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1.
Clin Endocrinol (Oxf) ; 88(3): 388-396, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29280189

RESUMO

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.

2.
Clin Endocrinol (Oxf) ; 88(3): 388-396, 2018.
Artigo em Inglês | Sec. Est. Saúde SP, SESSP-IDPCPROD, Sec. Est. Saúde SP | ID: ses-36558

RESUMO

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.(AU)


Assuntos
Adiponectina , Aterosclerose , Obesidade
3.
Curr Med Res Opin ; 33(2): 239-251, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27776432

RESUMO

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.


Assuntos
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 Risco
4.
Curr Med Res Opin ; 33(2): 239-251, 2017.
Artigo em Inglês | Sec. Est. Saúde SP, SESSP-IDPCPROD, Sec. Est. Saúde SP | ID: ses-36705

RESUMO

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...(AU)


Assuntos
Hipersensibilidade , Inibidores de Hidroximetilglutaril-CoA Redutases
5.
Int J Clin Exp Med ; 8(4): 5978-88, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26131194

RESUMO

BACKGROUND: Hypercholesterolemia is a complex trait, resulting from a genetic interaction with lifestyle habits. Polymorphisms are a major source of genetic heterogeneity, and variations in 2 key cholesterol homeostasis genes; low-density lipoprotein receptor (LDLR) and proprotein convertase subtilisin/kexin type-9 (PCSK9), lead to dyslipidemia. So, we investigated the relation of 2 variants located in the 3'-UTR (3'-untranslated region) of LDLR (rs14158, G>A) and PCSK9 (rs17111557, C>T) with lipid profile and atorvastatin response. METHODS: SNP influence on lipid profile was assessed in hypercholesterolemic patients (HC; n = 89) using atorvastatin (10 mg/day/4 weeks) and in normolipidemic subjects (NL; n = 171). Genotyping was completed through real-time PCR using TaqMan assays. RESULTS: rs14158 G allele was higher in HC than in NL group (P = 0.043). NL subjects carrying the T allele of the PCSK9 variant had lower high-density lipoprotein cholesterol (HDL-c) than C allele carriers (P = 0.009). There was no association between LDLR and PCSK9 SNPs and atorvastatin response. Additionally, the PCSK9 variant creates a microRNA interaction site, which could implicate an epigenetic mechanism in PCSK9-dependent HDL-C regulation. CONCLUSIONS: The rs14158 SNP contributes to hypercholesterolemia. Also, a putative microRNA regulation may influence HDL-C variability observed in rs17111557 carriers. Cholesterol-lowering response to atorvastatin is not influenced by LDLR and PCSK9 variants.

6.
Int J Clin Exp Med ; 8(4): 5978-5988, 2015. tab
Artigo em Inglês | Sec. Est. Saúde SP, SESSP-IDPCPROD, Sec. Est. Saúde SP | ID: ses-32873

RESUMO

BACKGROUND:Hypercholesterolemia is a complex trait, resulting from a genetic interaction with lifestyle habits. Polymorphisms are a major source of genetic heterogeneity, and variations in 2 key cholesterol homeostasis genes; low-density lipoprotein receptor (LDLR) and proprotein convertase subtilisin/kexin type-9 (PCSK9), lead to dyslipidemia. So, we investigated the relation of 2 variants located in the 3'-UTR (3'-untranslated region) of LDLR (rs14158, G>A) and PCSK9 (rs17111557, C>T) with lipid profile and atorvastatin response.METHODS:SNP influence on lipid profile was assessed in hypercholesterolemic patients (HC; n = 89) using atorvastatin (10 mg/day/4 weeks) and in normolipidemic subjects (NL; n = 171). Genotyping was completed through real-time PCR using TaqMan assays.RESULTS:rs14158 G allele was higher in HC than in NL group (P = 0.043). NL subjects carrying the T allele of the PCSK9 variant had lower high-density lipoprotein cholesterol (HDL-c) than C allele carriers (P = 0.009). There was no association between LDLR and PCSK9 SNPs and atorvastatin response. Additionally, the PCSK9 variant creates a microRNA interaction site, which could implicate an epigenetic mechanism in PCSK9-dependent HDL-C regulation.CONCLUSIONS:The rs14158 SNP contributes to hypercholesterolemia. Also, a putative microRNA regulation may influence HDL-C variability observed in rs17111557 carriers. Cholesterol-lowering response to atorvastatin is not influenced by LDLR and PCSK9 variants. (AU)


Assuntos
Atorvastatina , Colesterol , MicroRNAs
7.
J Clin Lipidol ; 8(3): 22017 Apr, 2014 May-Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24793346

RESUMO

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 Tratamento
8.
J Clin Lipidol ; 08(03): 256-264, 2014. ilus
Artigo em Inglês | Sec. Est. Saúde SP, SESSP-IDPCPROD, Sec. Est. Saúde SP | ID: ses-30287

RESUMO

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. (AU)


Assuntos
Colesterol , Polimorfismo de Nucleotídeo Único
9.
Journal of Clinical Lipidology ; 8: 256-264, 2014. tab
Artigo em Inglês | Sec. Est. Saúde SP, SESSP-IDPCPROD, Sec. Est. Saúde SP | ID: ses-29542

RESUMO

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. (AU)


Assuntos
Colesterol , Farmacogenética , Polimorfismo Genético
10.
J Steroid Biochem Mol Biol ; 138: 403-9, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24007717

RESUMO

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.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Anticolesterolemiantes/uso terapêutico , Apolipoproteína A-I/metabolismo , Ácidos Heptanoicos/uso terapêutico , Leucócitos Mononucleares/metabolismo , Pirróis/uso terapêutico , Receptores Depuradores Classe B/metabolismo , Transportador 1 de Cassete de Ligação de ATP/genética , Anticolesterolemiantes/administração & dosagem , Apolipoproteína A-I/genética , Atorvastatina , Células Cultivadas , Estradiol/uso terapêutico , Feminino , Ácidos Heptanoicos/administração & dosagem , Compostos Heterocíclicos/uso terapêutico , Humanos , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/genética , Hipercolesterolemia/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Pessoa de Meia-Idade , Pós-Menopausa , Pirróis/administração & dosagem , Receptores Depuradores Classe B/genética , Transcriptoma
11.
Clin Chim Acta ; 421: 157-63, 2013 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-23501331

RESUMO

BACKGROUND: Variability of response to statins has been related to polymorphisms in genes involved in cholesterol homeostasis and statin metabolism, such as CYP3A4 and CYP3A5. We investigated the effects of atorvastatin on CYP3A4 and CYP3A5 mRNA expression in mononuclear cells and on CYP3A activity and their interactions with common variants. METHODS: Unrelated individuals (n=121) with hypercholesterolemia (HC) were treated with atorvastatin (10 mg/day/4 weeks). Ninety-two normolipidemic (NL) subjects were selected as a control group. Genotype analysis of CYP3A4*1B (rs2740574), CYP3A4*22 (rs35599367), CYP3A5*3C (rs776746), and CYP3A5*1D (rs15524) and mRNA levels in peripheral blood mononuclear cells (PBMCs) were estimated. CYP3A activity was phenotyped by the urinary cortisol to 6-beta-hydroxy-cortisol ratio. RESULTS: LDL cholesterol reduction in response to atorvastatin was positively correlated with change in CYP3A4 (R(2)=0.039, p=0.037) and CYP3A5 (R(2)=0.047, p=0.019) mRNA levels and negatively correlated with CYP3A activity (R(2)=0.071, p=0.022). CYP3A5*3C (AGT haplotype) was associated to lower basal CYP3A5 mRNA expression in HC (p<0.045), however none of the haplotype groups impacted treatment. CONCLUSION: It is likely that cholesterolemia status changes promoted by atorvastatin play a role in regulating CYP3A4 and CYP3A5 mRNA expression in PBMCs, as well as CYP3A activity. CYP3A5*3C (AGT haplotype) also contributes for the variability of CYP3A5 mRNA levels in PBMCs.


Assuntos
Anticolesterolemiantes/farmacologia , Citocromo P-450 CYP3A/metabolismo , Expressão Gênica/efeitos dos fármacos , Ácidos Heptanoicos/farmacologia , Hipercolesterolemia/tratamento farmacológico , Leucócitos Mononucleares/efeitos dos fármacos , Pirróis/farmacologia , Adulto , Idoso , Anticolesterolemiantes/uso terapêutico , Atorvastatina , Estudos de Casos e Controles , LDL-Colesterol/metabolismo , Citocromo P-450 CYP3A/genética , Esquema de Medicação , Feminino , Heterogeneidade Genética , Haplótipos , Ácidos Heptanoicos/uso terapêutico , Humanos , Hipercolesterolemia/genética , Hipercolesterolemia/metabolismo , Hipercolesterolemia/patologia , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Pirróis/uso terapêutico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
12.
Genet Test Mol Biomarkers ; 16(6): 524-30, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22288895

RESUMO

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
Grupo com Ancestrais do Continente Africano/genética , Estudos de Casos e Controles , Hipercolesterolemia/genética , Índios Sul-Americanos/etnologia , Polimorfismo de Nucleotídeo Único , População Urbana , Grupo com Ancestrais do Continente Africano/etnologia , Grupo com Ancestrais do Continente Asiático/etnologia , Grupo com Ancestrais do Continente Asiático/genética , Brasil/etnologia , Grupo com Ancestrais do Continente Europeu/etnologia , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Humanos , Índios Sul-Americanos/genética , Masculino , Grupos Populacionais/etnologia , Grupos Populacionais/genética
14.
J Steroid Biochem Mol Biol ; 128(3-5): 139-44, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22094353

RESUMO

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.


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/metabolismo
15.
Journal of Steroid Biochemistry Biology ; 128: 139-144, 2012. tab, graf
Artigo em Inglês | Sec. Est. Saúde SP, SESSP-IDPCPROD, Sec. Est. Saúde SP | ID: ses-26866

RESUMO

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. (AU)


Assuntos
Menopausa , Terapia de Reposição Hormonal , Apolipoproteína E3 , Polimorfismo de Nucleotídeo Único , Genética
16.
Genetic Testing and Molecular Biomarkers ; 16(6): 524-530, 2012. tab, ilus
Artigo em Inglês | Sec. Est. Saúde SP, SESSP-IDPCPROD, Sec. Est. Saúde SP | ID: ses-28325

RESUMO

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. (AU)


Assuntos
Genômica , Polimorfismo Genético , População Urbana , População Urbana/classificação
17.
Lipids Health Dis ; 10: 206, 2011 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-22074026

RESUMO

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/metabolismo
18.
Int J Mol Sci ; 12(9): 5815-27, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22016628

RESUMO

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.


Assuntos
Ácidos Heptanoicos/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/genética , Transportadores de Ânions Orgânicos/genética , Polimorfismo de Nucleotídeo Único , Pirróis/uso terapêutico , Idoso , Anticolesterolemiantes/uso terapêutico , Atorvastatina , Feminino , Frequência do Gene , Genótipo , Haplótipos , Humanos , Desequilíbrio de Ligação , Transportador 1 de Ânion Orgânico Específico do Fígado , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Farmacogenética/métodos , Resultado do Tratamento
19.
Drug Metabol Drug Interact ; 26(1): 37-40, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21480818

RESUMO

BACKGROUND: Pioglitazone is a peroxisome proliferator-activated receptor gamma (PPARγ) activator used in the treatment of type 2 diabetes (DM2) patients and it has been suggested that can induce bone loss. Tumor necrosis factor-α (TNFα) and interleukin-6 (IL-6) mRNA expression in blood leukocytes and the relationship with polymorphisms and bone markers in DM2 treated with pioglitazone were investigated. METHODS: DM2 (n=53) and normoglycemic (NG, n=52) individuals were included. DM2 patients were treated with pioglitazone (45 mg/day/16 weeks). mRNA expression was evaluated by real-time polymerase chain reaction (PCR). TNFA -308G>A and IL6 -174G>C polymorphisms were detected by PCR-RFLP and high resolution melting polymerase chain reaction (HRM-PCR). RESULTS: Pioglitazone reduced bone specific alkaline phosphatase (bALP) and increased TNFα in DM2 group (p<0.001). DM2 or pioglitazone did not influence TNFα and IL-6 expression (p>0.05). TNFA -308A allele was associated with reduced basal TNFα mRNA levels in NG and DM2 and reduced alkaline phosphatase (tALP) after treatment (p<0.05). IL6 -174C allele was associated with decreased oral glucose tolerance test (OGTT)-2 h in DM2 individuals (p<0.05). CONCLUSIONS: TNFA -308G >A polymorphism appear to be involved in regulation of gene expression independently of hyperglycemia and its interaction with pioglitazone may modify tALP, a important bone marker. IL6 -174G>C variant is related with reduced risk of postprandial hyperglycemia but not with mRNA expression or bone markers.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Tiazolidinedionas/farmacologia , Adulto , Idoso , Fosfatase Alcalina/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Interleucina-6/genética , Leucócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Pioglitazona , Reação em Cadeia da Polimerase , Polimorfismo Genético , Fator de Necrose Tumoral alfa/genética
20.
Drug Metabol Drug Interact ; 26(1): 37-40, 2011.
Artigo em Inglês | Sec. Est. Saúde SP, SESSP-IDPCPROD, Sec. Est. Saúde SP | ID: ses-29086

RESUMO

BACKGROUND: Pioglitazone is a peroxisome proliferator-activated receptor gamma (PPARã) activator used in the treatment of type 2 diabetes (DM2) patients and it has been suggested that can induce bone loss. Tumor necrosis factor-á (TNFá) and interleukin-6 (IL-6) mRNA expression in blood leukocytes and the relationship with polymorphisms and bone markers in DM2 treated with pioglitazone were investigated.METHODS: DM2 (n=53) and normoglycemic (NG, n=52) individuals were included. DM2 patients were treated with pioglitazone (45 mg/day/16 weeks). mRNA expression was evaluated by real-time polymerase chain reaction (PCR). TNFA -308G>A and IL6 -174G>C polymorphisms were detected by PCR-RFLP and high resolution melting polymerase chain reaction (HRM-PCR).RESULTS: Pioglitazone reduced bone specific alkaline phosphatase (bALP) and increased TNFá in DM2 group (p<0.001). DM2 or pioglitazone did not influence TNFá and IL-6 expression (p>0.05). TNFA -308A allele was associated with reduced basal TNFá mRNA levels in NG and DM2 and reduced alkaline phosphatase (tALP) after treatment (p<0.05). IL6 -174C allele was associated with decreased oral glucose tolerance test (OGTT)-2 h in DM2 individuals (p<0.05).CONCLUSIONS: TNFA -308G >A polymorphism appear to be involved in regulation of gene expression independently of hyperglycemia and its interaction with pioglitazone may modify tALP, a important bone marker. IL6 -174G>C variant is related with reduced risk of postprandial hyperglycemia but not with mRNA expression or bone markers. (AU)


Assuntos
Interleucina-6 , Diabetes Mellitus Tipo 2
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