RESUMO
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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MicroRNAs , Epigenômica , Hiperlipoproteinemia Tipo II , Pró-Proteína Convertase 9RESUMO
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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Hiperlipoproteinemia Tipo II/genética , MicroRNAs , Pró-Proteína Convertase 9/genética , RNA Mensageiro , Regiões 3' não Traduzidas , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Variação Genética , Células HEK293 , Células Hep G2 , Humanos , Hiperlipoproteinemia Tipo II/metabolismo , Masculino , Pessoa de Meia-Idade , Pró-Proteína Convertase 9/metabolismo , Adulto JovemRESUMO
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 (ß = 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.
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Adiponectina/sangue , Aterosclerose/diagnóstico , Índice de Massa Corporal , Espessura Intima-Media Carotídea , Adulto , Antropometria , Biomarcadores/sangue , Estudos Transversais , Feminino , Humanos , Masculino , Medição de RiscoRESUMO
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.
Assuntos
Adiponectina , Aterosclerose , ObesidadeRESUMO
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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Doenças Cardiovasculares/prevenção & controle , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Doenças Musculares/induzido quimicamente , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Fatores de RiscoRESUMO
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.
Assuntos
Biomarcadores Farmacológicos/metabolismo , LDL-Colesterol/metabolismo , Hipercolesterolemia/genética , Mutação/genética , Pró-Proteína Convertases/genética , Serina Endopeptidases/genética , Adulto , Idoso , Atorvastatina , Brasil , Feminino , Ácidos Heptanoicos/administração & dosagem , Humanos , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/metabolismo , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Pró-Proteína Convertase 9 , Pró-Proteína Convertases/metabolismo , Pirróis/administração & dosagem , Serina Endopeptidases/metabolismo , Resultado do TratamentoRESUMO
BackgroundThe 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.ObjectiveTo investigate the influence of PCSK9 variants on plasma lipid profile and response to atorvastatin in Brazilian subjects.MethodsPCSK9 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.ResultsFrequencies 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.
Assuntos
Colesterol , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: The proprotein convertase subtilisin/kexin type 9 (PCSK9) has a key role in theregulation of plasma low-density lipoprotein (LDL) cholesterol by enhancing the degradation ofLDL receptor. Functional variants in PCSK9 have been associated with differences in plasma lipidsand 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 toatorvastatin in Brazilian subjects.METHODS: PCSK9 E670G, I474V, and R46L single nucleotide polymorphisms (SNPs) and plasmalipids were evaluated in 163 hypercholesterolemics (HC) and 171 normolipidemics (NL). HC patientswith indication for cholesterol-lowering drug therapy (n 5 128) 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. Logisticregression analysis showed a trend of association between PCSK9 E670G and hypercholesterolemiaafter adjustment for covariates (P 5 .059). The 670G allele was associated with high basal levels ofLDL cholesterol (P 5 .03) in HC patients using the extreme discordant phenotype method. Noassociation tests were performed for R46L variant because of its very low frequency, whereas theI474V polymorphism and PCSK9 haplotypes were not related to hypercholesterolemia or variabilityon plasma lipids in both NL and HC groups (P ..05). LDL cholesterol reduction in response to atorvastatinwas not influenced by PCSK9 genotypes or haplotypes.CONCLUSIONS: PCSK9 E670G polymorphism but not I474V contributes to the variability onplasma LDL cholesterol levels in hypercholesterolemic subjects. Both PCSK9 variants have no influenceon cholesterol-lowering response to atorvastatin. 2014 National Lipid Association. All rights reserved.
Assuntos
Colesterol , Farmacogenética , Polimorfismo GenéticoRESUMO
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.
Assuntos
População Negra/genética , Estudos de Casos e Controles , Hipercolesterolemia/genética , Indígenas Sul-Americanos/etnologia , Polimorfismo de Nucleotídeo Único , População Urbana , Povo Asiático/etnologia , Povo Asiático/genética , População Negra/etnologia , Brasil/etnologia , Feminino , Humanos , Indígenas Sul-Americanos/genética , Masculino , Grupos Populacionais/etnologia , Grupos Populacionais/genética , População Branca/etnologia , População Branca/genéticaRESUMO
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 É2/É3/É4 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 É3É3 than in É3É4 carriers. Atorvastatin down-regulates APOE mRNA expression and it is modified by APOE genotypes in PBMC from postmenopausal women.
Assuntos
Apolipoproteínas E/metabolismo , Regulação para Baixo/efeitos dos fármacos , Terapia de Reposição de Estrogênios , Ácidos Heptanoicos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Pós-Menopausa , Pirróis/uso terapêutico , Idoso , Análise do Polimorfismo de Comprimento de Fragmentos Amplificados , Apolipoproteínas/sangue , Apolipoproteínas E/genética , Atorvastatina , Brasil , LDL-Colesterol/sangue , Quimioterapia Combinada/efeitos adversos , Terapia de Reposição de Estrogênios/efeitos adversos , Terapia de Reposição de Estrogênios/métodos , Feminino , Ácidos Heptanoicos/efeitos adversos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Hipercolesterolemia/sangue , Hipercolesterolemia/genética , Hipercolesterolemia/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Receptores X do Fígado , Pessoa de Meia-Idade , Receptores Nucleares Órfãos/genética , Receptores Nucleares Órfãos/metabolismo , Polimorfismo de Nucleotídeo Único , Pirróis/efeitos adversos , RNA Mensageiro/metabolismoRESUMO
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 0.50 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.
Assuntos
Genômica , Polimorfismo Genético , População Urbana , População Urbana/classificaçãoRESUMO
Menopause is associated with changes in lipid levels resulting in increased risk of atherosclerosis andcardiovascular events. Hormone therapy (HT) and atorvastatin have been used to improve lipid profilein postmenopausal women.Effects of HT, atorvastatin and APOE polymorphisms on serum lipids and APOE and LXRA expressionwere evaluated in 87 hypercholesterolemic postmenopausal women, randomly selected for treatmentwith atorvastatin (AT, n = 17), estrogen or estrogen plus progestagen (HT, n = 34) and estrogen or estrogenplus progestagen associated with atorvastatin (HT + AT, n = 36). RNA was extracted from peripheralblood mononuclear cells (PBMC) and mRNA expression was measured by TaqMan® PCR. APOE 2/ 3/ 4genotyping 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 wereincreased after HT (p = 0.01). HT women had lower reduction on TC, LDL-c and apoB than AT and HT + ATgroups (p < 0.05). APOE mRNA expression was reduced after atorvastatin treatment (p = 0.03). AlthoughLXRA gene expression was not modified by atorvastatin, it was correlated with APOE mRNA before andafter treatments. Basal APOE mRNA expression was not influenced by gene polymorphisms, however thereduction on APOE expression was more pronounced in 3 3 than in 3 4 carriers.Atorvastatin down-regulates APOE mRNA expression and it is modified by APOE genotypes in PBMCfrom postmenopausal women.
Assuntos
Genética , Menopausa , Polimorfismo de Nucleotídeo Único , Terapia de Reposição HormonalRESUMO
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.
Assuntos
Anticolesterolemiantes/uso terapêutico , Apolipoproteínas E/genética , Expressão Gênica , Ácidos Heptanoicos/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Leucócitos Mononucleares/metabolismo , Pirróis/uso terapêutico , RNA Mensageiro/genética , Adulto , Idoso , Apolipoproteínas E/metabolismo , Atorvastatina , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , RNA Mensageiro/metabolismoRESUMO
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 andOPEN ACCESStreated 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%:1.38.0, p 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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Farmacogenética , Polimorfismo de Nucleotídeo ÚnicoRESUMO
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 å2/å3/å4 genotypes and atorvastatin treatment in Brazilian individuals. The relationship of APOE genotypes and plasma lipids and atorvastatin response was also tested in this population.MethodsAPOE å2/å3/å4 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.ResultsHC 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 å2 allele have reduced risk for hypercholesterolemia (OR: 0.27, 95% I.C.: 0.08-0.85, p < 0.05) and NL å2 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...
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Expressão Gênica , Hipercolesterolemia , Polimorfismo de Nucleotídeo ÚnicoRESUMO
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.
Assuntos
Ácidos Heptanoicos/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/genética , Lipídeos/sangue , Polimorfismo de Nucleotídeo Único/genética , Pirróis/uso terapêutico , Receptores Depuradores Classe B/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticolesterolemiantes/uso terapêutico , Apolipoproteína A-I/sangue , Apolipoproteínas B/sangue , Atorvastatina , Sangue/efeitos dos fármacos , Brasil , Colesterol/sangue , Colesterol/metabolismo , HDL-Colesterol/sangue , HDL-Colesterol/efeitos dos fármacos , HDL-Colesterol/genética , LDL-Colesterol/sangue , LDL-Colesterol/efeitos dos fármacos , LDL-Colesterol/genética , Feminino , Frequência do Gene/genética , Genótipo , Haplótipos/genética , Humanos , Hipercolesterolemia/sangue , Desequilíbrio de Ligação/genética , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Masculino , Pessoa de Meia-Idade , Triglicerídeos/sangueRESUMO
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.
Assuntos
Anticolesterolemiantes/uso terapêutico , Azetidinas/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Sinvastatina/uso terapêutico , Adolescente , Adulto , Idoso , Anticolesterolemiantes/administração & dosagem , Azetidinas/administração & dosagem , Artéria Braquial/diagnóstico por imagem , Artéria Braquial/metabolismo , Proteína C-Reativa/metabolismo , LDL-Colesterol/sangue , LDL-Colesterol/efeitos dos fármacos , Estudos Cross-Over , Quimioterapia Combinada , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Ezetimiba , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sinvastatina/administração & dosagem , Ultrassonografia , Vasodilatação/efeitos dos fármacos , Adulto JovemRESUMO
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 cardiovasculardisease. 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 responseto atorvastatin. Methods: c.4GNA, c.726+54CNT and c.1050CNT 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 (pN0.05). TheT allele for c.726+54CNT was associated with higher LDL-c in NL and with higher apoB and apoB/apoAI inHC (pb0.05). HC individuals carrying c.1050C allele carriers (CC and CT genotypes) had lower change of totalcholesterol, LDL-c, apoB and apoB/apoAI ratio (pb0.05) than the TT genotype carriers in response to atorvastatin. Conclusion: The SCARB1 polymorphisms are relatedwith variations in serumlipids in the Brazilian population and c.1050CNT SNP is associated with lipid-lowering atorvastatin response.