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Article ; Online: Predicted deleterious variants in ABCA1, LPL, LPA and KIF6 are associated with statin response and adverse events in patients with familial hypercholesterolemia and disturb protein structure and stability.

Dagli-Hernandez, Carolina / Ferreira, Glaucio Monteiro / Freitas, Renata Caroline Costa de / Borges, Jessica Bassani / Oliveira, Victor Fernandes de / Gonçalves, Rodrigo Marques / Faludi, Andre Arpad / Marçal, Elisangela da Silva Rodrigues / Bastos, Gisele Medeiros / Bortolin, Raul Hernandes / Hirata, Mario Hiroyuki / Hirata, Rosario Dominguez Crespo

Pharmacogenetics and genomics

2024 Volume 34, Issue 4, Page(s) 91–104

Abstract: Objectives: This study explored the association of deleterious variants in pharmacodynamics (PD) genes with statin response and adverse effects in patients with familial hypercholesterolemia (FH) and analyzed their potential effects on protein structure ...

Abstract	Objectives: This study explored the association of deleterious variants in pharmacodynamics (PD) genes with statin response and adverse effects in patients with familial hypercholesterolemia (FH) and analyzed their potential effects on protein structure and stability. Methods: Clinical and laboratory data were obtained from 144 adult FH patients treated with statins. A panel of 32 PD genes was analyzed by exon-targeted gene sequencing. Deleterious variants were identified using prediction algorithms and their structural effects were analyzed by molecular modeling studies. Results: A total of 102 variants were predicted as deleterious (83 missense, 8 stop-gain, 4 frameshift, 1 indel, 6 splicing). The variants ABCA1 rs769705621 (indel), LPA rs41267807 (p.Tyr2023Cys) and KIF6 rs20455 (p.Trp719Arg) were associated with reduced low-density lipoprotein cholesterol (LDLc) response to statins, and the LPL rs1801177 (p.Asp36Asn) with increased LDLc response (P < 0.05). LPA rs3124784 (p.Arg2016Cys) was predicted to increase statin response (P = 0.022), and ABCA1 rs769705621 to increase the risk of statin-related adverse events (SRAE) (P = 0.027). LPA p.Arg2016Cys and LPL p.Asn36Asp maintained interactions with solvent, LPA p.Tyr2023Cys reduced intramolecular interaction with Gln1987, and KIF6 p.Trp719Arg did not affect intramolecular interactions. DDMut analysis showed that LPA p.Arg2016Cys and p.Tyr2023Cys and LPL p.Asp36Asn caused energetically favorable changes, and KIF6 p.Trp719Arg resulted in unfavorable energetic changes, affecting protein stability. Conclusion: Deleterious variants in ABCA1, LPA, LPL and KIF6 are associated with variability in LDLc response to statins, and ABCA1 rs769705621 is associated with SRAE risk in FH patients. Molecular modeling studies suggest that LPA p.Tyr2023Cys and KIF6 p.Trp719Arg disturb protein conformational structure and stability.
MeSH term(s)	Humans ; Kinesins/genetics ; Male ; Female ; Middle Aged ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects ; Hyperlipoproteinemia Type II/genetics ; Hyperlipoproteinemia Type II/drug therapy ; ATP Binding Cassette Transporter 1/genetics ; Lipoprotein Lipase/genetics ; Adult ; Protein Stability ; Cholesterol, LDL/blood ; Polymorphism, Single Nucleotide
Chemical Substances	Kinesins (EC 3.6.4.4) ; KIF6 protein, human (EC 3.6.1.-) ; ABCA1 protein, human ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; ATP Binding Cassette Transporter 1 ; Lipoprotein Lipase (EC 3.1.1.34) ; LPL protein, human (EC 3.1.1.34) ; Cholesterol, LDL
Language	English
Publishing date	2024-02-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2175826-8
ISSN	1744-6880 ; 0960-314X ; 1744-6872
ISSN (online)	1744-6880
ISSN	0960-314X ; 1744-6872
DOI	10.1097/FPC.0000000000000524
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Article: Detection of Schistosoma mansoni long non-coding RNAs in the infected C57BL/6 mouse liver

Mota, Ester Alves / de Oliveira, Victor Fernandes / Barban do Patrocinio, Andressa / Rodrigues, Vanderlei / Guerra-Sá, Renata

Experimental parasitology. 2021 Mar., v. 222

2021

Abstract: Long non-coding RNAs (lncRNAs) perform several types of regulatory functions and have been recently explored in the genus Schistosoma. Although sequencing and bioinformatics approaches have demonstrated the presence of hundreds of lncRNAs and microRNAs ( ... ...

Abstract	Long non-coding RNAs (lncRNAs) perform several types of regulatory functions and have been recently explored in the genus Schistosoma. Although sequencing and bioinformatics approaches have demonstrated the presence of hundreds of lncRNAs and microRNAs (miRNAs) in this genus, information regarding their abundance, characteristics, and potential functions linked to Schistosoma mansoni biology and parasite-host interaction is limited. Our objectives in the present study were to verify whether 15 previously identified S. mansoni lncRNAs are detectable in the host liver. In addition, we assess whether these lncRNAs are present in the S. mansoni infective form and the stages inside the definitive host. The detection of these 15 S. mansoni lncRNAs and a long terminal repeat (LTR) retrotransposon Saci 4 was performed in the eggs, cercariae, and 3.5-h schistosomula. All lncRNAs were found to be expressed in these stages; some of the lncRNAs were found in the livers of the infected C57BL/6 mice. In conclusion, S. mansoni lncRNAs were detected in host livers and quantified. Furthermore, many of the lncRNAs analyzed showed differential expression in the larval stages, indicating that they play a stage-specific regulatory role.
Keywords	Schistosoma mansoni ; bioinformatics ; cercariae ; definitive hosts ; gene expression regulation ; liver ; mice ; microRNA ; parasitology ; retrotransposons ; schistosomula ; terminal repeat sequences
Language	English
Dates of publication	2021-03
Publishing place	Elsevier Inc.
Document type	Article
Note	NAL-AP-2-clean
ZDB-ID	391089-1
ISSN	1090-2449 ; 0014-4894
ISSN (online)	1090-2449
ISSN	0014-4894
DOI	10.1016/j.exppara.2020.108062
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Article ; Online: Lipidomic analysis identified potential predictive biomarkers of statin response in subjects with Familial hypercholesterolemia.

Cerda, Alvaro / Bortolin, Raul Hernandes / Yoshinaga, Marcos Yukio / Freitas, Renata Caroline Costa de / Dagli-Hernandez, Carolina / Borges, Jessica Bassani / Oliveira, Victor Fernandes de / Gonçalves, Rodrigo Marques / Faludi, Andre Arpad / Bastos, Gisele Medeiros / Hirata, Rosario Dominguez Crespo / Hirata, Mario Hiroyuki

Chemistry and physics of lipids

2023 Volume 257, Page(s) 105348

Abstract: Familial hypercholesterolemia (FH) is a disorder of lipid metabolism that causes elevated low-density lipoprotein cholesterol (LDL-c) and increased premature atherosclerosis risk. Statins inhibit endogenous cholesterol biosynthesis, which reduces LDL-c ... ...

Abstract	Familial hypercholesterolemia (FH) is a disorder of lipid metabolism that causes elevated low-density lipoprotein cholesterol (LDL-c) and increased premature atherosclerosis risk. Statins inhibit endogenous cholesterol biosynthesis, which reduces LDL-c plasma levels and prevent from cardiovascular events. This study aimed to explore the effects of statin treatment on serum lipidomic profile and to identify biomarkers of response in subjects with FH. Seventeen adult FH patients underwent a 6-week washout followed by 4-week treatment with atorvastatin (80 mg/day) or rosuvastatin (40 mg/day). LDL-c response was considered good (40-70 % reduction, n = 9) or poor (3-33 % reduction, n = 8). Serum lipidomic profile was analyzed by ultra-high-performance liquid chromatography combined with electrospray ionization tandem time-of-flight mass spectrometry, and data were analyzed using MetaboAnalyst v5.0. Lipidomic analysis identified 353 lipids grouped into 16 classes. Statin treatment reduced drastically 8 of 13 lipid classes, generating a characteristic lipidomic profile with a significant contribution of phosphatidylinositols (PI) 16:0/18:2, 18:0/18:1 and 18:0/18:2; and triacylglycerols (TAG) 18:2x2/18:3, 18:1/18:2/18:3, 16:1/18:2x2, 16:1/18:2/18:3 and 16:1/18:2/Arachidonic acid (p-adjusted <0.05). Biomarker analysis implemented in MetaboAnalyst subsequently identified PI 16:1/18:0, 16:0/18:2 and 18:0/18:2 as predictors of statin response with and receiver operating characteristic (ROC) areas under the curve of 0.98, 0.94 and 0.91, respectively. In conclusion, statins extensively modulate the overall serum lipid composition of FH individuals and these findings suggest that phosphatidyl-inositol molecules are potential predictive biomarkers of statin response.
MeSH term(s)	Adult ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use ; Cholesterol, LDL ; Lipidomics ; Hyperlipoproteinemia Type II/drug therapy ; Cholesterol ; Biomarkers
Chemical Substances	Hydroxymethylglutaryl-CoA Reductase Inhibitors ; Cholesterol, LDL ; Cholesterol (97C5T2UQ7J) ; Biomarkers
Language	English
Publishing date	2023-10-11
Publishing country	Ireland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	213869-4
ISSN	1873-2941 ; 0009-3084
ISSN (online)	1873-2941
ISSN	0009-3084
DOI	10.1016/j.chemphyslip.2023.105348
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Article ; Online: LDLR and PCSK9 3´UTR variants and their putative effects on microRNA molecular interactions in familial hypercholesterolemia: a computational approach.

de Freitas, Renata Caroline Costa / Bortolin, Raul Hernandes / Borges, Jessica Bassani / de Oliveira, Victor Fernandes / Dagli-Hernandez, Carolina / Marçal, Elisangela da Silva Rodrigues / Bastos, Gisele Medeiros / Gonçalves, Rodrigo Marques / Faludi, Andre Arpad / Silbiger, Vivian Nogueira / Luchessi, André Ducati / Hirata, Rosario Dominguez Crespo / Hirata, Mario Hiroyuki

Molecular biology reports

2023 Volume 50, Issue 11, Page(s) 9165–9177

Abstract: Background: Familial hypercholesterolemia (FH) is caused by pathogenic variants in low-density lipoprotein (LDL) receptor (LDLR) or its associated genes, including apolipoprotein B (APOB), proprotein convertase subtilisin/kexin type 9 (PCSK9), and LDLR ... ...

Abstract	Background: Familial hypercholesterolemia (FH) is caused by pathogenic variants in low-density lipoprotein (LDL) receptor (LDLR) or its associated genes, including apolipoprotein B (APOB), proprotein convertase subtilisin/kexin type 9 (PCSK9), and LDLR adaptor protein 1 (LDLRAP1). However, approximately 40% of the FH patients clinically diagnosed (based on FH phenotypes) may not carry a causal variant in a FH-related gene. Variants located at 3' untranslated region (UTR) of FH-related genes could elucidate mechanisms involved in FH pathogenesis. This study used a computational approach to assess the effects of 3'UTR variants in FH-related genes on miRNAs molecular interactions and to explore the association of these variants with molecular diagnosis of FH. Methods and results: Exons and regulatory regions of FH-related genes were sequenced in 83 FH patients using an exon-target gene sequencing strategy. In silico prediction tools were used to study the effects of 3´UTR variants on interactions between miRNAs and target mRNAs. Pathogenic variants in FH-related genes (molecular diagnosis) were detected in 44.6% FH patients. Among 59 3'UTR variants identified, LDLR rs5742911 and PCSK9 rs17111557 were associated with molecular diagnosis of FH, whereas LDLR rs7258146 and rs7254521 and LDLRAP1 rs397860393 had an opposite effect (p < 0.05). 3´UTR variants in LDLR (rs5742911, rs7258146, rs7254521) and PCSK9 (rs17111557) disrupt interactions with several miRNAs, and more stable bindings were found with LDLR (miR-4435, miR-509-3 and miR-502) and PCSK9 (miR-4796). Conclusion: LDLR and PCSK9 3´UTR variants disturb miRNA:mRNA interactions that could affect gene expression and are potentially associated with molecular diagnosis of FH.
MeSH term(s)	Humans ; Proprotein Convertase 9/genetics ; 3' Untranslated Regions/genetics ; MicroRNAs/genetics ; Hyperlipoproteinemia Type II/genetics ; Hyperlipoproteinemia Type II/diagnosis ; Receptors, LDL/genetics ; Mutation
Chemical Substances	PCSK9 protein, human (EC 3.4.21.-) ; Proprotein Convertase 9 (EC 3.4.21.-) ; 3' Untranslated Regions ; MicroRNAs ; Receptors, LDL
Language	English
Publishing date	2023-09-30
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	186544-4
ISSN	1573-4978 ; 0301-4851
ISSN (online)	1573-4978
ISSN	0301-4851
DOI	10.1007/s11033-023-08784-9
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Article ; Online: Effects of the Long-Term Consumption of a High-Sucrose Diet on microRNA Expression in Visceral Adipose Tissue of Rats.

Fernandes, Isabela Costa / Santos, Talita Adriana Pereira / Oliveira, Daiane Teixeira / Oliveira, Victor Fernandes / Sousa, Graziele Galdino / Pereira, Luciene Santos / Barboza, Natália Rocha / Evangelista, Elísio Alberto / Guerra-Sá, Renata

Nutrients

2022 Volume 14, Issue 17

Abstract: Noncoding microRNAs are involved in lipid and carbohydrate metabolism pathways and are powerful regulators of gene expression. The goals of this study were to evaluate the temporal expression profiles of miRNAs in rat adipose tissue and predict mRNA− ... ...

Abstract	Noncoding microRNAs are involved in lipid and carbohydrate metabolism pathways and are powerful regulators of gene expression. The goals of this study were to evaluate the temporal expression profiles of miRNAs in rat adipose tissue and predict mRNA−microRNA interactions. Newly weaned Wistar rats were divided into groups fed a standard diet and high-sucrose diet (HSD). The HSD contains 66.86% carbohydrates (40.45% standard diet, 40.45% condensed milk, and 8.58% crystal sugar), and the HSD was provided for 4, 8 and 15-week periods to investigate the expression levels of miRNAs in visceral adipose tissue using RT−qPCR. Target selection, enriched pathways and networks were analyzed in silico. The factor consumption time significantly was associated to decreases (p < 0.05) in the expression levels of the following miRNAs: 124-5p, 125-5p, 126-5p, 200c-3p, and 212-3p in all experimental groups. The factor diet significantly influenced rno-miR-124-5p, 200c-3p, and 212-3p expression (p < 0.05). A significant reduction (p < 0.05) in rno-miR-27a-3p expression was observed. The biological processes involved key pathways regulating fat deposition. Our findings provide important insights into downregulated miRNA expression patterns in visceral adipose tissue, adiposity level, hyperinsulinemia and increased VLDL-c and triglyceride levels.
MeSH term(s)	Animals ; Dietary Sucrose/adverse effects ; Intra-Abdominal Fat/metabolism ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Rats ; Rats, Wistar
Chemical Substances	Dietary Sucrose ; MIRN124 microRNA, rat ; MicroRNAs
Language	English
Publishing date	2022-08-24
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2518386-2
ISSN	2072-6643 ; 2072-6643
ISSN (online)	2072-6643
ISSN	2072-6643
DOI	10.3390/nu14173465
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Article: Effects of the Long-Term Consumption of a High-Sucrose Diet on microRNA Expression in Visceral Adipose Tissue of Rats

Nutrients. 2022 Aug. 24, v. 14, no. 17

2022

Abstract	Noncoding microRNAs are involved in lipid and carbohydrate metabolism pathways and are powerful regulators of gene expression. The goals of this study were to evaluate the temporal expression profiles of miRNAs in rat adipose tissue and predict mRNA–microRNA interactions. Newly weaned Wistar rats were divided into groups fed a standard diet and high-sucrose diet (HSD). The HSD contains 66.86% carbohydrates (40.45% standard diet, 40.45% condensed milk, and 8.58% crystal sugar), and the HSD was provided for 4, 8 and 15-week periods to investigate the expression levels of miRNAs in visceral adipose tissue using RT–qPCR. Target selection, enriched pathways and networks were analyzed in silico. The factor consumption time significantly was associated to decreases (p < 0.05) in the expression levels of the following miRNAs: 124-5p, 125-5p, 126-5p, 200c-3p, and 212-3p in all experimental groups. The factor diet significantly influenced rno-miR-124-5p, 200c-3p, and 212-3p expression (p < 0.05). A significant reduction (p < 0.05) in rno-miR-27a-3p expression was observed. The biological processes involved key pathways regulating fat deposition. Our findings provide important insights into downregulated miRNA expression patterns in visceral adipose tissue, adiposity level, hyperinsulinemia and increased VLDL-c and triglyceride levels.
Keywords	adipose tissue ; adiposity ; carbohydrate metabolism ; computer simulation ; concentrated milk ; gene expression ; high carbohydrate diet ; hyperinsulinemia ; microRNA ; rats ; sugars ; triacylglycerols
Language	English
Dates of publication	2022-0824
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2518386-2
ISSN	2072-6643
ISSN	2072-6643
DOI	10.3390/nu14173465
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Article ; Online: Detection of Schistosoma mansoni long non-coding RNAs in the infected C57BL/6 mouse liver.

Mota, Ester Alves / de Oliveira, Victor Fernandes / Barban do Patrocinio, Andressa / Rodrigues, Vanderlei / Guerra-Sá, Renata

Experimental parasitology

2020 Volume 222, Page(s) 108062

Abstract	Long non-coding RNAs (lncRNAs) perform several types of regulatory functions and have been recently explored in the genus Schistosoma. Although sequencing and bioinformatics approaches have demonstrated the presence of hundreds of lncRNAs and microRNAs (miRNAs) in this genus, information regarding their abundance, characteristics, and potential functions linked to Schistosoma mansoni biology and parasite-host interaction is limited. Our objectives in the present study were to verify whether 15 previously identified S. mansoni lncRNAs are detectable in the host liver. In addition, we assess whether these lncRNAs are present in the S. mansoni infective form and the stages inside the definitive host. The detection of these 15 S. mansoni lncRNAs and a long terminal repeat (LTR) retrotransposon Saci 4 was performed in the eggs, cercariae, and 3.5-h schistosomula. All lncRNAs were found to be expressed in these stages; some of the lncRNAs were found in the livers of the infected C57BL/6 mice. In conclusion, S. mansoni lncRNAs were detected in host livers and quantified. Furthermore, many of the lncRNAs analyzed showed differential expression in the larval stages, indicating that they play a stage-specific regulatory role.
MeSH term(s)	Animals ; Chromosome Mapping ; Liver/parasitology ; Liver/pathology ; Male ; Mice ; Mice, Inbred C57BL ; RNA, Long Noncoding/isolation & purification ; Real-Time Polymerase Chain Reaction ; Retroelements/physiology ; Reverse Transcription ; Schistosoma mansoni/genetics ; Schistosoma mansoni/growth & development ; Schistosoma mansoni/isolation & purification ; Schistosomiasis mansoni/parasitology ; Schistosomiasis mansoni/pathology
Chemical Substances	RNA, Long Noncoding ; Retroelements
Language	English
Publishing date	2020-12-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	391089-1
ISSN	1090-2449 ; 0014-4894
ISSN (online)	1090-2449
ISSN	0014-4894
DOI	10.1016/j.exppara.2020.108062
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Article: Genetic Variant

Dagli-Hernandez, Carolina / Borges, Jéssica Bassani / Marçal, Elisangela da Silva Rodrigues / de Freitas, Renata Caroline Costa / Mori, Augusto Akira / Gonçalves, Rodrigo Marques / Faludi, Andre Arpad / de Oliveira, Victor Fernandes / Ferreira, Glaucio Monteiro / Bastos, Gisele Medeiros / Zhou, Yitian / Lauschke, Volker M / Cerda, Alvaro / Hirata, Mario Hiroyuki / Hirata, Rosario Dominguez Crespo

Pharmaceutics

2022 Volume 14, Issue 5

Abstract: Statins are the first-line treatment for familial hypercholesterolemia (FH), but response is highly variable due to genetic and nongenetic factors. Here, we explored the association between response and genetic variability in 114 Brazilian adult FH ... ...

Abstract	Statins are the first-line treatment for familial hypercholesterolemia (FH), but response is highly variable due to genetic and nongenetic factors. Here, we explored the association between response and genetic variability in 114 Brazilian adult FH patients. Specifically, a panel of 84 genes was analyzed by exon-targeted gene sequencing (ETGS), and the functional impact of variants in pharmacokinetic (PK) genes was assessed using an array of functionality prediction methods. Low-density lipoprotein cholesterol (LDL-c) response to statins (reduction ≥ 50%) and statin-related adverse event (SRAE) risk were assessed in carriers of deleterious variants in PK-related genes using multivariate linear regression analyses. Fifty-eight (50.8%) FH patients responded to statins, and 24 (21.0%) had SRAE. Results of the multivariate regression analysis revealed that ABCC1 rs45511401 significantly increased LDL-c reduction after statin treatment (p < 0.05). In silico analysis of the amino-acid change using molecular docking showed that ABCC1 rs45511401 possibly impairs statin efflux. Deleterious variants in PK genes were not associated with an increased risk of SRAE. In conclusion, the deleterious variant ABCC1 rs45511401 enhanced LDL-c response in Brazilian FH patients. As such, this variant might be a promising candidate for the individualization of statin therapy.
Language	English
Publishing date	2022-04-27
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527217-2
ISSN	1999-4923
ISSN	1999-4923
DOI	10.3390/pharmaceutics14050944
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Article ; Online: Effects of LDLR variants rs5928, rs750518671 and rs879254797 on protein structure and functional activity in HepG2 cells transfected with CRISPR/Cas9 constructs.

Mori, Augusto Akira / Malaquias, Vanessa Barbosa / Bonjour, Kennedy / Ferreira, Glaucio Monteiro / Bortolin, Raul Hernandes / Borges, Jéssica Bassani / Oliveira, Victor Fernandes de / Gonçalves, Rodrigo Marques / Faludi, Andre Arpad / Bastos, Gisele Monteiro / Thurow, Helena / Sampaio, Marcelo Ferraz / Ciconelli, Rozana Mesquita / Cury, Adriano Namo / Fajardo, Cristina Moreno / Hirata, Rosario Dominguez Crespo / Hirata, Mario Hiroyuki

Gene

2023 Volume 890, Page(s) 147821

Abstract: Familial Hypercholesterolemia (FH) is a genetic disorder associated with premature atherosclerosis and increased risk of cardiovascular diseases. LDLR deleterious mutations are associated with FH, however the role of some missense variants in FH ... ...

Abstract	Familial Hypercholesterolemia (FH) is a genetic disorder associated with premature atherosclerosis and increased risk of cardiovascular diseases. LDLR deleterious mutations are associated with FH, however the role of some missense variants in FH pathogenicity remains to be elucidated. This study explored the predictive impact of LDLR missense variants on protein structure and investigated their functional effects on LDLR expression in HepG2 cells transfected with CRISPR/Cas9 constructs. FH (n = 287) and non-FH patients (n = 45) were selected, and lipid profile was obtained from medical records. LDLR variants were identified using an exon-targeted gene sequencing strategy, considering its cost-effective to increase accuracy in the identification step of the most likely FH-related variants in a less laborious process. LDLR variants were selected based on conflicting pathogenicity results found in Clinvar, in silico prediction tools, affected LDLR domains, and less common variants considering minor allele frequency < 0.05. Molecular modeling studies were used to predict the effects of LDLR missense variants on protein structure. Recombinant LDLR variants were constructed using CRISPR/Cas9 system and were used to transfect HepG2 cells. Functional assays in transfected cells were performed to assess LDLR expression using flow cytometry and western blotting, and LDLR activity using flow cytometry and confocal microscopy. The variants rs121908039 (c.551G>A, p.C184Y), rs879254797 (c.1118G>A, p.G373D), rs28941776 (c.1646G>A, p.G549D), rs750518671 (c.2389G>C, p.V797L), rs5928 (c.2441G>A, p.R814Q) and rs137853964 (c.2479G>A, p.V827I) were selected for molecular docking analysis. The p.C184Y exhibited a favorable energy change for protein stability due to its interaction with EGF-A/EGF-B regions; p.G373D and p.G549D displayed intermediate energy changes; and p.R814Q and p.V827I showed smaller energy changes. The results of functional assays showed that p.G373D, p.V797L and p.R814Q reduced LDLR expression and activity (p < 0.05). Microscopic analysis of the p.V797L and p.G373D variants revealed altered lipid localization and accumulation in transfected HepG2 cells. Carriers of p.G549D, p.V797L and p.R814Q had higher LDL cholesterol levels than non-FH group, and (p < 0.05). p.G373D and p.G549D were associated with clinical manifestations of FH. In conclusion, the p.C184Y, p.G373D, p.G549D and p.R814Q variants alter protein stability and intramolecular interactions, while p.V797L has a minimal impact on protein stability, and p.V827I has no significant intramolecular interactions. p.G373D, p.V767L and p.R814Q are associated with impaired LDLR expression and activity.
Language	English
Publishing date	2023-09-20
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	391792-7
ISSN	1879-0038 ; 0378-1119
ISSN (online)	1879-0038
ISSN	0378-1119
DOI	10.1016/j.gene.2023.147821
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Article ; Online: In silico analysis of upstream variants in Brazilian patients with Familial hypercholesterolemia.

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

Gene

2022 Volume 849, Page(s) 146908

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.
MeSH term(s)	Humans ; Proprotein Convertase 9/genetics ; Cholesterol, LDL/genetics ; Receptors, LDL/genetics ; Brazil ; Mutation ; Hyperlipoproteinemia Type II/genetics ; Phenotype ; Apolipoproteins B/genetics ; Nucleotides
Chemical Substances	PCSK9 protein, human (EC 3.4.21.-) ; Proprotein Convertase 9 (EC 3.4.21.-) ; Cholesterol, LDL ; Receptors, LDL ; Apolipoproteins B ; Nucleotides
Language	English
Publishing date	2022-09-24
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	391792-7
ISSN	1879-0038 ; 0378-1119
ISSN (online)	1879-0038
ISSN	0378-1119
DOI	10.1016/j.gene.2022.146908
Database	MEDical Literature Analysis and Retrieval System OnLINE

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