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1.
Gut ; 58(4): 537-44, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18987030

RESUMO

BACKGROUND: Intrahepatic cholestasis of pregnancy (ICP) has a complex aetiology with a significant genetic component. ABCB11 encodes the bile salt export pump (BSEP); mutations cause a spectrum of cholestatic disease, and are implicated in the aetiology of ICP. METHODS: ABCB11 variation in ICP was investigated by screening for five mutant alleles (E297G, D482G, N591S, D676Y and G855R) and the V444A polymorphism (c.1331T>C, rs2287622) in two ICP cohorts (n = 333 UK, n = 158 continental Europe), and controls (n = 261) for V444A. PCR primers were used to amplify and sequence patient and control DNA. The molecular basis for the observed phenotypes was investigated in silico by analysing the equivalent residues in the structure of the homologous bacterial transporter Sav1866. RESULTS: E297G was observed four times and D482G once. N591S was present in two patients; D676Y and G855R were not observed. The V444A polymorphism was associated with ICP (allelic analysis for C vs T: OR 1.7 (95% CI 1.4 to 2.1, p<0.001)). In addition, CC homozygotes were more likely to have ICP than TT homozygotes: OR 2.8 (95% CI 1.7 to 4.4 p<0.0001). Structural analyses suggest that E297G and D482G destabilize the protein fold of BSEP. The molecular basis of V444A and N591S was not apparent from the Sav1866 structure. CONCLUSIONS: Heterozygosity for the common ABCB11 mutations accounts for 1% of European ICP cases; these two mutants probably reduce the folding efficiency of BSEP. N591S is a recurrent mutation; however, the mechanism may be independent of protein stability or function. The V444A polymorphism is a significant risk factor for ICP in this population.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Colestase Intra-Hepática/genética , Mutação , Complicações na Gravidez/genética , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP , Estudos de Casos e Controles , Análise Mutacional de DNA/métodos , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Modelos Moleculares , Gravidez , Relação Estrutura-Atividade
2.
Ned Tijdschr Geneeskd ; 1642020 02 27.
Artigo em Holandês | MEDLINE | ID: mdl-32267638

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of fatty liver disease. NAFLD is defined as the presence of fatty liver disease observed in imaging or histopathological examinations when there is no secondary cause such as excessive alcohol use or use of certain medications. NAFLD encompasses a whole spectrum, from simple steatosis to steatohepatitis ('non-alcoholic steatohepatitis', NASH), fibrosis and - ultimately - cirrhosis and hepatocellular carcinoma. Several factors play a role in the complex pathogenesis of NAFLD such as genetic predisposition, overweight, insulin resistance, inflammation, bile salts, gut microbiome and nutrition. Patients with NAFLD have an increased risk of developing type 2 diabetes mellitus, cardiovascular disease and malignancies such as hepatocellular carcinoma. To date, no medicines have been authorised for the treatment of NAFLD. The cornerstone of NAFLD treatment is lifestyle adjustment aimed at weight reduction.


Assuntos
Carcinoma Hepatocelular/epidemiologia , Neoplasias Hepáticas/epidemiologia , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Peso Corporal , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/diagnóstico , Doenças Cardiovasculares/complicações , Diabetes Mellitus Tipo 2/complicações , Promoção da Saúde , Humanos , Inflamação/complicações , Resistência à Insulina , Estilo de Vida , Fígado/fisiopatologia , Cirrose Hepática/complicações , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/diagnóstico , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Redução de Peso
3.
Xenobiotica ; 38(10): 1289-97, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18800312

RESUMO

1. The purpose of this study was to evaluate the role of coding variation in hPXR (NR1I2) in intrahepatic cholestasis of pregnancy (ICP) and to functionally asses the response of PXR variants to ligands of interest in ICP. 2. The coding region of hPXR was sequenced in a cohort of 121 Caucasian ICP patients and exon 2 was sequenced in an additional 226 cases. Reporter assays were used to evaluate the function of all known hPXR variants in response to the secondary bile acid lithocholic acid and therapeutic agents rifampicin, ursodeoxycholic acid and dexamethasone. 3. Two coding single nucleotide polymorphisms (C79T and G106A) were detected in the ICP cohort at frequencies consistent with healthy populations. These do not alter hPXR function in response to ligands of interest to ICP. Analysis of all known coding hPXR variants demonstrates that while subtle changes in experimental design mask or may unveil the functional effects of genetic variation, these are not maintained in a standard functional assay. 4. Coding genetic variation in hPXR does not contribute to the aetiology of ICP in Caucasian populations.


Assuntos
Predisposição Genética para Doença/genética , Variação Genética/genética , Complicações na Gravidez/genética , Receptores de Esteroides/genética , Sequência de Bases , Feminino , Humanos , Dados de Sequência Molecular , Gravidez , Receptor de Pregnano X
4.
J Med Genet ; 42(6): 449-63, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15937079

RESUMO

Bile acids and bile salts have essential functions in the liver and in the small intestine. Their synthesis in the liver provides a metabolic pathway for the catabolism of cholesterol and their detergent properties promote the solubilisation of essential nutrients and vitamins in the small intestine. Inherited conditions that prevent the synthesis of bile acids or their excretion cause cholestasis, or impaired bile flow. These disorders generally lead to severe human liver disease, underscoring the essential role of bile acids in metabolism. Recent advances in the elucidation of gene defects underlying familial cholestasis syndromes has greatly increased knowledge about the process of bile flow. The expression of key proteins involved in bile flow is tightly regulated by transcription factors of the nuclear hormone receptor family, which function as sensors of bile acids and cholesterol. Here we review the genetics of familial cholestasis disorders, the functions of the affected genes in bile flow, and their regulation by bile acids and cholesterol.


Assuntos
Colestase Intra-Hepática/genética , Transportadores de Cassetes de Ligação de ATP/genética , Bile/metabolismo , Ácidos e Sais Biliares/biossíntese , Ácidos e Sais Biliares/química , Ácidos e Sais Biliares/metabolismo , Humanos , Proteínas de Membrana/genética , Mutação , Síndrome , Proteína da Zônula de Oclusão-2
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