In silico analysis of upstream variants in Brazilian patients with familial hypercholesterolemia
Gene
; 849(146908)Jan. 2023.
Article
in English
| CONASS, Sec. Est. Saúde SP, SESSP-IDPCPROD, Sec. Est. Saúde SP
| ID: biblio-1400150
Responsible library:
BR79.1
ABSTRACT
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.
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Collection:
National databases
/
Brazil
Health context:
SDG3 - Target 3.4 Reduce premature mortality due to noncommunicable diseases
Health problem:
Endocrine System Diseases
Database:
CONASS
/
Sec. Est. Saúde SP
/
SESSP-IDPCPROD
Main subject:
Receptors, LDL
/
Proprotein Convertase 9
Type of study:
Prognostic study
Country/Region as subject:
South America
/
Brazil
Language:
English
Journal:
Gene
Year:
2023
Document type:
Article
Institution/Affiliation country:
Department of Clinical and Toxicological Analyses, Federal University of Rio Grande do Norte/BR
/
Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo/BR
/
Laboratory of Genetics and Molecular Cardiology, Heart Institute, University of São Paulo/BR
/
Laboratory of Molecular Research in Cardiology, Institute Dante Pazzanese of Cardiology/BR
/
Medical Clinic Division, Institute Dante Pazzanese of Cardiology/BR
/
Northeast Biotechnology Network (RENORBIO), Graduate Program in Biotechnology, Federal University of Rio Grande do Norte/BR