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 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: 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/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 <0.25 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
Osteoporotic hip fractures (OHF) are not limited to elderly; however, studies in non-elderly are scarce. Thus, the aim of this study was to evaluate co-morbidities in non-elderly patients with OHF in a Community Teaching Hospital. All hospitalizations due to OHF during a 3-year period in a Community Teaching Hospital were retrospectively evaluated for co-morbidities, and patients 18-64 years old were compared with those ≥65 years old. Of all hospitalizations, 232 (0.73%) were due to hip fractures, and 120/232 (51.7%) patients had OHF. The comparison of the 13 (10.8%) OHF patients <65 years old (47.3 ± 9.7 years) with 107 (89.2%) ≥65 years old (80.4 ± 7.7 years) revealed a male predominance (61.5 vs. 27.1%, P = 0.022) and a distinct ethnic distribution with a lower proportion of Caucasians in the former (61.5 vs. 86.9%, P = 0.033). Moreover, non-elderly OHF patients had higher frequencies of insulin-dependent DM (38.5 vs. 3.7%, P = 0.001) and alcoholism (38.5 vs. 4.7%, P = 0.001) than aged patients. In contrast, rates of age-related co-morbidities such as stroke (7.7 vs. 18.7%, P = 0.461), heart failure (23.1 vs. 14.0%, P = 0.411), and dementia (7.7 vs. 15.9%, P = 0.689) were comparable in both groups. Logistic regression analysis demonstrated that insulin-dependent DM (OR = 25.4, 95% CI = 4.7-136.8, P < 0.001) and alcoholism (OR = 20.3, 95% CI = 3.9-103.3, P < 0.001) remained as independent risk factors for OHF in non-elderly patients. Osteoporosis is an important cause of HF in Community Hospital. Non-elderly patients with OHF have a peculiar demographic profile and associated co-morbidities. These findings reinforce the need of early osteoporosis diagnosis and rigorous fracture prevention in patients with DM and alcoholism.
Assuntos
Fraturas do Quadril/epidemiologia , Osteoporose/epidemiologia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Alcoolismo/epidemiologia , Brasil/epidemiologia , Doenças Cardiovasculares/epidemiologia , Distribuição de Qui-Quadrado , Comorbidade , Demência/epidemiologia , Diabetes Mellitus/epidemiologia , Feminino , Fraturas do Quadril/etnologia , Hospitais Comunitários , Hospitais de Ensino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Osteoporose/etnologia , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Adulto JovemRESUMO
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
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: 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.