RESUMEN
Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated with BP at our p < 8.56 × 10(-7) study-specific significance threshold and six suggestively associated SNPs in a further 59,349 individuals. We identified and replicated a SNP at LSP1/TNNT3, a SNP at MTHFR-NPPB independent (r(2) = 0.33) of previous reports, and replicated SNPs at AGT and ATP2B1 reported previously. An analysis of combined discovery and follow-up data identified SNPs significantly associated with BP at p < 8.56 × 10(-7) at four further loci (NPR3, HFE, NOS3, and SOX6). The high number of discoveries made with modest genotyping effort can be attributed to using a large-scale yet targeted genotyping array and to the development of a weighting scheme that maximized power when meta-analyzing results from samples ascertained with extreme phenotypes, in combination with results from nonascertained or population samples. Chromatin immunoprecipitation and transcript expression data highlight potential gene regulatory mechanisms at the MTHFR and NOS3 loci. These results provide candidates for further study to help dissect mechanisms affecting BP and highlight the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies.
Asunto(s)
Sitios Genéticos , Hipertensión/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Adulto , Anciano , Presión Sanguínea/genética , Estudios de Casos y Controles , Femenino , Perfilación de la Expresión Génica , Frecuencia de los Genes , Estudio de Asociación del Genoma Completo , Haplotipos , Humanos , Desequilibrio de Ligamiento , Masculino , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Persona de Mediana Edad , ATPasas Transportadoras de Calcio de la Membrana Plasmática/genética , Polimorfismo de Nucleótido Simple , Receptores del Factor Natriurético Atrial/genética , Análisis de Secuencia de ADNRESUMEN
The stable maintenance of the 2 microm circle plasmid depends on its ability to overcome intrinsic maternal inheritance bias, which in yeast normally results in the failure to transmit DNA molecules efficiently to daughter cells. In addition to the plasmid proteins Rep1 and Rep2 acting on the plasmid DNA locus STB, it is likely that other chromosomally encoded yeast proteins are required. We have isolated mutants of yeast unable to maintain 2 microm and found that RSC2 is essential for 2 microm to overcome maternal inheritance bias. Rsc2 is part of a multisubunit RSC chromatin remodeling complex, and we show that in the absence of Rsc2 the chromatin structure of the STB region is significantly altered and the Rep1 protein loses its normal localization to subnuclear foci. Rsc1, a closely related homolog of Rsc2 present in an alternative form of the RSC complex, is not required for 2 microm maintenance and does not replace the requirement for Rsc2 when overexpressed. This represents the first specific role for Rsc2 that has been related to a change in chromatin structure, as well as the first direct evidence linking chromatin structure to 2 microm segregation.
Asunto(s)
Proteínas Cromosómicas no Histona/genética , Nucleosomas/metabolismo , Plásmidos/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Cromatina/genética , Cromatina/ultraestructura , Proteínas Cromosómicas no Histona/metabolismo , Cromosomas Fúngicos , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Prueba de Complementación Genética , Mutación , Plásmidos/genética , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismoRESUMEN
Intrahepatic cholestasis of pregnancy (ICP) affects about 0.7% of deliveries in Britain. It is regarded as a benign condition for the mother but is associated with increased fetal mortality in late pregnancy and early delivery is advised. Ursodeoxycholic acid (UDCA) treatment is beneficial to the mother and does not appear to harm the fetus. ICP is often regarded as a disease of the maternal liver already made 'cholestatic' by high levels of circulating progesterone. We propose that ICP should be considered as a feto-maternal disease involving complex interactions between maternal and fetal bile acid metabolism across the placenta. During the late stages of gestation, when there is a rise in fetal and maternal bile acid levels, the placenta may fail to render potentially hepatotoxic bile acids water soluble and hence excretable. This might cause a vicious cycle leading to further cholestasis in the maternal liver already challenged by progesterone.