82 results on '"Faludi AA"'
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2. DIRETRIZ BRASILEIRA BASEADA EM EVIDÊNCIAS SOBRE PREVENÇÃO DE DOENÇAS CARDIOVASCULARES EM PACIENTES COM DIABETES: POSICIONAMENTO DA SOCIEDADE BRASILEIRA DE DIABETES (SBD), DA SOCIEDADE BRASILEIRA DE CARDIOLOGIA (SBC) E DA SOCIEDADE BRASILEIRA DE ENDOCRINOLOGIA E METABOLOGIA (SBEM)
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Faludi, AA, primary, Izar, MCO, additional, Saraiva, JFK, additional, Bianco, HT, additional, Chacra, APM, additional, Bertoluci, MC, additional, Moreira, RO, additional, Turatti, LAA, additional, Bertolami, A, additional, Sulzbach, ML, additional, Schaan, BD, additional, Valerio, CM, additional, Bertolami, MC, additional, Malachias, MVB, additional, Vencio, S, additional, Betti, RTB, additional, Fonseca, FAH, additional, Salles, JEN, additional, Hohl, A, additional, Trujilho, FR, additional, Lima, EG, additional, Miname, MH, additional, Zanella, MT, additional, Lamounier, R, additional, Sá, JR, additional, Amodeo, C, additional, Pires, AC, additional, Santos, RD, additional, Póvoa, RMS, additional, Berwanger, O, additional, and Rocha, AM, additional
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- 2017
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3. ATUALIZAÇÃO DA DIRETRIZ BRASILEIRA DE DISLIPIDEMIAS E PREVENÇÃO DA ATEROSCLEROSE - 2017
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Faludi, AA, primary, Izar, MCO, additional, Saraiva, JFK, additional, Chacra, APM, additional, Bianco, HT, additional, Afiune Neto, A, additional, Bertolami, A, additional, Pereira, AC, additional, Lottenberg, AMP, additional, Sposito, AC, additional, Chagas, ACP, additional, Casella-Filho, A, additional, Simão, AF, additional, Alencar Filho, AC, additional, Caramelli, B, additional, Magalhães, CC, additional, Magnoni, D, additional, Negrão, CE, additional, Ferreira, CES, additional, Scherr, C, additional, Feio, CMA, additional, Kovacs, C, additional, Araújo, DB, additional, Calderaro, D, additional, Gualandro, DM, additional, Mello Junior, EP, additional, Alexandre, ERG, additional, Sato, IE, additional, Moriguchi, EH, additional, Rached, FH, additional, Santos, FC, additional, Cesena, FHY, additional, Fonseca, FAH, additional, Fonseca, HAR, additional, Xavier, HT, additional, Pimentel, IC, additional, Giuliano, ICB, additional, Issa, JS, additional, Diament, J, additional, Pesquero, JB, additional, Santos, JE, additional, Neto JR, Faria, additional, Melo Filho, JX, additional, Kato, JT, additional, Torres, KP, additional, Bertolami, MC, additional, Assad, MHV, additional, Miname, MH, additional, Scartezini, M, additional, Forti, NA, additional, Coelho, OR, additional, Maranhão, RC, additional, Santos Filho, RD, additional, Alves, RJ, additional, Cassani, RL, additional, Betti, RTB, additional, Carvalho, T, additional, Martinez, TLR, additional, Giraldez, VZR, additional, and Salgado Filho, W, additional
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- 2017
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4. L 004 Inter Observer Variation in the Analyses of the Abdominal Circumference
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Calvilho, AA, primary, Rinaldi, FS, additional, Montano, ZT, additional, Motta, LGM, additional, Bertolami, A, additional, Faludi, AA, additional, Araújo, DB, additional, Zatz, HP, additional, Bertolami, MC, additional, and Amparo, FC, additional
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- 2009
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5. D 015 Glucose Tolerance Test – Important on the Assessment of the Glicidic Metabolism in Obese Patients with Low HDL Cholesterol
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Faludi, EP, primary, Faludi, AA, additional, Bertolami, A, additional, Araújo, DB, additional, Tome, ACN, additional, Zatz, HP, additional, Atanazio, MJ, additional, Nakamura, Y, additional, and Bertolami, MC, additional
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- 2009
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6. L 031 Obtaining the Prevention Goals for Cardiovascular Disease Following the Brazilian Society of Cardiology Guidelines
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Moreira, HG, primary, Junior, WG, additional, Neto, SA, additional, Nunes, GJ, additional, Trindade, PHDM, additional, Faludi, AA, additional, Araújo, DB, additional, Bertolami, A, additional, Zatz, HP, additional, and Bertolami, MC, additional
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- 2009
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7. A 030 Hypothireoidism and Metabolic Syndrome
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Faludi, EP, primary, Faludi, AA, additional, Bertolami, A, additional, Araújo, DB, additional, Zatz, HP, additional, Tome, ACN, additional, Atanazio, MJ, additional, Nakamura, Y, additional, and Bertolami, MC, additional
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- 2009
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8. L 029 First Degree Marriages in a Hypercholesterolemic Family
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Bertolami, A, primary, Faludi, AA, additional, Araújo, DB, additional, Zatz, HP, additional, Nakamura, Y, additional, and Bertolami, MC, additional
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- 2009
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9. L 018 The Nutritional State of the Medical Residents of a Cardiologic Hospital in São Paulo
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Keiralla, LCB, primary, Santana, MRO, additional, Alves, SG, additional, Sette, JBC, additional, Martins, TPG, additional, Bertolami, A, additional, Araújo, DB, additional, Magnoni, CD, additional, Faludi, AA, additional, and Amparo, FC, additional
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- 2009
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10. L 023 The Success of Cholesterol-lowering Treatment goes Beyond Pharmacological Therapy
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Ibañez, TLP, primary, Capeletti, JT, additional, Barbosa, RR, additional, Cestari, PF, additional, Peres, GMTLSR, additional, Bertolami, A, additional, Faludi, AA, additional, Araújo, DB, additional, Zatz, HP, additional, and Bertolami, MC, additional
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- 2009
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11. IA 013 Importance of Cardiovascular Risk Factors to Coronary Calcification in Patients with Dyslipidemia and Impaired Fasting Glucose
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Continentino, MA, primary, Bertolami, A, additional, Moreira, HG, additional, Trindade, PHDM, additional, Assaf, Neto S, additional, Grimaldi, W, additional, Nunes, GJ, additional, Shiozaki, AA, additional, Pinto, IF, additional, and Faludi, AA, additional
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- 2009
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12. L 030 Abdominal Circumference – Which Criterion to Use in the Clinical Practice
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Faludi, EP, primary, Araújo, DB, additional, Zatz, HP, additional, Bertolami, A, additional, Faludi, AA, additional, Tome, ACN, additional, Atanazio, MJ, additional, Nakamura, Y, additional, and Bertolami, MC, additional
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- 2009
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13. Effects of soy germ isoflavones and hormone therapy on nitric oxide derivatives, low-density lipoprotein oxidation, and vascular reactivity in hypercholesterolemic postmenopausal women.
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Pereira IR, Faludi AA, Aldrighi JM, Bertolami MC, Saleh MH, Silva RA, Nakamura Y, Campos MF, Novaes N, and Abdalla DS
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- 2006
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14. 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.
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Dagli-Hernandez C, Ferreira GM, Freitas RCC, Borges JB, Oliveira VF, Gonçalves RM, Faludi AA, Marçal EDSR, Bastos GM, Bortolin RH, Hirata MH, and Hirata RDC
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- Humans, Male, Female, Middle Aged, Adult, Protein Stability, Cholesterol, LDL blood, Polymorphism, Single Nucleotide, Kinesins genetics, Hydroxymethylglutaryl-CoA Reductase Inhibitors adverse effects, Hyperlipoproteinemia Type II genetics, Hyperlipoproteinemia Type II drug therapy, ATP Binding Cassette Transporter 1 genetics, Lipoprotein Lipase genetics
- 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., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2024
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15. Effects of LDLR variants rs5928, rs750518671 and rs879254797 on protein structure and functional activity in HepG2 cells transfected with CRISPR/Cas9 constructs.
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Mori AA, Malaquias VB, Bonjour K, Ferreira GM, Bortolin RH, Borges JB, Oliveira VF, Gonçalves RM, Faludi AA, Bastos GM, Thurow H, Sampaio MF, Ciconelli RM, Cury AN, Fajardo CM, Hirata RDC, and Hirata MH
- 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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)
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- 2024
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16. Methylation status of LDLR , PCSK9 and LDLRAP1 is associated with cardiovascular events in familial hypercholesterolemia.
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Silva Rodrigues Marçal ED, Borges JB, Bastos GM, Crespo Hirata TD, de Oliveira VF, Gonçalves RM, Faludi AA, Dias França JI, de Oliveira Silva DV, Malaquias VB, Luchessi AD, Silbiger VN, Nakazone MA, Carmo TS, Silva Souza DR, Sampaio MF, Crespo Hirata RD, and Hirata MH
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- Humans, Male, Female, Middle Aged, Adult, Cardiovascular Diseases genetics, Cardiovascular Diseases etiology, CpG Islands, Adaptor Proteins, Signal Transducing, Proprotein Convertase 9 genetics, Receptors, LDL genetics, DNA Methylation, Hyperlipoproteinemia Type II genetics, Hyperlipoproteinemia Type II blood, LDL-Receptor Related Protein-Associated Protein genetics
- Abstract
Aim: Methylation of LDLR , PCSK9 and LDLRAP1 CpG sites was assessed in patients with familial hypercholesterolemia (FH). Methods: DNA methylation of was analyzed by pyrosequencing in 131 FH patients and 23 normolipidemic (NL) subjects. Results: LDLR , PCSK9 and LDLRP1 methylation was similar between FH patients positive (MD) and negative (non-MD) for pathogenic variants in FH-related genes. LDLR and PCSK9 methylation was higher in MD and non-MD groups than NL subjects ( p < 0.05). LDLR , PCSK9 and LDLRAP1 methylation profiles were associated with clinical manifestations and cardiovascular events in FH patients ( p < 0.05). Conclusion: Differential methylation of LDLR , PCSK9 and LDLRAP1 is associated with hypercholesterolemia and cardiovascular events. This methylation profile maybe useful as a biomarker and contribute to the management of FH.
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- 2024
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17. Lipidomic analysis identified potential predictive biomarkers of statin response in subjects with Familial hypercholesterolemia.
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Cerda A, Bortolin RH, Yoshinaga MY, Freitas RCC, Dagli-Hernandez C, Borges JB, Oliveira VF, Gonçalves RM, Faludi AA, Bastos GM, Hirata RDC, and Hirata MH
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- Adult, Humans, Cholesterol, LDL, Lipidomics, Cholesterol, Biomarkers, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use, Hyperlipoproteinemia Type II drug therapy
- 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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)
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- 2023
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18. LDLR and PCSK9 3´UTR variants and their putative effects on microRNA molecular interactions in familial hypercholesterolemia: a computational approach.
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de Freitas RCC, Bortolin RH, Borges JB, de Oliveira VF, Dagli-Hernandez C, Marçal EDSR, Bastos GM, Gonçalves RM, Faludi AA, Silbiger VN, Luchessi AD, Hirata RDC, and Hirata MH
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- Humans, Proprotein Convertase 9 genetics, 3' Untranslated Regions genetics, Receptors, LDL genetics, Mutation, MicroRNAs genetics, Hyperlipoproteinemia Type II genetics, Hyperlipoproteinemia Type II diagnosis
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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., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)
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- 2023
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19. Identification of pathogenic variants in the Brazilian cohort with Familial hypercholesterolemia using exon-targeted gene sequencing.
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Borges JB, Oliveira VF, Dagli-Hernandez C, Ferreira GM, Barbosa TKAA, da Silva Rodrigues Marçal E, Los B, Malaquias VB, Bortolin RH, Freitas RCC, Mori AA, Bastos GM, Gonçalves RM, Araújo DB, Zatz H, Bertolami A, Faludi AA, Bertolami MC, de Moraes Rego Souza AG, França JÍD, Thurow HS, Hirata TDC, Nakaya HTI, Jannes CE, da Costa Pereira A, Silbiger VN, Luchessi AD, Araújo JNG, Nakazone MA, Carmo TS, Souza DRS, Moriel P, Wang JYT, Naslavsky MS, Gorjão R, Pithon-Curi TC, Curi R, Fajardo CM, Wang HL, Garófalo AR, Cerda A, Sampaio MF, Hirata RDC, and Hirata MH
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- Humans, Brazil, Mutation, Exons, Receptors, LDL genetics, Phenotype, Proprotein Convertase 9 genetics, Hyperlipoproteinemia Type II genetics
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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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)
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- 2023
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20. LDLR missense variants disturb structural conformation and LDLR activity in T-lymphocytes of Familial hypercholesterolemia patients.
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Barbosa TKA, Hirata RDC, Ferreira GM, Borges JB, Oliveira VF, Gorjão R, Marçal ERDS, Gonçalves RM, Faludi AA, Freitas RCC, Dagli-Hernandez C, Bortolin RH, Bastos GM, Pithon-Curi TC, Nader HB, and Hirata MH
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- Humans, Cholesterol, LDL genetics, Phenotype, Mutation, Missense, Apolipoproteins B genetics, Receptors, LDL genetics, T-Lymphocytes, Mutation, Hyperlipoproteinemia Type II genetics
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Familial hypercholesterolemia (FH) is caused by deleterious mutations in the LDLR that increase markedly low-density lipoprotein (LDL) cholesterol and cause premature atherosclerotic cardiovascular disease. Functional effects of pathogenic LDLR variants identified in Brazilian FH patients were assessed using in vitro and in silico studies. Variants in LDLR and other FH-related genes were detected by exon-target gene sequencing. T-lymphocytes were isolated from 26 FH patients, and 3 healthy controls and LDLR expression and activity were assessed by flow cytometry and confocal microscopy. The impact of LDLR missense variants on protein structure was assessed by molecular modeling analysis. Ten pathogenic or likely pathogenic LDLR variants (six missense, two stop-gain, one frameshift, and one in splicing region) and six non-pathogenic variants were identified. Carriers of pathogenic and non-pathogenic variants had lower LDL binding and uptake in activated T-lymphocytes compared to controls (p < 0.05), but these variants did not influence LDLR expression on cell surface. Reduced LDL binding and uptake was also observed in carriers of LDLR null and defective variants. Modeling analysis showed that p.(Ala431Thr), p.(Gly549Asp) and p.(Gly592Glu) disturb intramolecular interactions of LDLR, and p.(Gly373Asp) and p.(Ile488Thr) reduce the stability of the LDLR protein. Docking and molecular interactions analyses showed that p.(Cys184Tyr) and p.(Gly373Asp) alter interaction of LDLR with Apolipoprotein B (ApoB). In conclusion, LDLR null and defective variants reduce LDL binding capacity and uptake in activated T-lymphocytes of FH patients and LDLR missense variants affect LDLR conformational stability and dissociation of the LDLR-ApoB complex, having a potential role in FH pathogenesis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)
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- 2023
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21. Effects of PCSK9 missense variants on molecular conformation and biological activity in transfected HEK293FT cells.
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Los B, Ferreira GM, Borges JB, Kronenberger T, Oliveira VF, Dagli-Hernandez C, Bortolin RH, Gonçalves RM, Faludi AA, Mori AA, Barbosa TKA, Freitas RCC, Jannes CE, Pereira ADC, Bastos GM, Poso A, Hirata RDC, and Hirata MH
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- Humans, Receptors, LDL genetics, Receptors, LDL metabolism, Mutation, Missense, Molecular Conformation, Proprotein Convertase 9 genetics, Hyperlipoproteinemia Type II genetics
- Abstract
PCSK9 gain-of-function (GOF) variants increase degradation of low-density lipoprotein receptor (LDLR) and are potentially associated with Familial Hypercholesterolemia (FH). This study aimed to explore the effects of PCSK9 missense variants on protein structure and interactions with LDLR using molecular modeling analyses and in vitro functional studies. Variants in FH-related genes were identified in a Brazilian FH cohort using an exon-target gene sequencing strategy. Eight PCSK9 missense variants in pro- [p.(E32K) and p.(E57K)], catalytic [p.(R237W), p.(P279T) and p.(A443T)], and C-terminal histidine-cysteine rich (CHR) [p.(R469W), p.(Q619P) and p.(R680Q)] domains were identified. Molecular dynamics analyses revealed that GOF variants p.(E32K) and p.(R469W) increased extreme motions in PCSK9 amino acid backbone fluctuations and affected Hbond and water bridge interactions between the pro-domain and CM1 region of the CHR domain. HEK293FT cells transfected with plasmids carrying p.(E32K) and p.(R469W) variants reduced LDLR expression (8.7 % and 14.8 %, respectively) compared to wild type (p < 0.05) but these GOF variants did not affect PCSK9 expression and secretion. The missense variants p.(P279T) and p.(Q619P) also reduced protein stability and altered Hbond interactions. In conclusion, PCSK9 p.(E32K), p.(R469W), p.(P279T) and p.(Q619P) variants disrupt intramolecular interactions that are essential for PCSK9 structural conformation and biological activity and may have a potential role in FH pathogenesis., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Mario Hiroyuki Hirata reports financial support was provided by State of Sao Paulo Research Foundation. Mario Hiroyuki Hirata reports financial support was provided by National Council for Scientific and Technological Development. Mario Hiroyuki Hirata reports financial support was provided by Coordination of Higher Education Personnel Improvement., (Copyright © 2022 Elsevier B.V. All rights reserved.)
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- 2023
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22. In silico analysis of upstream variants in Brazilian patients with Familial hypercholesterolemia.
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de Araújo JNG, de Oliveira VF, Borges JB, Dagli-Hernandez C, Marçal EDSR, Freitas RCC, Bastos GM, Gonçalves RM, Faludi AA, Jannes CE, Pereira ADC, Hirata RDC, Hirata MH, Luchessi AD, and Silbiger VN
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- Humans, Cholesterol, LDL genetics, Receptors, LDL genetics, Brazil, Mutation, Phenotype, Apolipoproteins B genetics, Nucleotides, Proprotein Convertase 9 genetics, Hyperlipoproteinemia Type II genetics
- 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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)
- Published
- 2023
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23. Genetic Variant ABCC1 rs45511401 Is Associated with Increased Response to Statins in Patients with Familial Hypercholesterolemia.
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Dagli-Hernandez C, Borges JB, Marçal EDSR, de Freitas RCC, Mori AA, Gonçalves RM, Faludi AA, de Oliveira VF, Ferreira GM, Bastos GM, Zhou Y, Lauschke VM, Cerda A, Hirata MH, and Hirata RDC
- 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.
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- 2022
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24. Update of the Brazilian Guideline for Familial Hypercholesterolemia - 2021.
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Izar MCO, Giraldez VZR, Bertolami A, Santos Filho RDD, Lottenberg AM, Assad MHV, Saraiva JFK, Chacra APM, Martinez TLR, Bahia LR, Fonseca FAH, Faludi AA, Sposito AC, Chagas ACP, Jannes CE, Amaral CK, Araújo DB, Cintra DE, Coutinho EDR, Cesena F, Xavier HT, Mota ICP, Giuliano ICB, Faria Neto JR, Kato JT, Bertolami MC, Miname MH, Castelo MHCG, Lavrador MSF, Machado RM, Souza PG, Alves RJ, Machado VA, and Salgado Filho W
- Subjects
- Brazil, Humans, Risk Assessment, Hyperlipoproteinemia Type II diagnosis, Hyperlipoproteinemia Type II therapy
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- 2021
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25. Genomics, epigenomics and pharmacogenomics of familial hypercholesterolemia (FHBGEP): A study protocol.
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Borges JB, Oliveira VF, Ferreira GM, Los B, Barbosa TKAA, Marçal EDSR, Dagli-Hernandez C, de Freitas RCC, Bortolin RH, Mori AA, Hirata TDC, Nakaya HTI, Bastos GM, Thurow HS, Gonçalves RM, Araujo DB, Zatz HP, Bertolami A, Faludi AA, Bertolami MC, Sousa AGMR, França JÍD, Jannes CE, Pereira ADC, Nakazone MA, Souza DRS, Carmo TS, Sampaio MF, Gorjão R, Pithon-Curi TC, Moriel P, Silbiger VN, Luchessi AD, de Araújo JNG, Naslavsky MS, Wang JYT, Kronenberger T, Cerda A, Lin-Wang HT, Garofalo AR, Fajardo CM, Hirata RDC, and Hirata MH
- Subjects
- Brazil, Epigenomics, Genomics, Humans, Molecular Docking Simulation, Pharmacogenetics, Hyperlipoproteinemia Type II drug therapy, Hyperlipoproteinemia Type II genetics
- Abstract
Background: Familial hypercholesterolemia (FH) is a genetic disease that affects millions of people worldwide., Objectives: The study protocol FHBGEP was design to investigate the main genomic, epigenomic, and pharmacogenomic factors associated with FH and polygenic hypercholesterolemia (PH)., Methods: FH patients will be enrolled at six research centers in Brazil. An exon-targeted gene strategy will be used to sequence a panel of 84 genes related to FH, PH, pharmacogenomics and coronary artery disease. Variants in coding and regulatory regions will be identified using a proposed variant discovery pipeline and classified according to the American College Medical Genetics guidelines. Functional effects of variants in FH-related genes will be investigated by in vitro studies using lymphocytes and cell lines (HepG2, HUVEC and HEK293FT), CRISPR/Cas9 mutagenesis, luciferase reporter assay and other technologies. Functional studies in silico, such as molecular docking, molecular dynamics, and conformational analysis, will be used to explore the impact of novel variants on protein structure and function. DNA methylation profile and differential expression of circulating non-coding RNAs (miRNAs and lncRNAs) will be analyzed in FH patients and normolipidemic subjects (control group). The influence of genomic and epigenomic factors on metabolic and inflammatory status will be analyzed in FH patients. Pharmacogenomic studies will be conducted to investigate the influence of genomic and epigenomic factors on response to statins in FH patients., Summary: The FHBGEP protocol has the potential to elucidate the genetic basis and molecular mechanisms involved in the pathophysiology of FH and PH, particularly in the Brazilian population. This pioneering approach includes genomic, epigenomic and functional studies, which results will contribute to the improvement of the diagnosis, prognosis and personalized therapy of FH patients., (Copyright © 2020 Elsevier Inc. All rights reserved.)
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- 2021
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26. Functional analysis of PCSK9 3'UTR variants and mRNA-miRNA interactions in patients with familial hypercholesterolemia.
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Los B, Borges JB, Oliveira VF, Freitas RC, Dagli-Hernandez C, Bortolin RH, Gonçalves RM, Faludi AA, Rodrigues AC, Bastos GM, Jannes CE, Pereira AC, Hirata RD, and Hirata MH
- Subjects
- 3' Untranslated Regions, Adolescent, Adult, Aged, Aged, 80 and over, Child, Female, Genetic Variation, HEK293 Cells, Hep G2 Cells, Humans, Hyperlipoproteinemia Type II metabolism, Male, Middle Aged, Proprotein Convertase 9 metabolism, Young Adult, Hyperlipoproteinemia Type II genetics, MicroRNAs, Proprotein Convertase 9 genetics, RNA, Messenger
- Abstract
Aim: Functional analysis of PCSK9 3'UTR variants and mRNA-miRNA interactions were explored in patients with familial hypercholesterolemia (FH). Materials & methods: PCSK9 3'UTR variants were identified by exon-targeted gene sequencing. Functional effects of 3'UTR variants and mRNA-miRNA interactions were analyzed using in silico and in vitro studies in HEK293FT and HepG2 cells. Results: Twelve PCSK9 3'UTR variants were detected in 88 FH patients. c.*75C >T and c.*345C >T disrupted interactions with miR-6875, miR-4721 and miR-564. Transient transfection of the c.*345C >T decreased luciferase activity in HEK293FT cells. miR-4721 and miR-564 mimics reduced PCSK9 expression in HepG2 cells. Conclusion: PCSK9 c.*345C >T has a possible role as loss-of-function variant. miR-4721 and miR-564 downregulate PCSK9 and may be useful to improve lipid profile in FH patients.
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- 2021
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27. Late response to rosuvastatin and statin-related myalgia due to SLCO1B1 , SLCO1B3 , ABCB11 , and CYP3A5 variants in a patient with Familial Hypercholesterolemia: a case report.
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Dagli-Hernandez C, de Freitas RCC, Marçal EDSR, Gonçalves RM, Faludi AA, Borges JB, Bastos GM, Los B, Mori AA, Bortolin RH, Ferreira GM, de Oliveira VF, Hirata TDC, Hirata MH, and Hirata RDC
- Abstract
Statins are the most widely used cholesterol-lowering drugs for cardiovascular diseases prevention. However, some patients are refractory to treatment, whereas others experience statin-related adverse events (SRAE). It has been increasingly important to identify pharmacogenetic biomarkers for predicting statin response and adverse events. This case report describes a female patient with familial hypercholesterolemia (FH) who showed late response to rosuvastatin and experienced myalgia on statin treatment. In the first visit (V1), the patient reported myalgia to rosuvastatin 40 mg, which was interrupted for a 6-week wash-out period. In V2, rosuvastatin 20 mg was reintroduced, but her lipid profile did not show any changes after 6 weeks (V3) (LDL-c: 402 vs. 407 mg/dL). Her lipid profile markedly improved after 12 weeks of treatment (V4) (LDL-c: 208 mg/dL), suggesting a late rosuvastatin response. Her adherence to treatment was similar in V1 and V3 and no drug interactions were detected. Pharmacogenetic analysis revealed that the patient carries low-activity variants in SLCO1B1*1B and*5 , SLCO1B3 (rs4149117 and rs7311358), and ABCB11 rs2287622, and the non-functional variant in CYP3A5*3 . The combined effect of variants in pharmacokinetics-related genes may have contributed to the late response to rosuvastatin and statin-related myalgia. Therefore, they should be considered when assessing a patient's response to statin treatment. To the best of our knowledge, this is the first report of a pharmacogenetic analysis on a case of late rosuvastatin response., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-5540). The authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)
- Published
- 2021
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28. Position Statement on Fat Consumption and Cardiovascular Health - 2021.
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Izar MCO, Lottenberg AM, Giraldez VZR, Santos Filho RDD, Machado RM, Bertolami A, Assad MHV, Saraiva JFK, Faludi AA, Moreira ASB, Geloneze B, Magnoni CD, Scherr C, Amaral CK, Araújo DB, Cintra DEC, Nakandakare ER, Fonseca FAH, Mota ICP, Santos JED, Kato JT, Beda LMM, Vieira LP, Bertolami MC, Rogero MM, Lavrador MSF, Nakasato M, Damasceno NRT, Alves RJ, Lara RS, Costa RP, and Machado VA
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- Humans, Cardiovascular Diseases etiology, Cardiovascular System
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- 2021
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29. Adiponectin concentration data improve the estimation of atherosclerotic risk in normal and in overweight subjects.
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Bertolami A, de Lima-Júnior JC, Cintra RM, Carvalho LS, Gonzaga CC, Sulzbach ML, Petisco ACGP, Barbosa JEM, Faludi AA, Plutzky J, Bertolami MC, and Sposito AC
- Subjects
- Adult, Anthropometry, Biomarkers blood, Cross-Sectional Studies, Female, Humans, Male, Risk Assessment, Adiponectin blood, Atherosclerosis diagnosis, Body Mass Index, Carotid Intima-Media Thickness
- Abstract
Background: The combinations of adipokines and body mass parameters to estimate carotid atherosclerotic disease have not been completely delineated., Objective: To test the combinations of well-established, easily accessible body mass indices and circulating biomarkers to identify increased carotid intima-media thickness (cIMT) in a primary prevention setting., Design and Patients: In a cross-sectional analysis of 339 asymptomatic individuals with no history of cardiovascular events, inflammatory and insulin sensitivity biomarkers as well as adipokine levels were measured and combined with body mass parameters to evaluate the best marker for increased cIMT., Results: As isolated parameters, body mass index (BMI) and adiponectin best identified abnormal cIMT (P = .04). Adiponectin levels were also linked to the relationship between BMI and cIMT (β = 0.0371; P = .01). Twenty-nine individuals with increased cIMT were missed by BMI alone but detected by combining BMI and adiponectin measurements. When compared with BMI alone, the combination of adiponectin plus BMI improved the c-statistic (0.549-0.567) and the integrated discrimination improvement index (0.01725; P = .021). Segregation of individuals by the combined use of BMI + adiponectin is associated with significant differences in insulin sensitivity, glomerular filtration rate, systemic inflammatory activity, dyslipidaemia and cIMT., Conclusions: Combining plasma adiponectin measurements and BMI improves estimation of cIMT as compared to anthropometric parameters., (© 2017 John Wiley & Sons Ltd.)
- Published
- 2018
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30. Positioning about the Flexibility of Fasting for Lipid Profiling.
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Scartezini M, Ferreira CEDS, Izar MCO, Bertoluci M, Vencio S, Campana GA, Sumita NM, Barcelos LF, Faludi AA, Santos RD, Malachias MVB, Aquino JL, Galoro CAO, Sabino C, Gurgel MHC, Turatti LAA, Hohl A, and Martinez TLDR
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- Brazil, Humans, Reference Standards, Reference Values, Time Factors, Cholesterol blood, Fasting blood, Postprandial Period, Triglycerides blood
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- 2017
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31. Statin-associated muscle symptoms: position paper from the Luso-Latin American Consortium.
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Sposito AC, Faria Neto JR, Carvalho LS, Lorenzatti A, Cafferata A, Elikir G, Esteban E, Morales Villegas EC, Bodanese LC, Alonso R, Ruiz AJ, Rocha VZ, Faludi AA, Xavier HT, Coelho OR, Assad MH, Izar MC, Santos RD, Fonseca FA, Mello E Silva A, Silva PM, and Bertolami MC
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- Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use, Risk Factors, Cardiovascular Diseases prevention & control, Hydroxymethylglutaryl-CoA Reductase Inhibitors adverse effects, Muscular Diseases chemically induced
- Abstract
In the last two decades, statin therapy has proved to be the most potent isolated therapy for attenuation of cardiovascular risk. Its frequent use has been seen as one of the most important elements for the reduction of cardiovascular mortality in developed countries. However, the recurrent incidence of muscle symptoms in statin users raised the possibility of causal association, leading to a disease entity known as statin associated muscle symptoms (SAMS). Mechanistic studies and clinical trials, specifically designed for the study of SAMS have allowed a deeper understanding of the natural history and accurate incidence. This set of information becomes essential to avoid an unnecessary risk of severe forms of SAMS. At the same time, this concrete understanding of SAMS prevents overdiagnosis and an inadequate suspension of one of the most powerful prevention strategies of our times. In this context, the Luso-Latin American Consortium gathered all available information on the subject and presents them in detail in this document as the basis for the identification and management of SAMS.
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- 2017
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32. Predictive Potential of Twenty-Two Biochemical Biomarkers for Coronary Artery Disease in Type 2 Diabetes Mellitus.
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Pereira EC, Bertolami MC, Faludi AA, Monte O, Xavier HT, Pereira TV, and Abdalla DS
- Abstract
We investigated the potential of a panel of 22 biomarkers to predict the presence of coronary artery disease (CAD) in type 2 diabetes mellitus (DM2) patients. The study enrolled 96 DM2 patients with (n = 75) and without (n = 21) evidence of CAD. We assessed a biochemical profile that included 22 biomarkers: total cholesterol, LDL, HDL, LDL/HDL, triglycerides, glucose, glycated hemoglobin, fructosamine, homocysteine, cysteine, methionine, reduced glutathione, oxidized glutathione, reduced glutathione/oxidized glutathione, L-arginine, asymmetric dimethyl-L-arginine, symmetric dimethyl-L-arginine, asymmetric dimethyl-L-arginine/L-arginine, nitrate plus nitrite, S-nitrosothiols, nitrotyrosine, and n-acetyl-β-glucosaminidase. Prediction models were built using logistic regression models. We found that eight biomarkers (methionine, nitratate plus nitrite, n-acetyl-β-glucosaminidase, BMI, LDL, HDL, reduced glutathione, and L-arginine/asymmetric dimethyl-L-arginine) along with gender and BMI were significantly associated with the odds of CAD in DM2. These preliminary findings support the notion that emerging biochemical markers might be used for CAD prediction in patients with DM2. Our findings warrant further investigation with large, well-designed studies.
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- 2015
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33. Relevance of target-organ lesions as predictors of mortality in patients with diabetes mellitus.
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Bianco HT, Izar MC, Fonseca HA, Póvoa RM, Saraiva JF, Forti A, Jardim PC, Introcaso L, Yugar-Toledo J, Xavier HT, Faludi AA, and Fonseca FA
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- Aged, Brazil, Cardiovascular Diseases etiology, Cohort Studies, Diabetes Mellitus, Type 2 complications, Electrocardiography, Female, Glomerular Filtration Rate, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Obesity complications, Obesity mortality, Predictive Value of Tests, Prognosis, Renal Insufficiency mortality, Risk Assessment, Risk Factors, Statistics, Nonparametric, Cardiovascular Diseases mortality, Diabetes Mellitus, Type 2 mortality
- Abstract
Background: Patients with diabetes are in extract higher risk for fatal cardiovascular events., Objective: To evaluate major predictors of mortality in subjects with type 2 diabetes., Methods: A cohort of 323 individuals with type 2 diabetes from several regions of Brazil was followed for a long period. Baseline electrocardiograms, clinical and laboratory data obtained were used to determine hazard ratios (HR) and confidence interval (CI) related to cardiovascular and total mortality., Results: After 9.2 years of follow-up (median), 33 subjects died (17 from cardiovascular causes). Cardiovascular mortality was associated with male gender; smoking; prior myocardial infarction; long QTc interval; left ventricular hypertrophy; and eGFR <60 mL/min. These factors, in addition to obesity, were predictors of total mortality. Cardiovascular mortality was adjusted for age and gender, but remained associated with: smoking (HR = 3.8; 95% CI 1.3-11.8; p = 0.019); prior myocardial infarction (HR = 8.5; 95% CI 1.8-39.9; p = 0.007); eGFR < 60 mL/min (HR = 9.5; 95% CI 2.7-33.7; p = 0.001); long QTc interval (HR = 5.1; 95% CI 1.7-15.2; p = 0.004); and left ventricular hypertrophy (HR = 3.5; 95% CI 1.3-9.7; p = 0.002). Total mortality was associated with obesity (HR = 2.3; 95% CI 1.1-5.1; p = 0.030); smoking (HR = 2.5; 95% CI 1.0-6.1; p = 0.046); prior myocardial infarction (HR = 3.1; 95% CI 1.4-6.1; p = 0.005), and long QTc interval (HR = 3.1; 95% CI 1.4-6.1; p = 0.017)., Conclusions: Biomarkers of simple measurement, particularly those related to target-organ lesions, were predictors of mortality in subjects with type 2 diabetes.
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- 2014
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34. Influence of PCSK9 polymorphisms on plasma lipids and response to atorvastatin treatment in Brazilian subjects.
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Anderson JM, Cerda A, Hirata MH, Rodrigues AC, Dorea EL, Bernik MM, Bertolami MC, Faludi AA, and Hirata RD
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- Adult, Aged, Atorvastatin, Brazil, Female, Heptanoic Acids administration & dosage, Humans, Hypercholesterolemia drug therapy, Hypercholesterolemia metabolism, Male, Middle Aged, Polymorphism, Single Nucleotide, Proprotein Convertase 9, Proprotein Convertases metabolism, Pyrroles administration & dosage, Serine Endopeptidases metabolism, Treatment Outcome, Biomarkers, Pharmacological metabolism, Cholesterol, LDL metabolism, Hypercholesterolemia genetics, Mutation genetics, Proprotein Convertases genetics, Serine Endopeptidases genetics
- Abstract
Background: The proprotein convertase subtilisin/kexin type 9 (PCSK9) has a key role in the regulation of plasma low-density lipoprotein (LDL) cholesterol by enhancing the degradation of LDL receptor. Functional variants in PCSK9 have been associated with differences in plasma lipids and may contribute to the variability of the response to cholesterol-lowering drugs., Objective: To investigate the influence of PCSK9 variants on plasma lipid profile and response to atorvastatin in Brazilian subjects., Methods: PCSK9 E670G, I474V, and R46L single nucleotide polymorphisms (SNPs) and plasma lipids were evaluated in 163 hypercholesterolemics (HC) and 171 normolipidemics (NL). HC patients with indication for cholesterol-lowering drug therapy (n = 128) were treated with atorvastatin (10 mg/d/4 wk). PCSK9 SNPs were analyzed by real time polymerase chain reaction., Results: Frequencies of the PCSK9 SNPs were similar between the HC and NL groups. Logistic regression analysis showed a trend of association between PCSK9 E670G and hypercholesterolemia after adjustment for covariates (P = .059). The 670G allele was associated with high basal levels of LDL cholesterol (P = .03) in HC patients using the extreme discordant phenotype method. No association tests were performed for R46L variant because of its very low frequency, whereas the I474V polymorphism and PCSK9 haplotypes were not related to hypercholesterolemia or variability on plasma lipids in both NL and HC groups (P > .05). LDL cholesterol reduction in response to atorvastatin was not influenced by PCSK9 genotypes or haplotypes., Conclusions: PCSK9 E670G polymorphism but not I474V contributes to the variability on plasma LDL cholesterol levels in hypercholesterolemic subjects. Both PCSK9 variants have no influence on cholesterol-lowering response to atorvastatin., (Copyright © 2014 National Lipid Association. Published by Elsevier Inc. All rights reserved.)
- Published
- 2014
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35. Atorvastatin and hormone therapy influence expression of ABCA1, APOA1 and SCARB1 in mononuclear cells from hypercholesterolemic postmenopausal women.
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Cerda A, Issa MH, Genvigir FD, Rohde CB, Cavalli SA, Bertolami MC, Faludi AA, Hirata MH, and Hirata RD
- Subjects
- ATP Binding Cassette Transporter 1 genetics, Anticholesteremic Agents administration & dosage, Apolipoprotein A-I genetics, Atorvastatin, Cells, Cultured, Estradiol therapeutic use, Female, Heptanoic Acids administration & dosage, Heterocyclic Compounds therapeutic use, Humans, Hypercholesterolemia drug therapy, Hypercholesterolemia genetics, Hypercholesterolemia metabolism, Leukocytes, Mononuclear drug effects, Middle Aged, Postmenopause, Pyrroles administration & dosage, Scavenger Receptors, Class B genetics, Transcriptome, ATP Binding Cassette Transporter 1 metabolism, Anticholesteremic Agents therapeutic use, Apolipoprotein A-I metabolism, Heptanoic Acids therapeutic use, Leukocytes, Mononuclear metabolism, Pyrroles therapeutic use, Scavenger Receptors, Class B metabolism
- Abstract
Background: Reverse cholesterol transport (RCT) has been inversely related to atherosclerosis and cardiovascular risk. The influence of menopause in the RCT process is poorly understood and the effects of cholesterol-lowering interventions, including statins and hormone therapy (HT), on genes controlling the RCT in postmenopausal women are also unknown., Methods: The effects on serum lipids and expression profile of genes involved in RCT - APOA1, ABCA1, ABCG1, SCARB1 and LXRA - were evaluated by TaqMan(®) quantitative PCR in peripheral blood mononuclear cells (PBMC) from 87 postmenopausal hypercholesterolemic women treated with atorvastatin (AT, n=17), estrogen or estrogen plus progestin (HT, n=34) and estrogen or estrogen plus progestin associated with atorvastatin (HT+AT, n=36)., Results: Atorvastatin and HT treatments reduced the mRNA levels of APOA1 and SCARB1, respectively, whereas ABCA1 expression was reduced after all treatments. Although the expression of LXRA, an important transcription factor controlling the expression of genes involved in RCT, was not modified after any treatment, it was correlated with ABCA1, APOA1 and SCARB1 RNAm values before and after treatments, however no correlation with ABCG1 was observed. In a linear regression analysis, HT was related to an increase in apoAI levels after treatment when compared to atorvastatin and, moreover, higher SCARB1 and ABCA1 basal expression were also associated with decreased apoAI levels after treatments., Conclusion: ABCA1 mRNA levels are decreased by atorvastatin and HT, however these treatments have a differential effect on APOA1 and SCARB1 expression in PBMC from postmenopausal women. Basal ABCA1 and SCARB1 expression profile could be helpful markers in predicting the effect of atorvastatin and HT on RCT, according to the changes in apoAI levels in this sample population., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Published
- 2013
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36. [V Brazilian Guidelines on Dyslipidemias and Prevention of Atherosclerosis].
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Xavier HT, Izar MC, Faria Neto JR, Assad MH, Rocha VZ, Sposito AC, Fonseca FA, dos Santos JE, Santos RD, Bertolami MC, Faludi AA, Martinez TL, Diament J, Guimarães A, Forti NA, Moriguchi E, Chagas AC, Coelho OR, and Ramires JA
- Subjects
- Adolescent, Adult, Aged, Atherosclerosis prevention & control, Biomarkers blood, Cardiovascular Diseases etiology, Child, Cholesterol Esters blood, Dyslipidemias blood, Dyslipidemias prevention & control, Fatty Acids metabolism, Female, Fibric Acids metabolism, Humans, Hypercholesterolemia blood, Hypertriglyceridemia blood, Life Expectancy, Lipoproteins metabolism, Male, Middle Aged, Risk Factors, Triglycerides blood, Atherosclerosis therapy, Cholesterol blood, Dyslipidemias therapy
- Published
- 2013
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37. Genetic variants in genes related to lipid metabolism and atherosclerosis, dyslipidemia and atorvastatin response.
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Rodrigues AC, Sobrino B, Genvigir FD, Willrich MA, Arazi SS, Dorea EL, Bernik MM, Bertolami M, Faludi AA, Brion MJ, Carracedo A, Hirata MH, and Hirata RD
- Subjects
- Atorvastatin, Dyslipidemias complications, Dyslipidemias metabolism, Female, Genotype, Heptanoic Acids pharmacokinetics, Heptanoic Acids therapeutic use, Humans, Lipid Metabolism drug effects, Male, Middle Aged, Pyrroles pharmacokinetics, Pyrroles therapeutic use, Treatment Outcome, Atherosclerosis complications, Dyslipidemias drug therapy, Dyslipidemias genetics, Heptanoic Acids pharmacology, Lipid Metabolism genetics, Polymorphism, Single Nucleotide, Pyrroles pharmacology
- Abstract
Objective: Using candidate gene approach, we have investigated the effect of single nucleotide polymorphism (SNP) in genes related to lipid metabolism and atherosclerosis on dyslipidemia and atorvastatin response., Methods: The study included 157 patients treated with atorvastatin and 145 controls. Genomic DNA was isolated and genotyped using SNPlex technology., Results: Allele and genotype disease association test revealed that APOB rs693 (OR: 2.2 [1.5-3.2], p=0.0001) and CD36 rs1984112 (OR: 3.7 [1.9-7.0], p=0.0002) SNPs were independent risk factors for hypercholesterolemia. Only APOB rs693 T variant allele was associated with increased LDL cholesterol levels (>160mg/dL). After atorvastatin treatment (10mg/day/4weeks), LIPC -514T allele was positively associated with LDL cholesterol reduction., Conclusion: The current study reinforces the current knowledge that carrying APOB rs693 is an independent risk factor for dyslipidemia and higher LDL levels. Furthermore, we found that a variant of CD36 was associated with dyslipidemia as a risk (rs1984112) factor. Finally, atorvastatin response could be predicted by LIPC -514C>T SNP and physical activity. In conclusion, our data evidences the contribution of genetic markers and their interaction with environmental factor in the variability of statin response., (Copyright © 2012 Elsevier B.V. All rights reserved.)
- Published
- 2013
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38. [First Brazilian Guidelines for Familial Hypercholesterolemia].
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Santos RD, Gagliardi AC, Xavier HT, Casella Filho A, Araújo DB, Cesena FY, Alves RJ, Pereira AC, Lottemberg AM, Chacra AP, Faludi AA, Sposito AC, Ribeiro Filho FF, Helfenstein Fonseca FA, de Carlos Back Giuliano I, Catani LH, Bertolami MC, Hiroshi Miname M, Izar MC, Monte O, Maranhão RC, Martinez TL, Arruda Machado V, Zorzanelli Rocha V, and Salgado Filho W
- Subjects
- Brazil, Cardiovascular Diseases etiology, Humans, Hyperlipoproteinemia Type II genetics, Hyperlipoproteinemia Type II mortality, Lipid Metabolism physiology, Nutritional Requirements, Risk Factors, Hyperlipoproteinemia Type II diagnosis, Hyperlipoproteinemia Type II therapy
- Published
- 2012
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39. Differentiation of African components of ancestry to stratify groups in a case-control study of a Brazilian urban population.
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Silbiger VN, Hirata MH, Luchessi AD, Genvigir FD, Cerda A, Rodrigues AC, Willrich MA, Arazi SS, Dorea EL, Bernik MM, Faludi AA, Bertolami MC, Santos C, Carracedo A, Salas A, Freire A, Lareu MV, Phillips C, Porras-Hurtado L, Fondevila M, and Hirata RD
- Subjects
- Asian People ethnology, Asian People genetics, Black People ethnology, Brazil ethnology, Female, Humans, Indians, South American genetics, Male, Population Groups ethnology, Population Groups genetics, White People ethnology, White People genetics, Black People genetics, Case-Control Studies, Hypercholesterolemia genetics, Indians, South American ethnology, Polymorphism, Single Nucleotide, Urban Population
- Abstract
Background: Balancing the subject composition of case and control groups to create homogenous ancestries between each group is essential for medical association studies., Methods: We explored the applicability of single-tube 34-plex ancestry informative markers (AIM) single nucleotide polymorphisms (SNPs) to estimate the African Component of Ancestry (ACA) to design a future case-control association study of a Brazilian urban sample., Results: One hundred eighty individuals (107 case group; 73 control group) self-described as white, brown-intermediate or black were selected. The proportions of the relative contribution of a variable number of ancestral population components were similar between case and control groups. Moreover, the case and control groups demonstrated similar distributions for ACA <0.25 and >0.50 categories. Notably a high number of outlier values (23 samples) were observed among individuals with ACA <0.25. These individuals presented a high probability of Native American and East Asian ancestral components; however, no individuals originally giving these self-described ancestries were observed in this study., Conclusions: The strategy proposed for the assessment of ancestry and adjustment of case and control groups for an association study is an important step for the proper construction of the study, particularly when subjects are taken from a complex urban population. This can be achieved using a straight forward multiplexed AIM-SNPs assay of highly discriminatory ancestry markers.
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- 2012
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40. Atorvastatin and hormone therapy effects on APOE mRNA expression in hypercholesterolemic postmenopausal women.
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Issa MH, Cerda A, Genvigir FD, Cavalli SA, Bertolami MC, Faludi AA, Hirata MH, and Hirata RD
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- Aged, Amplified Fragment Length Polymorphism Analysis, Apolipoproteins blood, Apolipoproteins E genetics, Atorvastatin, Brazil, Cholesterol, LDL blood, Drug Therapy, Combination adverse effects, Female, Heptanoic Acids adverse effects, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors adverse effects, Hypercholesterolemia blood, Hypercholesterolemia genetics, Hypercholesterolemia metabolism, Leukocytes, Mononuclear drug effects, Leukocytes, Mononuclear metabolism, Liver X Receptors, Middle Aged, Orphan Nuclear Receptors genetics, Orphan Nuclear Receptors metabolism, Polymorphism, Single Nucleotide, Pyrroles adverse effects, RNA, Messenger metabolism, Apolipoproteins E metabolism, Down-Regulation drug effects, Estrogen Replacement Therapy adverse effects, Estrogen Replacement Therapy methods, Heptanoic Acids therapeutic use, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use, Hypercholesterolemia drug therapy, Postmenopause, Pyrroles therapeutic use
- Abstract
Menopause is associated with changes in lipid levels resulting in increased risk of atherosclerosis and cardiovascular events. Hormone therapy (HT) and atorvastatin have been used to improve lipid profile in postmenopausal women. Effects of HT, atorvastatin and APOE polymorphisms on serum lipids and APOE and LXRA expression were evaluated in 87 hypercholesterolemic postmenopausal women, randomly selected for treatment with atorvastatin (AT, n=17), estrogen or estrogen plus progestagen (HT, n=34) and estrogen or estrogen plus progestagen associated with atorvastatin (HT+AT, n=36). RNA was extracted from peripheral blood mononuclear cells (PBMC) and mRNA expression was measured by TaqMan(®) PCR. APOE ɛ2/ɛ3/ɛ4 genotyping was performed using PCR-RFLP. Total cholesterol (TC), LDL-c and apoB were reduced after each treatment (p<0.001). Triglycerides, VLDL-c and apoAI were reduced only after atorvastatin (p<0.05), whereas triglycerides and VLDL-c were increased after HT (p=0.01). HT women had lower reduction on TC, LDL-c and apoB than AT and HT+AT groups (p<0.05). APOE mRNA expression was reduced after atorvastatin treatment (p=0.03). Although LXRA gene expression was not modified by atorvastatin, it was correlated with APOE mRNA before and after treatments. Basal APOE mRNA expression was not influenced by gene polymorphisms, however the reduction on APOE expression was more pronounced in ɛ3ɛ3 than in ɛ3ɛ4 carriers. Atorvastatin down-regulates APOE mRNA expression and it is modified by APOE genotypes in PBMC from postmenopausal women., (Copyright © 2011 Elsevier Ltd. All rights reserved.)
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- 2012
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41. Apolipoprotein E mRNA expression in mononuclear cells from normolipidemic and hypercholesterolemic individuals treated with atorvastatin.
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Cerda A, Genvigir FD, Willrich MA, Arazi SS, Bernik MM, Dorea EL, Bertolami MC, Faludi AA, Hirata MH, and Hirata RD
- Subjects
- Adult, Aged, Apolipoproteins E metabolism, Atorvastatin, Case-Control Studies, Female, Genetic Association Studies, Genotype, Humans, Leukocytes, Mononuclear drug effects, Lipids blood, Male, Middle Aged, Polymorphism, Genetic, RNA, Messenger metabolism, Anticholesteremic Agents therapeutic use, Apolipoproteins E genetics, Gene Expression, Heptanoic Acids therapeutic use, Hypercholesterolemia drug therapy, Leukocytes, Mononuclear metabolism, Pyrroles therapeutic use, RNA, Messenger genetics
- Abstract
Background: Apolipoprotein E (apoE) is a key component of the lipid metabolism. Polymorphisms at the apoE gene (APOE) have been associated with cardiovascular disease, lipid levels and lipid-lowering response to statins. We evaluated the effects on APOE expression of hypercholesterolemia, APOE ε2/ε3/ε4 genotypes and atorvastatin treatment in Brazilian individuals. The relationship of APOE genotypes and plasma lipids and atorvastatin response was also tested in this population., Methods: APOE ε2/ε3/ε4 and plasma lipids were evaluated in 181 normolipidemic (NL) and 181 hypercholesterolemic (HC) subjects. HC individuals with indication for lowering-cholesterol treatment (n = 141) were treated with atorvastatin (10 mg/day/4-weeks). APOE genotypes and APOE mRNA in peripheral blood mononuclear cells (PBMC) were analyzed by TaqMan real time PCR., Results: HC had lower APOE expression than NL group (p < 0.05) and individuals with low APOE expression showed higher plasma total and LDL cholesterol and apoB, as well as higher apoAI (p < 0.05). Individuals carrying ε2 allele have reduced risk for hypercholesterolemia (OR: 0.27, 95% I.C.: 0.08-0.85, p < 0.05) and NL ε2 carriers had lower total and LDL cholesterol and apoB levels, and higher HDL cholesterol than non-carriers (p < 0.05). APOE genotypes did not affect APOE expression and atorvastatin response. Atorvastatin treatment do not modify APOE expression, however those individuals without LDL cholesterol goal achievement after atorvastatin treatment according to the IV Brazilian Guidelines for Dyslipidemia and Atherosclerosis Prevention had lower APOE expression than patients with desirable response after the treatment (p < 0.05)., Conclusions: APOE expression in PBMC is modulated by hypercholesterolemia and the APOE mRNA level regulates the plasma lipid profile. Moreover the expression profile is not modulated neither by atorvastatin nor APOE genotypes. In our population, APOE ε2 allele confers protection against hypercholesterolemia and a less atherogenic lipid profile. Moreover, low APOE expression after treatment of patients with poor response suggests a possible role of APOE level in atorvastatin response.
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- 2011
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42. Pharmacogenetics of OATP transporters reveals that SLCO1B1 c.388A>G variant is determinant of increased atorvastatin response.
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Rodrigues AC, Perin PM, Purim SG, Silbiger VN, Genvigir FD, Willrich MA, Arazi SS, Luchessi AD, Hirata MH, Bernik MM, Dorea EL, Santos C, Faludi AA, Bertolami MC, Salas A, Freire A, Lareu MV, Phillips C, Porras-Hurtado L, Fondevila M, Carracedo A, and Hirata RD
- Subjects
- Aged, Anticholesteremic Agents therapeutic use, Atorvastatin, Female, Gene Frequency, Genotype, Haplotypes, Humans, Linkage Disequilibrium, Liver-Specific Organic Anion Transporter 1, Logistic Models, Male, Middle Aged, Multivariate Analysis, Pharmacogenetics methods, Treatment Outcome, Heptanoic Acids therapeutic use, Hypercholesterolemia drug therapy, Hypercholesterolemia genetics, Organic Anion Transporters genetics, Polymorphism, Single Nucleotide, Pyrroles therapeutic use
- Abstract
Aims: The relationship between variants in SLCO1B1 and SLCO2B1 genes and lipid-lowering response to atorvastatin was investigated., Material and Methods: One-hundred-thirty-six unrelated individuals with hypercholesterolemia were selected and treated with atorvastatin (10 mg/day/4 weeks). They were genotyped with a panel of ancestry informative markers for individual African component of ancestry (ACA) estimation by SNaPshot(®) and SLCO1B1 (c.388A>G, c.463C>A and c.521T>C) and SLCO2B1 (-71T>C) gene polymorphisms were identified by TaqMan(®) Real-time PCR., Results: Subjects carrying SLCO1B1 c.388GG genotype exhibited significantly high low-density lipoprotein (LDL) cholesterol reduction relative to c.388AA+c.388AG carriers (41 vs. 37%, p = 0.034). Haplotype analysis revealed that homozygous of SLCO1B1*15 (c.521C and c.388G) variant had similar response to statin relative to heterozygous and non-carriers. A multivariate logistic regression analysis confirmed that c.388GG genotype was associated with higher LDL cholesterol reduction in the study population (OR: 3.2, CI95%:1.3-8.0, p < 0.05)., Conclusion: SLCO1B1 c.388A>G polymorphism causes significant increase in atorvastatin response and may be an important marker for predicting efficacy of lipid-lowering therapy.
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- 2011
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43. Influence of SCARB1 polymorphisms on serum lipids of hypercholesterolemic individuals treated with atorvastatin.
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Cerda A, Genvigir FD, Arazi SS, Hirata MH, Dorea EL, Bernik MM, Bertolami MC, Faludi AA, and Hirata RD
- Subjects
- Adult, Aged, Aged, 80 and over, Anticholesteremic Agents therapeutic use, Apolipoprotein A-I blood, Apolipoproteins B blood, Atorvastatin, Blood drug effects, Brazil, Cholesterol blood, Cholesterol metabolism, Cholesterol, HDL blood, Cholesterol, HDL drug effects, Cholesterol, HDL genetics, Cholesterol, LDL blood, Cholesterol, LDL drug effects, Cholesterol, LDL genetics, Female, Gene Frequency genetics, Genotype, Haplotypes genetics, Humans, Hypercholesterolemia blood, Linkage Disequilibrium genetics, Lipid Metabolism drug effects, Lipid Metabolism genetics, Male, Middle Aged, Triglycerides blood, Heptanoic Acids therapeutic use, Hypercholesterolemia drug therapy, Hypercholesterolemia genetics, Lipids blood, Polymorphism, Single Nucleotide genetics, Pyrroles therapeutic use, Scavenger Receptors, Class B genetics
- Abstract
Background: The SR-BI is a key component on the cholesterol metabolism. Polymorphisms in the SR-BI gene (SCARB1) were related with variations on plasma lipoprotein profile and other risk factors for cardiovascular disease. We tested the relationship of 3 SCARB1 single nucleotide polymorphisms (SNPs) with hypercholesterolemia in a Brazilian population and whether these variants can influence lipid-lowering response to atorvastatin., Methods: c.4G>A, c.726+54C>T and c.1050C>T SNPs and serum concentrations of lipid and apolipoproteins were evaluated in 147 hypercholesterolemic (HC) and 185 normolipidemic (NL) unrelated Brazilian subjects. HC patients were treated with atorvastatin (10 mg/day/4 weeks)., Results: Frequencies of SCARB1 polymorphisms were similar between the HC and NL groups (p>0.05). The T allele for c.726+54C>T was associated with higher LDL-c in NL and with higher apoB and apoB/apoAI in HC (p<0.05). HC individuals carrying c.1050C allele carriers (CC and CT genotypes) had lower change of total cholesterol, LDL-c, apoB and apoB/apoAI ratio (p<0.05) than the TT genotype carriers in response to atorvastatin., Conclusion: The SCARB1 polymorphisms are related with variations in serum lipids in the Brazilian population and c.1050C>T SNP is associated with lipid-lowering atorvastatin response., (Copyright 2010 Elsevier B.V. All rights reserved.)
- Published
- 2010
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44. Pleiotropic effects with equivalent low-density lipoprotein cholesterol reduction: comparative study between simvastatin and simvastatin/ezetimibe coadministration.
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Araujo DB, Bertolami MC, Ferreira WP, Abdalla DS, Faludi AA, Nakamura Y, and Bricharello LP
- Subjects
- Adolescent, Adult, Aged, Anticholesteremic Agents administration & dosage, Azetidines administration & dosage, Brachial Artery diagnostic imaging, Brachial Artery metabolism, C-Reactive Protein metabolism, Cholesterol, LDL blood, Cholesterol, LDL drug effects, Cross-Over Studies, Drug Therapy, Combination, Endothelium, Vascular drug effects, Endothelium, Vascular metabolism, Ezetimibe, Female, Humans, Male, Middle Aged, Simvastatin administration & dosage, Ultrasonography, Vasodilation drug effects, Young Adult, Anticholesteremic Agents therapeutic use, Azetidines therapeutic use, Hypercholesterolemia drug therapy, Simvastatin therapeutic use
- Abstract
Background: Coadministration of any statin with ezetimibe is as effective as using high doses of the same statin in the reduction of low-density lipoprotein cholesterol (LDL-c). There may be other effects called pleiotropics., Objective: To compare the effectiveness of 2 different treatments that obtain equivalent LDL-c reductions (80 mg of simvastatin, once a day and coadministration of 10 mg of simvastatin and 10 mg of ezetimibe, once a day) over endothelial function and inflammation., Methods: Twenty-three randomized patients with hypercholesterolemia in a 2 x 2 crossover protocol were studied. Endothelial function was analyzed by ultrasound assessment of endothelial dependent flow-mediated vasodilation of the brachial artery, and inflammation was estimated by high-sensitivity C-reactive protein (hs-CRP)., Results: LDL-c reduction was similar between the 2 treatments with simvastatin/ezetimibe and with simvastatin (P < 0.001); no difference between treatments was found (P = 0.968). Both treatments improved significantly the endothelial function [3.61% with simvastatin/ezetimibe (P = 0.003) and 5.08% with simvastatin (P < 0.001)]; no difference was found between the 2 treatments (P = 0.291). hs-CRP had a 23% reduction with simvastatin/ezetimibe (P = 0.004) and a 30% reduction with simvastatin alone (P = 0.01), with no significant difference between the 2 treatments (P = 0.380)., Conclusion: The 2 forms of treatment presented similar pleiotropic effects: improvement in endothelial function and decrease in hs-CRP levels.
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- 2010
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45. ABCB1 and ABCC1 expression in peripheral mononuclear cells is influenced by gene polymorphisms and atorvastatin treatment.
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Rebecchi IM, Rodrigues AC, Arazi SS, Genvigir FD, Willrich MA, Hirata MH, Soares SA, Bertolami MC, Faludi AA, Bernik MM, Dorea EL, Dagli ML, Avanzo JL, and Hirata RD
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism, Aged, Anticholesteremic Agents pharmacology, Atorvastatin, Female, Gene Expression Regulation drug effects, Humans, Leukocytes, Mononuclear drug effects, Male, Middle Aged, Multidrug Resistance-Associated Proteins metabolism, Polymorphism, Genetic drug effects, ATP Binding Cassette Transporter, Subfamily B, Member 1 biosynthesis, ATP Binding Cassette Transporter, Subfamily B, Member 1 genetics, Gene Expression Regulation genetics, Heptanoic Acids pharmacology, Leukocytes, Mononuclear metabolism, Multidrug Resistance-Associated Proteins biosynthesis, Multidrug Resistance-Associated Proteins genetics, Polymorphism, Genetic genetics, Pyrroles pharmacology
- Abstract
This study investigated the effects of atorvastatin on ABCB1 and ABCC1 mRNA expression on peripheral blood mononuclear cells (PBMC) and their relationship with gene polymorphisms and lowering-cholesterol response. One hundred and thirty-six individuals with hypercholesterolemia were selected and treated with atorvastatin (10 mg/day/4 weeks). Blood samples were collected for serum lipids and apolipoproteins measurements and DNA and RNA extraction. ABCB1 (C3435T and G2677T/A) and ABCC1 (G2012T) gene polymorphisms were identified by polymerase chain reaction-restriction (PCR)-RFLP and mRNA expression was measured in peripheral blood mononuclear cells by singleplex real-time PCR. ABCB1 polymorphisms were associated with risk for coronary artery disease (CAD) (p<0.05). After atorvastatin treatment, both ABCB1 and ABCC1 genes showed 50% reduction of the mRNA expression (p<0.05). Reduction of ABCB1 expression was associated with ABCB1 G2677T/A polymorphism (p=0.039). Basal ABCB1 mRNA in the lower quartile (<0.024) was associated with lower reduction rate of serum low-density lipoprotein (LDL) cholesterol (33.4+/-12.4%) and apolipoprotein B (apoB) (17.0+/-31.3%) when compared with the higher quartile (>0.085: LDL-c=40.3+/-14.3%; apoB=32.5+/-10.7%; p<0.05). ABCB1 substrates or inhibitors did not affect the baseline expression, while ABCB1 inhibitors reversed the effects of atorvastatin on both ABCB1 and ABCC1 transporters. In conclusion, ABCB1 and ABCC1 mRNA levels in PBMC are modulated by atorvastatin and ABCB1 G2677T/A polymorphism and ABCB1 baseline expression is related to differences in serum LDL cholesterol and apoB in response to atorvastatin.
- Published
- 2009
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46. Biomarkers of oxidative stress and endothelial dysfunction in glucose intolerance and diabetes mellitus.
- Author
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Pereira EC, Ferderbar S, Bertolami MC, Faludi AA, Monte O, Xavier HT, Pereira TV, and Abdalla DS
- Subjects
- Arginine analogs & derivatives, Arginine blood, Arginine chemistry, Body Mass Index, Diabetes Mellitus, Type 2 physiopathology, Female, Glucose Intolerance physiopathology, Glutathione chemistry, Glutathione metabolism, Hexosaminidases metabolism, Humans, Lipids blood, Male, Middle Aged, Nitrates metabolism, Nitric Oxide metabolism, Nitrites metabolism, Biomarkers blood, Diabetes Mellitus, Type 2 metabolism, Endothelium metabolism, Glucose Intolerance metabolism, Oxidative Stress
- Abstract
Objectives: To evaluate biomarkers of endothelial dysfunction and oxidative stress in glucose intolerance (GI) compared to overt diabetes (DM2)., Design and Methods: 140 volunteers including 96 with DM2, 32 with GI and 12 controls (C) were studied. (*)NO metabolites, (*)NO synthase inhibitors, thiols and N-acetyl-beta-glucosaminidase (NAGase) activity were analyzed by chemiluminescence, capillary electrophoresis, ELISA and colorimetric assay, respectively., Results: (*)NO metabolites were higher in GI (NOx: p=0.03; S-nitrosothiols: p=0.001) and DM2 (p=0.006; p=0.0006) groups in relation to group C, while nitrotyrosine was higher only in the DM2 group in comparison to the other groups. NAGase activity was elevated in GI (p=0.003) and DM2 (p=0.0004) groups in relation to group C, as well as, ADMA (p=0.01; p=0.003) and GSSG (p=0.01; p=0.002)., Conclusions: (*)NO metabolites, (*)NO synthase inhibitors, thiols and NAGase are biomarkers suitable to indicate endothelial dysfunction and oxidative stress in the early stages of impaired response to insulin.
- Published
- 2008
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47. CYP3A53A allele is associated with reduced lowering-lipid response to atorvastatin in individuals with hypercholesterolemia.
- Author
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Willrich MA, Hirata MH, Genvigir FD, Arazi SS, Rebecchi IM, Rodrigues AC, Bernik MM, Dorea EL, Bertolami MC, Faludi AA, and Hirata RD
- Subjects
- Aged, Alleles, Atorvastatin, Black People, Body Mass Index, Brazil epidemiology, Cholesterol, LDL blood, DNA genetics, DNA Primers, Female, Gene Frequency, Genotype, Humans, Hypercholesterolemia epidemiology, Male, Middle Aged, Polymorphism, Restriction Fragment Length, Reverse Transcriptase Polymerase Chain Reaction, Cytochrome P-450 CYP3A genetics, Heptanoic Acids therapeutic use, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use, Hypercholesterolemia drug therapy, Hypercholesterolemia genetics, Pyrroles therapeutic use
- Abstract
Background: The cytochrome P450 isoenzyme 3A5 (CYP3A5) has an important role on biotransformation of xenobiotics. CYP3A5 SNPs have been associated with variations on enzyme activity that can modify the metabolism of several drugs., Methods: In order to evaluate the influence of CYP3A5 variants on response to lowering-cholesterol drugs, 139 individuals with hypercholesterolemia were selected. After a wash-out period of 4 weeks, individuals were treated with atorvastatin (10 mg/day/4 weeks). Genomic DNA was extracted by a salting-out procedure. CYP3A5*3C, CYP3A5*6 and CYP3A5*1D were analyzed by PCR-RFLP and DNA sequencing., Results: >Frequencies of the CYP3A5*3C and CYP3A5*1D alleles were lower in individuals of African descent (*3C: 47.8% and *1D: 55.2%) than in non-Africans (*3C: 84.9% and *1D 84.8%, p<0.01). Non-Africans carrying *3A allele (*3C and *1D combined alleles) had lower total and LDL-cholesterol response to atorvastatin than non-*3A allele carriers (p<0.05)., Conclusion: CYP3A5*3A allele is associated with reduced cholesterol-lowering response to atorvastatin in non-African individuals.
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- 2008
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48. [IV Brazilian Guideline for Dyslipidemia and Atherosclerosis prevention: Department of Atherosclerosis of Brazilian Society of Cardiology].
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Sposito AC, Caramelli B, Fonseca FA, Bertolami MC, Afiune Neto A, Souza AD, Lottenberg AM, Chacra AP, Faludi AA, Loures-Vale AA, Carvalho AC, Duncan B, Gelonese B, Polanczyk C, Rodrigues Sobrinho CR, Scherr C, Karla C, Armaganijan D, Moriguchi E, Saraiva F, Pichetti G, Xavier HT, Chaves H, Borges JL, Diament J, Guimarães JI, Nicolau JC, dos Santos JE, de Lima JJ, Vieira JL, Novazzi JP, Faria Neto JR, Torres KP, Pinto Lde A, Bricarello L, Bodanese LC, Introcaso L, Malachias MV, Izar MC, Magalhães ME, Schmidt MI, Scartezini M, Nobre M, Foppa M, Forti NA, Berwanger O, Gebara OC, Coelho OR, Maranhão RC, dos Santos Filho RD, Costa RP, Barreto S, Kaiser S, Ihara S, Carvalho Td, Martinez TL, Relvas WG, and Salgado W
- Subjects
- Adult, Age Distribution, Aged, Cholesterol blood, Clofibric Acid therapeutic use, Coronary Artery Disease etiology, Coronary Artery Disease physiopathology, Diet, Female, Humans, Hyperlipidemias complications, Hyperlipidemias physiopathology, Hypolipidemic Agents therapeutic use, Lipid Metabolism drug effects, Male, Metabolic Syndrome complications, Middle Aged, Naphthalenes therapeutic use, Risk Factors, Sex Distribution, Smoking adverse effects, Triglycerides blood, Coronary Artery Disease prevention & control, Hyperlipidemias therapy, Lipid Metabolism physiology
- Published
- 2007
- Full Text
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49. High baseline serum total and LDL cholesterol levels are associated with MDR1 haplotypes in Brazilian hypercholesterolemic individuals of European descent.
- Author
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Rodrigues AC, Rebecchi IM, Bertolami MC, Faludi AA, Hirata MH, and Hirata RD
- Subjects
- Adult, Aged, Anticholesteremic Agents therapeutic use, Atorvastatin, Brazil, Cholesterol, LDL genetics, Female, Gene Frequency, Heptanoic Acids therapeutic use, Humans, Hypercholesterolemia blood, Hypercholesterolemia drug therapy, Hypercholesterolemia ethnology, Male, Middle Aged, Polymerase Chain Reaction, Polymorphism, Genetic, Polymorphism, Restriction Fragment Length, Polymorphism, Single Nucleotide, Pyrroles therapeutic use, White People, ATP Binding Cassette Transporter, Subfamily B, Member 1 genetics, Cholesterol, LDL blood, Genes, MDR genetics, Haplotypes genetics, Hypercholesterolemia genetics
- Abstract
The MDR1 gene encodes the P-glycoprotein, an efflux transporter with broad substrate specificity. P-glycoprotein has raised great interest in pharmacogenetics because it transports a variety of structurally divergent drugs, including lipid-lowering drugs. The synonymous single-nucleotide polymorphism C3435T and the nonsynonymous single-nucleotide polymorphism G2677T/A in MDR1 have been indicated as potential determinants of variability in drug disposition and efficacy. In order to evaluate the effect of G2677T/A and C3435T MDR1 polymorphisms on serum levels of lipids before and after atorvastatin administration, 69 unrelated hypercholesterolemic individuals from São Paulo city, Brazil, were selected and treated with 10 mg atorvastatin orally once daily for four weeks. MDR1 polymorphisms were analyzed by PCR-RFLP. C3435T and G2677T polymorphisms were found to be linked. The allelic frequencies for C3435T polymorphism were 0.536 and 0.464 for the 3435C and 3435T alleles, respectively, while for G2677T/A polymorphism allele frequencies were 0.580 for the 2677G allele, 0.384 for the 2677T allele and 0.036 for the 2677A allele. There was no significant relation between atorvastatin response and MDR1 polymorphisms (repeated measures ANOVA; P > 0.05). However, haplotype analysis revealed an association between T/T carriers and higher basal serum total (TC) and LDL cholesterol levels (TC: 303 +/- 56, LDL-C: 216 +/- 57 mg/dl, respectively) compared with non-T/T carriers (TC: 278 +/- 28, LDL-C: 189 +/- 24 mg/dl; repeated measures ANOVA/Tukey test; P < 0.05). These data indicate that MDR1 polymorphism may have an important contribution to the control of basal serum cholesterol levels in Brazilian hypercholesterolemic individuals of European descent.
- Published
- 2005
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50. Antioxidant effect of simvastatin is not enhanced by its association with alpha-tocopherol in hypercholesterolemic patients.
- Author
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Pereira EC, Bertolami MC, Faludi AA, Sevanian A, and Abdalla DS
- Subjects
- Cholesterol blood, Cholesterol, HDL blood, Cholesterol, LDL blood, Female, Humans, Hypercholesterolemia blood, Lipids blood, Male, Middle Aged, Sulfhydryl Compounds blood, Triglycerides blood, Anticholesteremic Agents therapeutic use, Antioxidants pharmacology, Hypercholesterolemia drug therapy, Simvastatin therapeutic use, alpha-Tocopherol pharmacology
- Abstract
Among the pleiotropic effects of statins, their antioxidant action may be involved in their protective effects. Thus, we investigated the antioxidant effect of simvastatin, associated or not with alpha-tocopherol, on levels of electronegative low-density lipoprotein (LDL-), nitrotyrosine, thiols (homocysteine, glutathione, cysteine, methionine), and lipid-soluble antioxidants in blood plasma of hypercholesterolemic subjects. In this study, 25 hypercholesterolemic subjects were treated for 2 months with simvastatin (20 mg/day) and with simvastatin (20 mg/day) + alpha-tocopherol (400 IU/day). Concentrations of thiols were determined by high-performance capillary electrophoresis-laser-induced fluorescene. Lipid-soluble antioxidants were determined by HPLC, and LDL-, and nitrotyrosine by ELISA. Simvastatin, independent of its association with alpha-tocopherol, reduced plasma concentrations of LDL-, nitrotyrosine, total cholesterol, and LDL cholesterol and the LDL cholesterol/HDL cholesterol ratio. Neither simvastatin nor simvastatin plus alpha-tocopherol altered plasma levels of the thiols analyzed. alpha-Tocopherol did not change the antioxidant effect of simvastatin on the levels of LDL- and nitrotyrosine in hypercholesterolemic subjects. The reduction of LDL- and nitrotyrosine by simvastatin seems to be related to the pleiotropic effects of this statin, and it may have an important protective effect against endothelial dysfunction and atherosclerosis.
- Published
- 2004
- Full Text
- View/download PDF
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