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1.
Biochem Biophys Res Commun ; 446(4): 1126-31, 2014 Apr 18.
Artículo en Inglés | MEDLINE | ID: mdl-24680834

RESUMEN

Risk alleles within a gene desert at the 9p21 locus constitute the most prevalent genetic determinant of cardiovascular disease. Previous research has demonstrated that 9p21 risk variants influence gene expression in vascular tissues, yet the biological mechanisms by which this would mediate atherosclerosis merits further investigation. To investigate possible influences of this locus on other tissues, we explored expression patterns of 9p21-regulated genes in a panel of multiple human tissues and found that the tumor suppressor CDKN2B was highly expressed in subcutaneous adipose tissue (SAT). CDKN2B expression was regulated by obesity status, and this effect was stronger in carriers of 9p21 risk alleles. Covariation between expression of CDKN2B and genes implemented in adipogenesis was consistent with an inhibitory effect of CDKN2B on SAT proliferation. Moreover, studies of postprandial triacylglycerol clearance indicated that CDKN2B is involved in down-regulation of SAT fatty acid trafficking. CDKN2B expression in SAT correlated with indicators of ectopic fat accumulation, including markers of hepatic steatosis. Among genes regulated by 9p21 risk variants, CDKN2B appears to play a significant role in the regulation of SAT expandability, which is a strong determinant of lipotoxicity and therefore might contribute to the development of atherosclerosis.


Asunto(s)
Aterosclerosis/genética , Cromosomas Humanos Par 9/genética , Inhibidor p15 de las Quinasas Dependientes de la Ciclina/genética , Regulación de la Expresión Génica , Grasa Subcutánea/metabolismo , Adulto , Aterosclerosis/metabolismo , Índice de Masa Corporal , Inhibidor p15 de las Quinasas Dependientes de la Ciclina/metabolismo , Metabolismo Energético , Femenino , Sitios Genéticos , Humanos , Metabolismo de los Lípidos , Masculino , Persona de Mediana Edad , Periodo Posprandial
2.
PLoS Genet ; 6(10): e1001177, 2010 Oct 28.
Artículo en Inglés | MEDLINE | ID: mdl-21082022

RESUMEN

Hypertension is a heritable and major contributor to the global burden of disease. The sum of rare and common genetic variants robustly identified so far explain only 1%-2% of the population variation in BP and hypertension. This suggests the existence of more undiscovered common variants. We conducted a genome-wide association study in 1,621 hypertensive cases and 1,699 controls and follow-up validation analyses in 19,845 cases and 16,541 controls using an extreme case-control design. We identified a locus on chromosome 16 in the 5' region of Uromodulin (UMOD; rs13333226, combined P value of 3.6 × 10⁻¹¹). The minor G allele is associated with a lower risk of hypertension (OR [95%CI]: 0.87 [0.84-0.91]), reduced urinary uromodulin excretion, better renal function; and each copy of the G allele is associated with a 7.7% reduction in risk of CVD events after adjusting for age, sex, BMI, and smoking status (H.R. = 0.923, 95% CI 0.860-0.991; p = 0.027). In a subset of 13,446 individuals with estimated glomerular filtration rate (eGFR) measurements, we show that rs13333226 is independently associated with hypertension (unadjusted for eGFR: 0.89 [0.83-0.96], p = 0.004; after eGFR adjustment: 0.89 [0.83-0.96], p = 0.003). In clinical functional studies, we also consistently show the minor G allele is associated with lower urinary uromodulin excretion. The exclusive expression of uromodulin in the thick portion of the ascending limb of Henle suggests a putative role of this variant in hypertension through an effect on sodium homeostasis. The newly discovered UMOD locus for hypertension has the potential to give new insights into the role of uromodulin in BP regulation and to identify novel drugable targets for reducing cardiovascular risk.


Asunto(s)
Presión Sanguínea , Estudio de Asociación del Genoma Completo/métodos , Hipertensión/genética , Uromodulina/genética , Anciano , Alelos , Cromosomas Humanos Par 16/genética , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo/estadística & datos numéricos , Genotipo , Tasa de Filtración Glomerular , Humanos , Hipertensión/fisiopatología , Modelos Lineales , Masculino , Metaanálisis como Asunto , Persona de Mediana Edad , Análisis Multivariante , Polimorfismo de Nucleótido Simple , Modelos de Riesgos Proporcionales , Factores de Riesgo , Análisis de Supervivencia , Uromodulina/sangre
3.
Arch Dermatol Res ; 297(6): 261-5, 2005 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-16215760

RESUMEN

Propylene glycol (propane-1,2-diol) is the only diol widely used in dermatology. Pentane-1,5-diol is mainly used as a plasticizer in cellulose products and adhesives, in dental composites and in brake fluid compositions and as a preservative for grain. However, pentane-1,5-diol is also an effective solvent, water-binding substance, antimicrobial agent and preservative and may therefore replace several ingredients in a skin composition. The release of tri-iodothyroacetic acid (TRIAC) and percutaneous absorption of hydrocortisone and mometasone furoate with either pentane-1,5-diol or propane-1,2-diol and 2-methyl-pentane-2,4-diol (hexylene glycol), respectively, as enhancers was compared. The release of TRIAC was 21% higher when pentane-1,5-diol was used as an enhancer instead of propane-1,2-diol. The percutaneous absorption of hydrocortisone through the skin was increased 12 times with propane-1,2-diol compared to 4.4 times with pentane-1,5-diol. However, the percutaneous absorption of hydrocortisone into the skin was 50% higher with pentane-1,5-diol compared to propane-1,2-diol. There was no significant difference, between the original mometasone furoate cream, with 2-methyl-pentane-2,4-diol, and the new cream with pentane-1,5-diol in the amount of mometasone furoate that was absorbed into the skin and through the skin. However, the cosmetic properties of the new mometasone furoate cream was superior to the original mometasone furoate cream, for examples, no bad odour, more even texture, goes better into the skin and has less greasiness. Pentane-1,5-diol can be used as a technology platform, which adds a series of desirable properties to dermatological preparations and enhances product usability. This will result in improved formulations for a series of major and commonly used dermatological drugs. When used in pharmaceutical topical preparations, pentane-1,5-diol will increase the percutaneous absorption of the active substance and it is an efficient antimicrobial agent that will act as an effective preservative in topical formulations. Pentane-1,5-diol is cosmetically attractive, has low risk for skin and eye irritation compared to other diols, low toxicity risk and no bad odour.


Asunto(s)
Glicoles/farmacología , Conservadores Farmacéuticos/farmacología , Absorción Cutánea/efectos de los fármacos , Solventes/farmacología , Administración Cutánea , Antiinflamatorios/administración & dosificación , Química Farmacéutica , Humanos , Hidrocortisona/administración & dosificación , Técnicas In Vitro , Furoato de Mometasona , Pentanos , Pregnadienodioles/administración & dosificación , Propilenglicol/farmacología , Triyodotironina/análogos & derivados , Triyodotironina/química
4.
PLoS One ; 10(4): e0124907, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25915632

RESUMEN

AIMS: In a recent genome-wide association study, WD-repeat domain 12 (WDR12) was associated with early-onset myocardial infarction (MI). However, the function of WDR12 in the heart is unknown. METHODS AND RESULTS: We characterized cardiac expression of WDR12, used adenovirus-mediated WDR12 gene delivery to examine effects of WDR12 on left ventricular (LV) remodeling, and analyzed relationship between MI associated WDR12 allele and cardiac function in human subjects. LV WDR12 protein levels were increased in patients with dilated cardiomyopathy and rats post-infarction. In normal adult rat hearts, WDR12 gene delivery into the anterior wall of the LV decreased interventricular septum diastolic and systolic thickness and increased the diastolic and systolic diameters of the LV. Moreover, LV ejection fraction (9.1%, P<0.05) and fractional shortening (12.2%, P<0.05) were declined. The adverse effects of WDR12 gene delivery on cardiac function were associated with decreased cellular proliferation, activation of p38 mitogen-activated protein kinase (MAPK)/heat shock protein (HSP) 27 pathway, and increased protein levels of Block of proliferation 1 (BOP1), essential for ribosome biogenesis. Post-infarction WDR12 gene delivery decreased E/A ratio (32%, P<0.05) suggesting worsening of diastolic function. In human subjects, MI associated WDR12 allele was associated significantly with diastolic dysfunction and left atrial size. CONCLUSIONS: WDR12 triggers distinct deterioration of cardiac function in adult rat heart and the MI associated WDR12 variant is associated with diastolic dysfunction in human subjects.


Asunto(s)
Insuficiencia Cardíaca/metabolismo , Hemodinámica , Infarto del Miocardio/metabolismo , Proteínas Nucleares/metabolismo , Regulación hacia Arriba , Adulto , Alelos , Animales , Proteínas de Ciclo Celular , Células Cultivadas , Femenino , Proteínas de Choque Térmico HSP27/genética , Proteínas de Choque Térmico HSP27/metabolismo , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/genética , Infarto del Miocardio/fisiopatología , Miocitos Cardíacos/metabolismo , Proteínas Nucleares/genética , Proteínas de Unión al ARN , Ratas , Ratas Sprague-Dawley , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
5.
J Hypertens ; 32(1): 75-81, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24061546

RESUMEN

OBJECTIVE: Impact of SBP vs. DBP decrement during orthostasis on cardiovascular events in hypertension is not clear. METHODS: We assessed prospective association of orthostatic hypotension with mortality and major cardiovascular events [myocardial infarction (MI) and stroke] among 8788 treated hypertensive patients (52.2% men; mean age 52 years, mean BP 161/99  mmHg) without history of MI or stroke at baseline. Orthostatic hypotension was defined according to combined international consensus criteria, and as either systolic (decrease ≥20  mmHg) or diastolic orthostatic hypotension (decrease ≥10  mmHg). Final Cox regression model was adjusted for age, sex, supine SBP and DBP, diabetes, smoking, and total cholesterol. RESULTS: A total of 1060 (12.1%) study participants fulfilled combined orthostatic hypotension criteria, of these 886 (10.1%) met systolic and 290 (3.3%) diastolic criterion. In the crude analysis, combined orthostatic hypotension criteria were predictive of the composite endpoint, major cardiovascular event, total mortality, and stroke but not MI. After full adjustment, combined orthostatic hypotension criteria and systolic orthostatic hypotension were independently associated with stroke only (hazard ratio: 1.48, 1.07-2.05, P = 0.019, and 1.53, 1.08-2.15, P = 0.015, respectively), whereas the composite endpoint tended in the same direction (hazard ratio: 1.21, 0.98-1.51, P = 0.075, and 1.24, 0.99-1.55, P = 0.066, respectively). In contrast, diastolic orthostatic hypotension was associated with increased risk of MI (hazard ratio: 2.04, 1.20-3.46, P = 0.008). CONCLUSION: Orthostatic hypotension has a dual role in cardiovascular events among hypertensive patients: SBP fall indicates higher risk of stroke, whereas DBP fall confers higher risk of MI.


Asunto(s)
Antihipertensivos/uso terapéutico , Bloqueadores de los Canales de Calcio/uso terapéutico , Captopril/uso terapéutico , Diástole , Hipertensión/fisiopatología , Hipotensión Ortostática/prevención & control , Sístole , Adulto , Anciano , Antihipertensivos/efectos adversos , Captopril/efectos adversos , Femenino , Humanos , Hipotensión Ortostática/inducido químicamente , Masculino , Persona de Mediana Edad
6.
PLoS One ; 8(4): e62035, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23637959

RESUMEN

Genome-wide association (GWA) studies usually detect common genetic variants with low-to-medium effect sizes. Many contributing variants are not revealed, since they fail to reach significance after strong correction for multiple comparisons. The WTCCC study for hypertension, for example, failed to identify genome-wide significant associations. We hypothesized that genetic variation in genes expressed specifically in the endothelium may be important for hypertension development. Results from the WTCCC study were combined with previously published gene expression data from mice to specifically investigate SNPs located within endothelial-specific genes, bypassing the requirement for genome-wide significance. Six SNPs from the WTCCC study were selected for independent replication in 5205 hypertensive patients and 5320 population-based controls, and successively in a cohort of 16,537 individuals. A common variant (rs10860812) in the DRAM (damage-regulated autophagy modulator) locus showed association with hypertension (P = 0.008) in the replication study. The minor allele (A) had a protective effect (OR = 0.93; 95% CI 0.88-0.98 per A-allele), which replicates the association in the WTCCC GWA study. However, a second follow-up, in the larger cohort, failed to reveal an association with blood pressure. We further tested the endothelial-specific genes for co-localization with a panel of newly discovered SNPs from large meta-GWAS on hypertension or blood pressure. There was no significant overlap between those genes and hypertension or blood pressure loci. The result does not support the hypothesis that genetic variation in genes expressed in endothelium plays an important role for hypertension development. Moreover, the discordant association of rs10860812 with blood pressure in the case control study versus the larger Malmö Preventive Project-study highlights the importance of rigorous replication in multiple large independent studies.


Asunto(s)
Endotelio/metabolismo , Hipertensión/genética , Polimorfismo de Nucleótido Simple , Animales , Femenino , Sitios Genéticos/genética , Marcadores Genéticos/genética , Estudio de Asociación del Genoma Completo , Humanos , Hipertensión/patología , Masculino , Proteínas de la Membrana/genética , Ratones , Persona de Mediana Edad , Especificidad de Órganos
7.
Heart ; 99(13): 949-53, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23624487

RESUMEN

OBJECTIVE: The brain derived neurotrophic factor (BDNF) locus has been implicated in psychiatric and substance related disorders. Recent genome-wide association studies (GWAS) have shown strong associations between single nucleotide polymorphisms in BDNF, smoking behaviour and high body mass index (BMI). Our aim was to test whether genetic BDNF variation alters the risk of smoking related morbidity and mortality. DESIGN: Cox proportional hazards models were used to relate the BDNF rs4923461(A/G) polymorphisms to all-cause, cancer and cardiovascular mortality and cardiovascular disease (CVD) incidence adjusted for age, sex, BMI, and smoking quantity. SETTING: The Malmö Diet and Cancer Study (MDCS), a population based prospective cohort study (n=30 447). PATIENTS: We obtained complete data on 25 071 subjects, of whom 6507 were current smokers and 18 564 were non-smokers who underwent a baseline examination from 1991-1996. MAIN OUTCOME MEASURES: During a mean follow-up time of 12 years, 1049 deaths (346 cardiovascular deaths and 492 cancer deaths) and 802 incident CVD events occurred among current smokers. RESULTS: The major allele (A) of rs4923461 was significantly associated with ever having smoked (p=0.03) and high BMI (p=0.001). The A-allele was associated with risk of all-cause (HR=1.12, 95% CI 1.00 to 1.25; p<0.05) and CVD (HR=1.23, 95% CI 1.01 to 1.49; p=0.04) mortality. There was no significant association between the rs4923461 and cancer mortality or CVD incidence. CONCLUSIONS: Our data suggest that smoking- and obesity-associated variation of the BDNF gene affects the risk of death, especially due to cardiovascular causes, in smokers. Determination of the BDNF genotype in smokers may guide the need for smoking cessation interventions.


Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/genética , Enfermedades Cardiovasculares/genética , Obesidad/genética , Polimorfismo de Nucleótido Simple , Fumar/genética , Factores de Edad , Anciano , Índice de Masa Corporal , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/prevención & control , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Análisis Multivariante , Obesidad/complicaciones , Obesidad/mortalidad , Oportunidad Relativa , Fenotipo , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Medición de Riesgo , Factores de Riesgo , Conducta de Reducción del Riesgo , Factores Sexuales , Fumar/efectos adversos , Fumar/mortalidad , Cese del Hábito de Fumar , Prevención del Hábito de Fumar , Suecia/epidemiología , Factores de Tiempo
8.
PLoS One ; 8(8): e71846, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23967253

RESUMEN

AIMS: We tested whether characteristic changes of the plasma lipidome in individuals with comparable total lipids level associate with future cardiovascular disease (CVD) outcome and whether 23 validated gene variants associated with coronary artery disease (CAD) affect CVD associated lipid species. METHODS AND RESULTS: Screening of the fasted plasma lipidome was performed by top-down shotgun analysis and lipidome compositions compared between incident CVD cases (n = 211) and controls (n = 216) from the prospective population-based MDC study using logistic regression adjusting for Framingham risk factors. Associations with incident CVD were seen for eight lipid species (0.21≤q≤0.23). Each standard deviation unit higher baseline levels of two lysophosphatidylcholine species (LPC), LPC16∶0 and LPC20∶4, was associated with a decreased risk for CVD (P = 0.024-0.028). Sphingomyelin (SM) 38∶2 was associated with increased odds of CVD (P = 0.057). Five triglyceride (TAG) species were associated with protection (P = 0.031-0.049). LPC16∶0 was negatively correlated with the carotid intima-media thickness (P = 0.010) and with HbA1c (P = 0.012) whereas SM38∶2 was positively correlated with LDL-cholesterol (P = 0.0*10(-6)) and the q-values were good (q≤0.03). The risk allele of 8 CAD-associated gene variants showed significant association with the plasma level of several lipid species. However, the q-values were high for many of the associations (0.015≤q≤0.75). Risk allele carriers of 3 CAD-loci had reduced level of LPC16∶0 and/or LPC 20∶4 (P≤0.056). CONCLUSION: Our study suggests that CVD development is preceded by reduced levels of LPC16∶0, LPC20∶4 and some specific TAG species and by increased levels of SM38∶2. It also indicates that certain lipid species are intermediate phenotypes between genetic susceptibility and overt CVD. But it is a preliminary study that awaits replication in a larger population because statistical significance was lost for the associations between lipid species and future cardiovascular events when correcting for multiple testing.


Asunto(s)
Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/epidemiología , Lípidos/sangre , Anciano , Enfermedades Cardiovasculares/genética , Estudios de Casos y Controles , Análisis por Conglomerados , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/epidemiología , Enfermedad de la Arteria Coronaria/genética , Femenino , Perfilación de la Expresión Génica , Predisposición Genética a la Enfermedad , Humanos , Masculino , Metaboloma , Persona de Mediana Edad , Evaluación del Resultado de la Atención al Paciente , Vigilancia en Salud Pública , Riesgo , Factores de Riesgo
9.
Hypertension ; 61(1): 232-9, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23150505

RESUMEN

The locus encompassing the corticosteroidogenic genes CYP11B2 and CYP11B1 is of potential importance in essential hypertension. We analyzed the association of polymorphisms at this locus with risk of essential hypertension, using 2 white case-control collections for discovery (n=3340) and confirmation (n=2929). Single-marker and haplotype analyses were performed, with the CYP11B2 Intron 2 Conversion polymorphism showing strongest association with hypertension in both cohorts and in combined analysis (odds ratio=1.16, P=8.54×10(-5)). The CYP11B1 ACA haplotype associated with increased risk of hypertension relative to the alternative, GTC (odds ratio=1.11; P=7.4×10(-3)), whereas the CYP11B2 TWtC haplotype seemed protective relative to the contrasting CConvT (odds ratio=0.88, P=2.2×10(-3)). Analysis spanning the whole CYP11B1/CYP11B2 locus showed that haplotypes associated with raised risk of hypertension tend to coexist. Functional analysis of heterozygous human adrenal tissue demonstrated decreased CYP11B2 expression and increased CYP11B1 expression for those alleles associating with reduced risk of hypertension. These results confirm the hypertensive influence of this locus, with data suggesting a complex digenic mechanism whereby altered relative CYP11B1 and CYP11B2 gene expression could have a chronic effect on enzyme activity and corticosteroid synthesis.


Asunto(s)
Glándulas Suprarrenales/metabolismo , Citocromo P-450 CYP11B2/genética , Hipertensión/genética , Polimorfismo de Nucleótido Simple , Esteroide 11-beta-Hidroxilasa/genética , Adolescente , Adulto , Anciano , Alelos , Estudios de Casos y Controles , Citocromo P-450 CYP11B2/metabolismo , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Genotipo , Haplotipos , Humanos , Hipertensión/metabolismo , Masculino , Persona de Mediana Edad , Esteroide 11-beta-Hidroxilasa/metabolismo
10.
Hypertension ; 62(2): 391-7, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23753411

RESUMEN

To identify novel genes influencing blood pressure response to thiazide diuretic therapy for hypertension, we conducted genome-wide association meta-analyses of ≈1.1 million single-nucleotide polymorphisms in a combined sample of 424 European Americans with primary hypertension treated with hydrochlorothiazide from the Pharmacogenomic Evaluation of Antihypertensive Responses study (n=228) and the Genetic Epidemiology of Responses to Antihypertensive study (n=196). Polymorphisms associated with blood pressure response at P<10(-5) were tested for replication of the associations in independent samples of hydrochlorothiazide-treated European hypertensives. The rs16960228 polymorphism in protein kinase C, α replicated for same-direction association with diastolic blood pressure response in the Nordic Diltiazem study (n=420) and the Genetics of Drug Responsiveness in Essential Hypertension study (n=206), and the combined 4-study meta-analysis P value achieved genome-wide significance (P=3.3 × 10(-8)). Systolic or diastolic blood pressure responses were consistently greater in carriers of the rs16960228 A allele than in GG homozygotes (>4/4 mm Hg) across study samples. The rs2273359 polymorphism in the GNAS-EDN3 region also replicated for same-direction association with systolic blood pressure response in the Nordic Diltiazem study, and the combined 3-study meta-analysis P value approached genome-wide significance (P=5.5 × 10(-8)). The findings document clinically important effects of genetic variation at novel loci on blood pressure response to a thiazide diuretic, which may be a basis for individualization of antihypertensive drug therapy and identification of new drug targets.


Asunto(s)
Antihipertensivos/uso terapéutico , Diuréticos/uso terapéutico , Estudio de Asociación del Genoma Completo , Hidroclorotiazida/uso terapéutico , Hipertensión/tratamiento farmacológico , Polimorfismo de Nucleótido Simple , Adulto , Atenolol/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Cromosomas Humanos Par 17 , Femenino , Humanos , Hipertensión/genética , Masculino , Persona de Mediana Edad , Proteína Quinasa C-alfa/genética , Factores de Transcripción/genética
11.
J Hypertens ; 30(6): 1151-60, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22525200

RESUMEN

OBJECTIVE: We aimed to test whether eight common recently identified single-nucleotide polymorphisms (SNPs), strongly associated with blood pressure (BP) in the population, also have impact on the degree of BP reduction by antihypertensive agents with different mechanisms. METHODS: In 3863 Swedish hypertensive patients, we related number of unfavorable alleles of each SNP (i.e. alleles associated with higher baseline BP) to the magnitude of BP reduction during 6 months of monotherapy with either a beta-blocker, a thiazide diuretic or diltiazem. RESULTS: For six SNPs (rs16998073, rs1378942, rs3184504, rs1530440, rs16948048, rs17367504) no pharmacogenetic interactions were suggested, whereas two SNPs showed nominal evidence of association with treatment response: PLCD3-rs12946454 associated with more SBP (beta = 1.53 mmHg per unfavorable allele; P = 0.010) and DBP (beta = 0.73 mmHg per unfavorable allele; P = 0.014) reduction in patients treated with diltiazem, in contrast to those treated with beta-blockers or diuretics wherein no treatment response association was found. CYP17A1-rs11191548 associated with less DBP reduction (beta = -1.26 mmHg per unfavorable allele; P = 0.018) in patients treated with beta-blockers or diuretics, whereas there was no treatment response association in diltiazem-treated patients. However, if accounting for multiple testing, the significant associations for rs12946454 and rs11191548 were attenuated. CONCLUSION: For a majority of these, eight recently identified BP-associated SNPs, there are probably no important pharmacogenetic interactions for BP reduction with use of beta-blockers, diuretics or diltiazem. Whether the nominally significant associations for rs12946454 and rs11191548 are true signals and could be of possible clinical relevance for deciding treatment of polygenic essential hypertension should be further tested.


Asunto(s)
Presión Sanguínea/genética , Farmacogenética , Polimorfismo de Nucleótido Simple , Anciano , Antihipertensivos/uso terapéutico , Femenino , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/genética , Hipertensión/fisiopatología , Masculino , Persona de Mediana Edad , Suecia
12.
J Hypertens ; 29(2): 388-95, 2011 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-21052022

RESUMEN

OBJECTIVE: The capability of the protein NEDD4L to reduce renal tubular expression of epithelial Na+ channel (ENaC) is influenced by a functional rs4149601 G→A NEDD4L polymorphism. As diuretics and ß-blockers inhibit renal sodium reabsorption and renin release, respectively, we hypothesized that the ß-blocker or diuretic-induced blood pressure reduction and prevention of cardiovascular disease would be greater in patients with the highest ENaC expression (rs4149601 G-allele), whereas there would be no such genetically mediated differences in treatment efficacy among patients treated with the vasodilator diltiazem. METHODS: We related rs4149601 status to 6-month blood pressure reduction and risk of cardiovascular events in 5152 hypertensive patients (DBP ≥ 100 mmHg) from the Nordic Diltiazem Study (NORDIL) randomized to either ß-blocker and/or diuretic-based treatment or diltiazem-based treatment. RESULTS: In patients on ß-blocker or diuretic monotherapy, carriers of the G-allele had greater SBP reduction (19.5 ± 16.8 vs. 15.0 ± 19.3 mmHg, P < 0.001) and DBP reduction (15.4 ± 8.3vs. 14.1 ± 8.4 mmHg, P = 0.02) and during 4.5 years of follow-up among patients randomized to ß-blockers and/or diuretics, carriers of the G-allele had greater protection from cardiovascular events [relative risk (RR) = 0.52, 95% confidence interval (CI) = 0.36-0.74, P < 0.001] as compared to AA homozygotes. Within the diltiazem group, there was no difference in blood pressure reduction or risk of cardiovascular events according to genotype. CONCLUSION: The functional NEDD4L rs4149601 polymorphism influences the efficacy of ß-blocker and/or diuretic-based antihypertensive treatment both in terms of blood pressure reduction and cardiovascular disease protection, whereas diltiazem-based antihypertensive treatment efficacy is not influenced by this NEDD4L polymorphism.


Asunto(s)
Antagonistas Adrenérgicos beta/uso terapéutico , Complejos de Clasificación Endosomal Requeridos para el Transporte/genética , Hipertensión/tratamiento farmacológico , Hipertensión/genética , Polimorfismo de Nucleótido Simple , Inhibidores de los Simportadores del Cloruro de Sodio/uso terapéutico , Ubiquitina-Proteína Ligasas/genética , Anciano , Alelos , Antihipertensivos/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/genética , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/prevención & control , Diltiazem/uso terapéutico , Canales Epiteliales de Sodio/metabolismo , Femenino , Genotipo , Humanos , Hipertensión/fisiopatología , Masculino , Persona de Mediana Edad , Ubiquitina-Proteína Ligasas Nedd4 , Resultado del Tratamiento , Vasodilatadores/uso terapéutico
13.
J Obes ; 20102010.
Artículo en Inglés | MEDLINE | ID: mdl-20847932

RESUMEN

Aims. Evaluation of bariatric surgery as secondary prevention in obese patients with ischemic heart disease (IHD). Methods. Analysis of data from 4047 subjects in the Swedish Obese Subjects (SOSs) study. Thirty-five patients with IHD are treated with bariatric surgery (n = 21) or conventional treatment (n = 14). Mean follow-up is 10.8 years. Results. Bariatric surgery resulted in sustained weight loss during the study period. After 2 years, the surgery group displayed significant reductions in cardiovascular risk factors, relief from cardiorespiratory symptoms, increments in physical activity, and improved quality of life. After 10 years, recovery from hypertension, diabetes, physical inactivity, and depression was still more common in the surgery group. There were no signs of increased cardiovascular morbidity or mortality in the surgery group. Conclusion. Bariatric surgery appears to be a safe and feasible treatment to achieve long-term weight loss and improvement in cardiovascular risk factors, symptoms, and quality of life in obese subjects with IHD.

14.
J Hypertens ; 27(4): 769-73, 2009 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-19293724

RESUMEN

OBJECTIVE: We tested whether two single-nucleotide polymorphisms (SNPs) (rs2383207 and rs10757278), previously strongly associated with myocardial infarction, are independently associated with stroke and coronary events in patients with hypertension. METHODS: The Nordic Diltiazem study compared the effects of calcium antagonist and beta-blocker or diuretic-based antihypertensive treatment on cardiovascular events in 10 881 patients with hypertension, of whom 5262 patients provided DNA for the present study. We related SNPs rs2383207 and rs10757278 to stroke and to myocardial infarction and coronary revascularizations (coronary events) using crude and multivariate adjusted Cox proportional hazards models. RESULTS: The G-allele of both SNPs predicted coronary events in crude recessive models [hazard ratios = 1.36, 95% confidence interval (CI) = 1.04-1.79, P = 0.02 for rs10757278 and hazard ratios = 1.40, 95% CI = 1.08-1.81, P = 0.01 for rs2383207] as well as after adjustment for classical cardiovascular risk factors. The G-allele of both SNPs predicted incident stroke in crude additive models [rs2383207 hazard ratios = 1.25 (95% CI = 1.02-1.53), P = 0.04 and rs10757278 hazard ratios = 1.34 (95% CI = 1.09-1.65), P = 0.006], as well as after adjustment for classical cardiovascular risk factors and after additional adjustment for prevalent and incident coronary events, atrial fibrillation, ischemic heart disease and congestive heart failure. As was the case for coronary events, the excess genetic risk of stroke was driven by subjects homozygous for the risk allele. CONCLUSION: Genetic variation at the CDKN2A/CDKN2B locus predicts stroke in hypertensive patients. The genetic association with stroke is independent of classical cardiovascular risk factors and of all prevalent and incident coronary events, suggesting that gene variation at this locus promotes either atherosclerosis or another disease mechanism that is common to both coronary and cerebrovascular disease.


Asunto(s)
Cromosomas Humanos Par 9 , Enfermedad de la Arteria Coronaria/genética , Inhibidor p15 de las Quinasas Dependientes de la Ciclina/genética , Genes p16 , Hipertensión/complicaciones , Infarto del Miocardio/genética , Polimorfismo de Nucleótido Simple , Accidente Cerebrovascular/genética , Anciano , Mapeo Cromosómico , Femenino , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/genética , Masculino , Persona de Mediana Edad , Accidente Cerebrovascular/etiología
15.
Hypertension ; 52(1): 115-22, 2008 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-18504324

RESUMEN

We investigated whether renal function and microalbuminuria are independent predictors and whether any interaction exists between them, regarding future cardiovascular disease in hypertensive patients (n=10 881) followed for 4.5 years. The primary end points (PEs) were fatal and nonfatal myocardial infarction and stroke and other cardiovascular deaths. Creatinine and glomerular filtration rate (GFR), estimated using the formulas of the Modification of Diet in Renal Disease study group and Cockroft and Gault and in a subsample (n=4929) of microalbuminuria and interaction terms of microalbuminuria and renal function, were related to the risk of the PE using Cox proportional hazards model after full adjustment. Increased creatinine (P<0.001), decreased GFR from Cockroft and Gault (P=0.001), and decreased GFR from the Modification of Diet in Renal Disease study group (P=0.001) were all independent risk factors for the PE. Stepwise exclusion of patients with the poorest renal function excluded the possibility that the relationship between decreasing renal function and the PE was driven only by patients with severely impaired renal function. Microalbuminuria and all 3 of the indices of renal function predicted the PE independent of each other. There was a significant interaction between microalbuminuria and GFR from Cockroft and Gault (P=0.040) in prediction of the PE. Both renal function and microalbuminuria add independent prognostic information regarding cardiovascular risk in hypertensive patients. The cardiovascular risk associated with microalbuminuria increases with a decline in GFR, as demonstrated by a significant interaction between microalbuminuria and GFR from Cockroft and Gault. Because estimation of the total cardiovascular risk is essential for the aggressiveness of risk factor interventions, simultaneous inclusion of GFR and microalbuminuria in global cardiovascular risk assessment is essential.


Asunto(s)
Albuminuria/fisiopatología , Antihipertensivos/uso terapéutico , Enfermedades Cardiovasculares/epidemiología , Diltiazem/uso terapéutico , Hipertensión/tratamiento farmacológico , Hipertensión/fisiopatología , Riñón/fisiopatología , Anciano , Albuminuria/complicaciones , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/mortalidad , Femenino , Tasa de Filtración Glomerular , Humanos , Hipertensión/complicaciones , Masculino , Persona de Mediana Edad , Noruega/epidemiología , Pronóstico , Factores de Riesgo , Suecia/epidemiología
16.
Nat Genet ; 40(2): 189-97, 2008 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-18193044

RESUMEN

Blood concentrations of lipoproteins and lipids are heritable risk factors for cardiovascular disease. Using genome-wide association data from three studies (n = 8,816 that included 2,758 individuals from the Diabetes Genetics Initiative specific to the current paper as well as 1,874 individuals from the FUSION study of type 2 diabetes and 4,184 individuals from the SardiNIA study of aging-associated variables reported in a companion paper in this issue) and targeted replication association analyses in up to 18,554 independent participants, we show that common SNPs at 18 loci are reproducibly associated with concentrations of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and/or triglycerides. Six of these loci are new (P < 5 x 10(-8) for each new locus). Of the six newly identified chromosomal regions, two were associated with LDL cholesterol (1p13 near CELSR2, PSRC1 and SORT1 and 19p13 near CILP2 and PBX4), one with HDL cholesterol (1q42 in GALNT2) and five with triglycerides (7q11 near TBL2 and MLXIPL, 8q24 near TRIB1, 1q42 in GALNT2, 19p13 near CILP2 and PBX4 and 1p31 near ANGPTL3). At 1p13, the LDL-associated SNP was also strongly correlated with CELSR2, PSRC1, and SORT1 transcript levels in human liver, and a proxy for this SNP was recently shown to affect risk for coronary artery disease. Understanding the molecular, cellular and clinical consequences of the newly identified loci may inform therapy and clinical care.


Asunto(s)
HDL-Colesterol/sangre , HDL-Colesterol/genética , LDL-Colesterol/sangre , LDL-Colesterol/genética , Triglicéridos/sangre , Triglicéridos/genética , Anciano , Alelos , Estudios de Casos y Controles , Cromosomas Humanos Par 1 , Cromosomas Humanos Par 19 , Cromosomas Humanos Par 7 , Cromosomas Humanos Par 8 , Estudios de Cohortes , Femenino , Frecuencia de los Genes , Marcadores Genéticos , Variación Genética , Genoma Humano , Humanos , Desequilibrio de Ligamiento , Hígado/metabolismo , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Probabilidad , Estudios Prospectivos , ARN Mensajero/metabolismo , Ensayos Clínicos Controlados Aleatorios como Asunto , Análisis de Secuencia de ADN
17.
Diabetes ; 57(11): 3112-21, 2008 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-18678614

RESUMEN

OBJECTIVE: Using the genome-wide association approach, we recently identified the glucokinase regulatory protein gene (GCKR, rs780094) region as a novel quantitative trait locus for plasma triglyceride concentration in Europeans. Here, we sought to study the association of GCKR variants with metabolic phenotypes, including measures of glucose homeostasis, to evaluate the GCKR locus in samples of non-European ancestry and to fine- map across the associated genomic interval. RESEARCH DESIGN AND METHODS: We performed association studies in 12 independent cohorts comprising >45,000 individuals representing several ancestral groups (whites from Northern and Southern Europe, whites from the U.S., African Americans from the U.S., Hispanics of Caribbean origin, and Chinese, Malays, and Asian Indians from Singapore). We conducted genetic fine-mapping across the approximately 417-kb region of linkage disequilibrium spanning GCKR and 16 other genes on chromosome 2p23 by imputing untyped HapMap single nucleotide polymorphisms (SNPs) and genotyping 104 SNPs across the associated genomic interval. RESULTS: We provide comprehensive evidence that GCKR rs780094 is associated with opposite effects on fasting plasma triglyceride (P(meta) = 3 x 10(-56)) and glucose (P(meta) = 1 x 10(-13)) concentrations. In addition, we confirmed recent reports that the same SNP is associated with C-reactive protein (CRP) level (P = 5 x 10(-5)). Both fine-mapping approaches revealed a common missense GCKR variant (rs1260326, Pro446Leu, 34% frequency, r(2) = 0.93 with rs780094) as the strongest association signal in the region. CONCLUSIONS: These findings point to a molecular mechanism in humans by which higher triglycerides and CRP can be coupled with lower plasma glucose concentrations and position GCKR in central pathways regulating both hepatic triglyceride and glucose metabolism.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Glucemia/metabolismo , Proteína C-Reactiva/metabolismo , Mutación Missense , Triglicéridos/sangre , Adulto , Anciano , Análisis de Varianza , Ayuno/sangre , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple
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