RESUMEN
In this study, we determined the association of 1180 non-synonymous single-nucleotide polymorphisms (SNPs) with systolic blood pressure (SBP) and hypertensive status. A total of 8842 subjects were taken from two community-based cohorts--Ansung (n=4183) and Ansan (n=4659), South Korea--which had been established for genome-wide association studies (GWAS). Five SNPs (rs16835244, rs2286672, rs6265, rs17237198 and rs7312017) were significantly associated (P-values: 0.003-0.0001, not corrected for genome-wide significance) with SBP in both cohorts. Of these SNPs, rs16835244 and rs2286672 correlated with risk for hypertension. The rs16835244 SNP replaces Ala288 in arginine decarboxylase (ADC) with serine, and rs2286672 replaces Arg172 in phospholipase D2 (PLD2) with cysteine. A comparison of peptide sequences between vertebrate homologues revealed that the SNPs identified occur at conserved amino-acid residues. In silico analysis of the protein structure showed that the substitution of a polar residue, serine, for a non-polar alanine at amino-acid residue 288 affects a conformational change in ADC, and that Arg172 in PLD2 resides in the PX domain, which is important for membrane trafficking. These results provide insights into the function of these non-synonymous SNPs in the development of hypertension. The study investigating non-synonymous SNPs from GWAS not only by statistical association analysis but also by biological relevance through the protein structure might be a good approach for identifying genetic risk factors for hypertension, in addition to discovering causative variations.
Asunto(s)
Presión Sanguínea/genética , Hipertensión/genética , Polimorfismo de Nucleótido Simple , Adulto , Anciano , Secuencia de Aminoácidos , Pueblo Asiatico/genética , Estudios de Casos y Controles , Distribución de Chi-Cuadrado , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Hipertensión/etnología , Hipertensión/fisiopatología , Modelos Lineales , Masculino , Persona de Mediana Edad , Modelos Moleculares , Datos de Secuencia Molecular , Oportunidad Relativa , Fenotipo , Conformación Proteica , República de Corea/epidemiología , Medición de Riesgo , Factores de Riesgo , Relación Estructura-ActividadRESUMEN
Blood pressure, one of the important vital signs, is affected by multiple genetic and environmental factors. Recently, several genome-wide association (GWA) studies have successfully identified genetic factors that influence blood pressure and hypertension risk. In this study, we report results of the Korean Association REsource (KARE, 8842 subjects) GWA study on blood pressure and hypertension risk. In all, 10 single-nucleotide polymorphisms (SNPs) that showed significant association with hypertension were further analysed for replication associations in the Health2 project (7861 subjects). Among these 10 SNPs, 3 were replicated in the Health2 cohort for an association with systolic or diastolic blood pressure. The most significant SNP (rs17249754 located in ATPase, Ca(++) transporting, plasma membrane 1 (ATP2B1)) has been previously reported, and the other two SNPs are rs1378942 in the c-src tyrosine kinase (CSK) gene and rs12945290 in the arylsulphatase G (ARSG) gene. An additional hypertension case-control study confirmed that rs17249754 (in ATP2B1) increases hypertension risk in both the KARE and Health2 (meta-analysis, P-value=4.25 x 10(-9)) cohorts. One more SNP, rs995322, located in the CUB and Sushi multiple domains 1 (CSMD1), is also associated with increased risk of hypertension (meta-analysis, P-value=1.00 x 10(-4)). Despite the difficulty of obtaining replication results for a complex trait genetic association between blood pressure and hypertension, we were able to identify consistent genetic factors in both the Korean cohorts in ATP2B1, CSK, ARSG and CSMD1 genes.
Asunto(s)
Arilsulfatasas/genética , Presión Sanguínea/genética , Hipertensión/genética , Proteínas de la Membrana/genética , ATPasas Transportadoras de Calcio de la Membrana Plasmática/genética , Proteínas Tirosina Quinasas/genética , Proteínas Proto-Oncogénicas/genética , Adulto , Anciano , Pueblo Asiatico/genética , Índice de Masa Corporal , Proteína Tirosina Quinasa CSK , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Sitios Genéticos , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Hipertensión/epidemiología , Corea (Geográfico)/epidemiología , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Proteínas Supresoras de Tumor , Familia-src QuinasasRESUMEN
The Notch receptor mediates cell interactions controlling the developmental fate of a broad spectrum of undifferentiated cells. By modulating Notch signaling in specific precursor cells during Drosophila imaginal disc development, we demonstrate that Notch activity can influence cell proliferation. The activation of the Notch receptor in the wing disc induces the expression of the wing margin patterning genes vestigial and wingless, and strong mitotic activity. However, the effect of Notch signaling on cell proliferation is not the simple consequence of the upregulation of either vestigial or wingless. Vestigial and Wingless, on the contrary, display synergistic effects with Notch signaling, resulting in the stimulation of cell proliferation in imaginal discs.
Asunto(s)
Comunicación Celular , Proteínas de Drosophila , Drosophila/embriología , Proteínas de la Membrana/metabolismo , Receptores de Superficie Celular/metabolismo , Alas de Animales/embriología , Animales , Proteínas de la Membrana/genética , Mitosis , Modelos Biológicos , Morfogénesis/genética , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Receptores Notch , Supresión Genética , Alas de Animales/citología , Proteína Wnt1RESUMEN
The clinical efficacy and the rebound phenomenon were studied in a left-right double-blind trial comparing triamcinolone acetonide (TA) and hydrocortisone 17-butyrate (HC 17-B, Locoid). The trial comprised 19 patients with rosacea-like dermatitis of whom 7 did not receive treatment and 12 were pretreated with betamethasone valerate (BMV). Tetracyclince was given all the time as additional treatment. Clinically there was no significant difference between TA and HC 17-B. No rebound phenomenon was observed. If corticosteroids are to be used at all in rosacea or resoacea-like dermatitis, preference is given to HC 17-B.