, reliable method to screen for such mutations.
    Materialart: Online-Ressource
    ISSN: 0028-3878 , 1526-632X
    URL: Article
    DOI: 10.1212/WNL.0000000000008544
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: Ovid Technologies (Wolters Kluwer Health)
    Publikationsdatum: 2019
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 5
    Online-Ressource
    Online-Ressource
    Plasma Proteomics of Renal Function: A Transethnic Meta-Analysis and Mendelian Randomization Study
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Journal of the American Society of Nephrology Vol. 32, No. 7 ( 2021-7), p. 1747-1763
    Details
    In: Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 32, No. 7 ( 2021-7), p. 1747-1763
    Kurzfassung: Studies on the plasma proteome of renal function have identified several biomarkers, but have lacked replication, were limited to European populations, and/or did not investigate causality with eGFR. Among four cohorts in a transethnic cross-sectional study, 57 plasma proteins were associated with eGFR, 23 of them also with CKD. Furthermore, Mendelian randomization and gene expression analyses in kidney tissue highlighted testican-2 as a physiological marker of kidney disease progression with potential clinical relevance, and identified a few additional proteins warranting further investigation. Background Studies on the relationship between renal function and the human plasma proteome have identified several potential biomarkers. However, investigations have been conducted largely in European populations, and causality of the associations between plasma proteins and kidney function has never been addressed. Methods A cross-sectional study of 993 plasma proteins among 2882 participants in four studies of European and admixed ancestries (KORA, INTERVAL, HUNT, QMDiab) identified transethnic associations between eGFR/CKD and proteomic biomarkers. For the replicated associations, two-sample bidirectional Mendelian randomization (MR) was used to investigate potential causal relationships. Publicly available datasets and transcriptomic data from independent studies were used to examine the association between gene expression in kidney tissue and eGFR. Results In total, 57 plasma proteins were associated with eGFR, including one novel protein. Of these, 23 were additionally associated with CKD. The strongest inferred causal effect was the positive effect of eGFR on testican-2, in line with the known biological role of this protein and the expression of its protein-coding gene ( SPOCK2 ) in renal tissue. We also observed suggestive evidence of an effect of melanoma inhibitory activity (MIA), carbonic anhydrase III, and cystatin-M on eGFR. Conclusions In a discovery-replication setting, we identified 57 proteins transethnically associated with eGFR. The revealed causal relationships are an important stepping stone in establishing testican-2 as a clinically relevant physiological marker of kidney disease progression, and point to additional proteins warranting further investigation.
    Materialart: Online-Ressource
    ISSN: 1046-6673 , 1533-3450
    URL: Article
    DOI: 10.1681/ASN.2020071070
    Sprache: Englisch
    Verlag: Ovid Technologies (Wolters Kluwer Health)
    Publikationsdatum: 2021
    ZDB Id: 2029124-3
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 6
    Online-Ressource
    Online-Ressource
    Abstract 5507: Toll Like Receptor 4 Activation Elicits Pro-atherogenic Gene Activation In Monocytes In Humans
    Ovid Technologies (Wolters Kluwer Health) ; 2008
    In:  Circulation Vol. 118, No. suppl_18 ( 2008-10-28)
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 118, No. suppl_18 ( 2008-10-28)
    Kurzfassung: Introduction: Inflammatory activation of both circulating blood cells as well as vessel wall cells is a hallmark of atherogenesis. Agonists of the Toll-like receptor 4 pathway, present on white blood cells as well as endothelial cells, have been associated with a pro-atherogenic state. Recently, standardized inflammatory challenge models using lipopolysaccharide (LPS) have been suggested to mimick these atherogenic changes. However, similarity between circulating pathways and ’vessel wall’ pathways need further validation. Therefore, we evaluated the effects of in vivo LPS challenge on circulating monocytes in humans. Methods: A bolus of Escherichia coli endotoxin (LPS 1 ng/kg bodyweight) or NaCl was infused intravenously in healthy male volunteers (n=13). Blood was drawn at 0, 1 and 4 hours after the challenge. The monocytes (CD14+ cells) were isolated using positive MACS selection. Subsequently, mRNA sample extraction using RnaseBee was performed. cDNA was prepared, amplified, labeled and then hybridized onto spotted oligonucleotide microarrays before scanning. Data were analyzed using R-project version 2.2.0. Validation Taqman took place. Results: Following LPS challenge, CD14+ count dropped by 48% in the first hour due to margination of monocytes, followed by normalization at 4 hours. Purity of CD14+ fraction approximated 90%. LPS was associated with upregulation of a series of pro-atherogenic genes (BID, DIPA, FRA-1, HSP27, HSP70, ILRN, MIP-1a, MIP1b, S100A9, SLA1, TIMPS, TLR2), immune system related genes (CLP1, DF, CD45-AP, HLA-DPB1, BATF, C3AR1, CD14) as well as a series of unrelated genes. No genes were differentially expressed during saline control experiments. RT-PCR confirmed upregulation of CD14, SLA1, BATF, C3AR1, MIP-B, TLR-2, VCAN and ILRN. Conclusion: TLR4 activation following LPS challenge is associated with potent activation of monocytic pathways involved in chemotaxis and immune activation. These activation patterns bear great resemblance to those reported in atherogenic vessel wall. It is tempting to speculate that circulating cells (’vulnerable blood’) can be used as a surrogate to detect high-risk vessel wall lesions (vulnerable patient).
    Materialart: Online-Ressource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/circ.118.suppl_18.S_563-b
    Sprache: Englisch
    Verlag: Ovid Technologies (Wolters Kluwer Health)
    Publikationsdatum: 2008
    ZDB Id: 1466401-X
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 7
    Online-Ressource
    Online-Ressource
    Repeated Replication and a Prospective Meta-Analysis of the Association Between Chromosome 9p21.3 and Coronary Artery Disease
    Ovid Technologies (Wolters Kluwer Health) ; 2008
    In:  Circulation Vol. 117, No. 13 ( 2008-04), p. 1675-1684
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 117, No. 13 ( 2008-04), p. 1675-1684
    Kurzfassung: Background— Recently, genome-wide association studies identified variants on chromosome 9p21.3 as affecting the risk of coronary artery disease (CAD). We investigated the association of this locus with CAD in 7 case-control studies and undertook a meta-analysis. Methods and Results— A single-nucleotide polymorphism (SNP), rs1333049, representing the 9p21.3 locus, was genotyped in 7 case-control studies involving a total of 4645 patients with myocardial infarction or CAD and 5177 controls. The mode of inheritance was determined. In addition, in 5 of the 7 studies, we genotyped 3 additional SNPs to assess a risk-associated haplotype (ACAC). Finally, a meta-analysis of the present data and previously published samples was conducted. A limited fine mapping of the locus was performed. The risk allele (C) of the lead SNP, rs1333049, was uniformly associated with CAD in each study ( P 〈 0.05). In a pooled analysis, the odds ratio per copy of the risk allele was 1.29 (95% confidence interval, 1.22 to 1.37; P =0.0001). Haplotype analysis further suggested that this effect was not homogeneous across the haplotypic background (test for interaction, P =0.0079). An autosomal-additive mode of inheritance best explained the underlying association. The meta-analysis of the rs1333049 SNP in 12 004 cases and 28 949 controls increased the overall level of evidence for association with CAD to P =6.04×10 −10 (odds ratio, 1.24; 95% confidence interval, 1.20 to 1.29). Genotyping of 31 additional SNPs in the region identified several with a highly significant association with CAD, but none had predictive information beyond that of the rs1333049 SNP. Conclusion— This broad replication provides unprecedented evidence for association between genetic variants at chromosome 9p21.3 and risk of CAD.
    Materialart: Online-Ressource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/CIRCULATIONAHA.107.730614
    Sprache: Englisch
    Verlag: Ovid Technologies (Wolters Kluwer Health)
    Publikationsdatum: 2008
    ZDB Id: 1466401-X
    Standort Signatur Einschränkungen Verfügbarkeit
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