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1.
Acta Diabetol ; 50(2): 241-9, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22684314

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is associated with all the components of metabolic syndrome (MS) and might to be considered an additional component of MS itself. The Italian Society for the Study of Atherosclerosis (SISA) in 2005 started a research project aimed to study the NAFLD, using ultrasound (US), in nondiabetic MS subjects matching at least one of the ATP III criteria for HDL-C or triglycerides [TG]. Prevalence of US-NAFLD and its associated risk factors and prevalence of hypertransaminasemia and its possible determinants were evaluated. NAFLD prevalence was 0.78. Men with steatosis compared to men without steatosis were younger (P < 0.05) with higher TG (P < 0.03), homeostasis model assessment insulin resistance (HOMA-R) (P < 0.003), and visceral fat thickness (VFT) (P < 0.0001). Women with steatosis showed higher TG (P < 0.05), HOMA-R (P < 0.04), VFT (P < 0.0001), and lower age (P < 0.05). At multivariate analyses, VFT (P < 0.0001), HOMA-R (P < 0.02), and TG/HDL (P < 0.05) were associated with severity of NAFLD. Age (P < 0.05), LogTG (P < 0.005), and VFT (P < 0.01) were associated with higher ALT. The US prevalence of steatosis in this study (0.78) is the highest reported in patients with MS. Considering the exclusion of severe obese and diabetic patients and the recruitment criteria, this finding highlights the prominent role played by the alterations of lipid metabolism in the pathogenesis of NAFLD.


Assuntos
Aterosclerose , Fígado Gorduroso/epidemiologia , Síndrome Metabólica/epidemiologia , Idoso , Índice de Massa Corporal , Fígado Gorduroso/diagnóstico por imagem , Feminino , Humanos , Itália/epidemiologia , Lipídeos/sangue , Fígado/diagnóstico por imagem , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica , Fatores de Risco , Fatores Sexuais , Ultrassonografia
2.
J Pediatr ; 155(2): 199-204.e2, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19446849

RESUMO

OBJECTIVE: To ascertain whether the molecular characterization of a defect in the low-density lipoprotein (LDL) receptor gene (LDLR) in children with heterozygous familial hypercholesterolemia (heFH) identifies subjects at greater risk of developing premature coronary artery disease (pCAD) later in life. STUDY DESIGN: We investigated 264 children with heFH from 201 families, along with 148 affected parents and 100 unaffected siblings. The lipid profile was assessed before any treatment was provided, and genotype analysis was performed to characterize LDLR defects. In a subgroup of children with heFH and controls, we measured aorta and carotid intima-media thickness (aIMT and cIMT). The prevalence of pCAD in parents and/or grandparents with heFH was recorded. RESULTS: The children with heFH with a family history of pCAD had higher LDL cholesterol and apolipoprotein B levels and greater aIMT and cIMT than those with negative family history. Compared with carriers of LDLR-defective mutations, carriers of LDLR-negative mutations had a more severe phenotype, in terms of plasma lipid levels and IMT, and a higher prevalence of pCAD in first-degree relatives (36% vs 6.7%; P < .001). CONCLUSIONS: The study of heFH in children, in which other risk factors for CAD play a minor role, allows early identification of those at increased risk for developing pCAD, who merit more stringent clinical control and early pharmacologic treatment.


Assuntos
Doença da Artéria Coronariana/genética , Predisposição Genética para Doença , Hiperlipoproteinemia Tipo II/genética , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Mutação , Adolescente , Adulto , Aorta/patologia , Apolipoproteínas B/sangue , Artérias Carótidas/patologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Colesterol/sangue , LDL-Colesterol/sangue , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Risco , Túnica Íntima/patologia , Túnica Média/patologia , Adulto Jovem
3.
Mol Genet Metab ; 96(2): 66-72, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19084451

RESUMO

Familial hypobetalipoproteinemia (FHBL) is a co-dominant disorder characterized by reduced plasma levels of low density lipoprotein cholesterol (LDL-C) and its protein constituent apolipoprotein B (apoB), which may be due to mutations in APOB gene, mostly located in the coding region of this gene. We report two novel APOB gene mutations involving the acceptor splice site of intron 11 (c.1471-1G>A) and of intron 23 (c.3697-1G>C), respectively, which were identified in two patients with heterozygous FHBL associated with severe fatty liver disease. The effects of these mutations on APOB pre-mRNA splicing were assessed in COS-1 cells expressing the mutant APOB minigenes. The c.1471-1G>A APOB minigene generated two abnormal mRNAs. In one mRNA the entire intron 11 was retained; in the other mRNA exon 11 joined to exon 12, in which the first nucleotide was deleted due to the activation of a novel acceptor splice site. The predicted products of these mRNAs are truncated proteins of 546 and 474 amino acids, designated apoB-12.03 and apoB-10.45, respectively. The c.3697-1G>C APOB minigene generated a single abnormal mRNA in which exon 23 joined to exon 25, with the complete skipping of exon 24. This abnormal mRNA is predicted to encode a truncated protein of 1220 amino acids, designated apoB-26.89. These splice site mutations cause the formation of short truncated apoBs, which are not secreted into the plasma as lipoprotein constituents. This secretion defect is the major cause of severe fatty liver observed in carriers of these mutations.


Assuntos
Apolipoproteínas B/genética , Hipobetalipoproteinemia Familiar por Apolipoproteína B/genética , Mutação , Splicing de RNA , Adolescente , Animais , Células COS , Chlorocebus aethiops , Éxons , Humanos , Masculino
4.
Atherosclerosis ; 204(1): 202-7, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-18926541

RESUMO

Cholesteryl ester transfer protein (CETP) is a plasma glycoprotein that catalyses the transfer of cholesteryl esters from HDL to the other plasma lipoproteins. Genetic deficiency of CETP is one of the known causes of elevation of plasma HDL-C (primary hyperalphalipoproteinemia, HALP). We sequenced CETP gene in a group of 24 Italian subjects with primary HALP (HDL-C>80 mg/dl) suspected to have CETP deficiency. Two unrelated subjects both coming from the same geographical district, were found to be heterozygous for a nucleotide substitution in exon 6 (c.544C>T) and another subject was found to be heterozygous for a C>T transition in exon 9 (c.802C>T). Both mutations introduce a premature stop codon and are predicted to cause the production of truncated proteins (Q165X and R268X, respectively) devoid of function. The fourth proband was found to carry a T>C substitution in intron 15 (c.1407+2T>C) predicted to abolish the function of the donor splice site. To define the effect of this mutation on CETP pre-mRNA splicing we analysed CETP mRNA in COS-1 cells expressing a CETP minigene harbouring the mutation. The analysis of minigene transcript in COS-1 cells showed that IVS15+2T>C mutation caused the formation of an abnormal mRNA in which exon 14 joins directly to exon 16, predicted to encode a truncated peptide of 435 amino acids. In mutation carriers plasma CETP activity was found to be reduced by 38-60%. These are the first mutations in the CETP gene found in Italian subjects with HALP.


Assuntos
Proteínas de Transferência de Ésteres de Colesterol/genética , Hiperlipoproteinemias/genética , Mutação , População Branca/genética , Adolescente , Adulto , Idoso , Animais , Biomarcadores/sangue , Células COS , Chlorocebus aethiops , Proteínas de Transferência de Ésteres de Colesterol/sangue , Proteínas de Transferência de Ésteres de Colesterol/deficiência , HDL-Colesterol/sangue , Análise Mutacional de DNA , Feminino , Humanos , Hiperlipoproteinemias/sangue , Hiperlipoproteinemias/enzimologia , Hiperlipoproteinemias/etnologia , Itália , Masculino , Pessoa de Meia-Idade , Fenótipo , RNA Mensageiro/metabolismo , Transfecção , Regulação para Cima , Adulto Jovem
5.
Atherosclerosis ; 174(1): 57-65, 2004 May.
Artigo em Inglês | MEDLINE | ID: mdl-15135251

RESUMO

The clinical expression of heterozygous familial hypercholesterolemia (FH) is highly variable even in patients carrying the same LDL receptor (LDL-R) gene mutation. This variability might be due to environmental factors as well as to modifying genes affecting lipoprotein metabolism. We investigated Apo E (2, 3, 4), MTP (-493G/T), Apo B (-516C/T), Apo A-V (-1131T/C), HL (-514C/T and -250G/A), FABP-2 (A54T), LPL (D9N, N291S, S447X) and ABCA1 (R219K) polymorphisms in 221 unrelated FH index cases and 349 FH relatives with defined LDL-R gene mutations. We found a significant and independent effect of the following polymorphisms on: (i) plasma LDL-C (Apo E, MTP and Apo B); (ii) plasma HDL-C (HL, FABP-2 and LPL S447X); (iii) plasma triglycerides (Apo E and Apo A-V). In subjects with coronary artery disease (CAD+), the prevalence of FABP-2 54TT genotype was higher (16.5% versus 5.2%) and that of ABCA1 219RK and KK genotypes lower (33.0% versus 51.5%) than in subjects with no CAD. Independent predictors of increased risk of CAD were male sex, age, arterial hypertension, LDL-C level and FABP-2 54TT genotype, and of decreased risk the 219RK and KK genotypes of ABCA1. These findings show that several common genetic variants influence the lipid phenotype and the CAD risk in FH heterozygotes.


Assuntos
Apolipoproteínas/genética , Doença da Artéria Coronariana/genética , Predisposição Genética para Doença , Hiperlipoproteinemia Tipo II/epidemiologia , Hiperlipoproteinemia Tipo II/genética , Polimorfismo Genético , Adulto , Sequência de Bases , Estudos de Casos e Controles , HDL-Colesterol/análise , LDL-Colesterol/análise , Estudos de Coortes , Intervalos de Confiança , Doença da Artéria Coronariana/epidemiologia , Feminino , Regulação da Expressão Gênica , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Razão de Chances , Fenótipo , Reação em Cadeia da Polimerase , Valor Preditivo dos Testes , Receptores de LDL/genética , Medição de Risco
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