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  1. Artikel: In silico analysis of upstream variants in Brazilian patients with Familial Hypercholesterolemia

    Nayara Góes de Araújo, Jéssica / Fernandes de Oliveira, Victor / Bassani Borges, Jéssica / Dagli-Hernandez, Carolina / da Silva Rodrigues Marçal, Elisangela / Caroline Costa de Freitas, Renata / Medeiros Bastos, Gisele / Marques Gonçalves, Rodrigo / Arpad Faludi, André / Elim Jannes, Cinthia / da Costa Pereira, Alexandre / Dominguez Crespo Hirata, Rosario / Hiroyuki Hirata, Mario / Ducati Luchessi, André / Nogueira Silbiger, Vivian

    Gene. 2022 Sept. 19,

    2022  

    Abstract: Familial hypercholesterolemia (FH) is a prevalent autosomal genetic disease associated with increased risk of early cardiovascular events and death due to chronic exposure to very high levels of low-density lipoprotein cholesterol (LDL-c). Pathogenic ... ...

    Abstract Familial hypercholesterolemia (FH) is a prevalent autosomal genetic disease associated with increased risk of early cardiovascular events and death due to chronic exposure to very high levels of low-density lipoprotein cholesterol (LDL-c). Pathogenic variants in the coding regions of LDLR, APOB and PCSK9 account for most FH cases, and variants in non-coding regions maybe involved in FH as well. Variants in the upstream region of LDLR, APOB and PCSK9 were screened by targeted next-generation sequencing and their effects were explored using in silico tools. Twenty-five patients without pathogenic variants in FH-related genes were selected. 3 kb upstream regions of LDLR, APOB and PCSK9 were sequenced using the AmpliSeq (Illumina) and Miseq Reagent Nano Kit v2 (Illumina). Sequencing data were analyzed using variant discovery and functional annotation tools. Potentially regulatory variants were selected by integrating data from public databases, published data and context-dependent regulatory prediction score. Thirty-four single nucleotide variants (SNVs) in upstream regions were identified (6 in LDLR, 15 in APOB, and 13 in PCSK9). Five SNVs were prioritized as potentially regulatory variants (rs934197, rs9282606, rs36218923, rs538300761, g.55038486A>G). APOB rs934197 was previously associated with increased rate of transcription, which in silico analysis suggests that could be due to reducing binding affinity of a transcriptional repressor. Our findings highlight the importance of variant screening outside of coding regions of all relevant genes. Further functional studies are necessary to confirm that prioritized variants could impact gene regulation and contribute to the FH phenotype.
    Schlagwörter chronic exposure ; computer simulation ; death ; genes ; genetic disorders ; hypercholesterolemia ; low density lipoprotein cholesterol ; phenotype ; prediction ; repressor proteins ; risk
    Sprache Englisch
    Erscheinungsverlauf 2022-0919
    Erscheinungsort Elsevier B.V.
    Dokumenttyp Artikel
    Anmerkung Pre-press version
    ZDB-ID 391792-7
    ISSN 1879-0038 ; 0378-1119
    ISSN (online) 1879-0038
    ISSN 0378-1119
    DOI 10.1016/j.gene.2022.146908
    Datenquelle NAL Katalog (AGRICOLA)

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    Verfügbar in ZB MED Bonn

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  2. Artikel ; Online: Identification of pathogenic variants in the Brazilian cohort with Familial hypercholesterolemia using exon-targeted gene sequencing

    Borges, Jéssica Bassani / Oliveira, Victor Fernandes / Dagli-Hernandez, Carolina / Ferreira, Glaucio Monteiro / Barbosa, Thais Kristini Almendros Afonso / da Silva Rodrigues Marçal, Elisangela / Los, Bruna / Malaquias, Vanessa Barbosa / Bortolin, Raul Hernandes / Freitas, Renata Caroline Costa / Mori, Augusto Akira / Bastos, Gisele Medeiros / Gonçalves, Rodrigo Marques / Araújo, Daniel Branco / Zatz, Henry / Bertolami, Adriana / Faludi, André Arpad / Bertolami, Marcelo Chiara / de Moraes Rego Souza, Amanda Guerra /
    França, João Ítalo Dias / Thurow, Helena Strelow / Hirata, Thiago Dominguez Crespo / Nakaya, Helder Takashi Imoto / Jannes, Cinthia Elim / da Costa Pereira, Alexandre / Silbiger, Vivian Nogueira / Luchessi, André Ducati / Araújo, Jéssica Nayara Góes / Nakazone, Marcelo Arruda / Carmo, Tayanne Silva / Souza, Dorotéia Rossi Silva / Moriel, Patricia / Wang, Jaqueline Yu Ting / Naslavsky, Michel Satya / Gorjão, Renata / Pithon-Curi, Tania Cristina / Curi, Rui / Fajardo, Cristina Moreno / Wang, Hui-Tzu Lin / Garófalo, Adriana Regina / Cerda, Alvaro / Sampaio, Marcelo Ferraz / Hirata, Rosario Dominguez Crespo / Hirata, Mário Hiroyuki

    Gene. 2023 July, v. 875 p.147501-

    2023  

    Abstract: Familial hypercholesterolemia (FH) is a monogenic disease characterized by high plasma low-density lipoprotein cholesterol (LDL-c) levels and increased risk of premature atherosclerotic cardiovascular disease. Mutations in FH‐related genes account for 40% ...

    Abstract Familial hypercholesterolemia (FH) is a monogenic disease characterized by high plasma low-density lipoprotein cholesterol (LDL-c) levels and increased risk of premature atherosclerotic cardiovascular disease. Mutations in FH‐related genes account for 40% of FH cases worldwide. In this study, we aimed to assess the pathogenic variants in FH-related genes in the Brazilian FH cohort FHBGEP using exon-targeted gene sequencing (ETGS) strategy. FH patients (n = 210) were enrolled at five clinical sites and peripheral blood samples were obtained for laboratory testing and genomic DNA extraction. ETGS was performed using MiSeq platform (Illumina). To identify deleterious variants in LDLR, APOB, PCSK9, and LDLRAP1, the long-reads were subjected to Burrows-Wheeler Aligner (BWA) for alignment and mapping, followed by variant calling using Genome Analysis Toolkit (GATK) and ANNOVAR for variant annotation. The variants were further filtered using in-house custom scripts and classified according to the American College Medical Genetics and Genomics (ACMG) guidelines. A total of 174 variants were identified including 85 missense, 3 stop-gain, 9 splice-site, 6 InDel, and 71 in regulatory regions (3′UTR and 5′UTR). Fifty-two patients (24.7%) had 30 known pathogenic or likely pathogenic variants in FH-related genes according to the American College Medical and Genetics and Genomics guidelines. Fifty-three known variants were classified as benign, or likely benign and 87 known variants have shown uncertain significance. Four novel variants were discovered and classified as such due to their absence in existing databases. In conclusion, ETGS and in silico prediction studies are useful tools for screening deleterious variants and identification of novel variants in FH-related genes, they also contribute to the molecular diagnosis in the FHBGEP cohort.
    Schlagwörter DNA ; blood ; cardiovascular diseases ; computer simulation ; genes ; genomics ; hypercholesterolemia ; low density lipoprotein cholesterol ; prediction ; risk ; sequence analysis ; Familial hypercholesterolemia ; Exon-targeted gene sequencing ; Molecular diagnosis ; Single nucleotide variant ; Brazilian cohort
    Sprache Englisch
    Erscheinungsverlauf 2023-07
    Erscheinungsort Elsevier B.V.
    Dokumenttyp Artikel ; Online
    ZDB-ID 391792-7
    ISSN 1879-0038 ; 0378-1119
    ISSN (online) 1879-0038
    ISSN 0378-1119
    DOI 10.1016/j.gene.2023.147501
    Datenquelle NAL Katalog (AGRICOLA)

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    Verfügbar in ZB MED Bonn

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  3. Artikel ; Online: Identification of pathogenic variants in the Brazilian cohort with Familial hypercholesterolemia using exon-targeted gene sequencing.

    Borges, Jéssica Bassani / Oliveira, Victor Fernandes / Dagli-Hernandez, Carolina / Ferreira, Glaucio Monteiro / Barbosa, Thais Kristini Almendros Afonso / da Silva Rodrigues Marçal, Elisangela / Los, Bruna / Malaquias, Vanessa Barbosa / Bortolin, Raul Hernandes / Freitas, Renata Caroline Costa / Mori, Augusto Akira / Bastos, Gisele Medeiros / Gonçalves, Rodrigo Marques / Araújo, Daniel Branco / Zatz, Henry / Bertolami, Adriana / Faludi, André Arpad / Bertolami, Marcelo Chiara / de Moraes Rego Souza, Amanda Guerra /
    França, João Ítalo Dias / Thurow, Helena Strelow / Hirata, Thiago Dominguez Crespo / Nakaya, Helder Takashi Imoto / Jannes, Cinthia Elim / da Costa Pereira, Alexandre / Silbiger, Vivian Nogueira / Luchessi, André Ducati / Araújo, Jéssica Nayara Góes / Nakazone, Marcelo Arruda / Carmo, Tayanne Silva / Souza, Dorotéia Rossi Silva / Moriel, Patricia / Wang, Jaqueline Yu Ting / Naslavsky, Michel Satya / Gorjão, Renata / Pithon-Curi, Tania Cristina / Curi, Rui / Fajardo, Cristina Moreno / Wang, Hui-Tzu Lin / Garófalo, Adriana Regina / Cerda, Alvaro / Sampaio, Marcelo Ferraz / Hirata, Rosario Dominguez Crespo / Hirata, Mario Hiroyuki

    Gene

    2023  Band 875, Seite(n) 147501

    Abstract: Familial hypercholesterolemia (FH) is a monogenic disease characterized by high plasma low-density lipoprotein cholesterol (LDL-c) levels and increased risk of premature atherosclerotic cardiovascular disease. Mutations in FH-related genes account for 40% ...

    Abstract Familial hypercholesterolemia (FH) is a monogenic disease characterized by high plasma low-density lipoprotein cholesterol (LDL-c) levels and increased risk of premature atherosclerotic cardiovascular disease. Mutations in FH-related genes account for 40% of FH cases worldwide. In this study, we aimed to assess the pathogenic variants in FH-related genes in the Brazilian FH cohort FHBGEP using exon-targeted gene sequencing (ETGS) strategy. FH patients (n = 210) were enrolled at five clinical sites and peripheral blood samples were obtained for laboratory testing and genomic DNA extraction. ETGS was performed using MiSeq platform (Illumina). To identify deleterious variants in LDLR, APOB, PCSK9, and LDLRAP1, the long-reads were subjected to Burrows-Wheeler Aligner (BWA) for alignment and mapping, followed by variant calling using Genome Analysis Toolkit (GATK) and ANNOVAR for variant annotation. The variants were further filtered using in-house custom scripts and classified according to the American College Medical Genetics and Genomics (ACMG) guidelines. A total of 174 variants were identified including 85 missense, 3 stop-gain, 9 splice-site, 6 InDel, and 71 in regulatory regions (3'UTR and 5'UTR). Fifty-two patients (24.7%) had 30 known pathogenic or likely pathogenic variants in FH-related genes according to the American College Medical and Genetics and Genomics guidelines. Fifty-three known variants were classified as benign, or likely benign and 87 known variants have shown uncertain significance. Four novel variants were discovered and classified as such due to their absence in existing databases. In conclusion, ETGS and in silico prediction studies are useful tools for screening deleterious variants and identification of novel variants in FH-related genes, they also contribute to the molecular diagnosis in the FHBGEP cohort.
    Mesh-Begriff(e) Humans ; Proprotein Convertase 9/genetics ; Brazil ; Hyperlipoproteinemia Type II/genetics ; Mutation ; Exons ; Receptors, LDL/genetics ; Phenotype
    Chemische Substanzen PCSK9 protein, human (EC 3.4.21.-) ; Proprotein Convertase 9 (EC 3.4.21.-) ; Receptors, LDL
    Sprache Englisch
    Erscheinungsdatum 2023-05-20
    Erscheinungsland Netherlands
    Dokumenttyp Journal Article
    ZDB-ID 391792-7
    ISSN 1879-0038 ; 0378-1119
    ISSN (online) 1879-0038
    ISSN 0378-1119
    DOI 10.1016/j.gene.2023.147501
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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