RESUMEN
OBJECTIVES: Two diallelic polymorphisms, one in the transcriptional regulatory region (promoter) and the other in the second intron, have been identified in the aldosterone synthase (CYP11B2) gene encoding aldosterone synthase, the enzyme catalysing the last steps of aldosterone biosynthesis. We have examined the associations between these genetic variations and adrenocortical function in a cohort of Finnish males. DESIGN: A cross-sectional study. SETTING: Helsinki University Central Hospital, Finland. SUBJECTS: Ninety-two males aged 30-55 years. MAIN OUTCOME MEASURES: Basal adrenocortical function was assessed by measuring urinary excretion of aldosterone and cortisol. Functional activity was determined by responses of several adrenal steroids to dexamethasone suppression followed by ACTH stimulation. Polymerase chain reactions were used to identify the polymorphisms in the CYP11B2 gene. RESULTS: The -344TT genotype group in the CYP11B2 promoter had lower systolic blood pressures (P=0.039), but higher urinary aldosterone excretion (P=0.016), and 11-deoxycortisol responses to ACTH stimulation (P=0.021) than the-344CC genotype group. Urinary aldosterone excretion (P=0.033), 11-deoxycortisol (P=0.026), and aldosterone (P=0.013) responses to ACTH were higher in the intron 2 conversion than the nonconversion genotype groups. CONCLUSIONS: Polymorphisms in or near the aldosterone synthase gene are associated with variations in aldosterone and 11-deoxycortisol production in males. This may modulate the activity of the renin-angiotensin system and thereby contribute to blood pressure regulation.
Asunto(s)
Corteza Suprarrenal/fisiología , Citocromo P-450 CYP11B2/genética , Corteza Suprarrenal/efectos de los fármacos , Corteza Suprarrenal/metabolismo , Hormona Adrenocorticotrópica/farmacología , Adulto , Aldosterona/sangre , Aldosterona/orina , Análisis de Varianza , Estudios de Cohortes , Estudios Transversales , Dexametasona/farmacología , Finlandia , Genotipo , Glucocorticoides/farmacología , Humanos , Hidrocortisona/sangre , Hidrocortisona/orina , Hipertensión/fisiopatología , Intrones/genética , Masculino , Persona de Mediana Edad , Polimorfismo Genético , Regiones Promotoras Genéticas/genéticaRESUMEN
BACKGROUND: Aldosterone has direct and indirect effects on the heart, and genetic variations in aldosterone synthesis could therefore influence cardiac structure and function. Such variations might be associated with polymorphisms in the gene encoding aldosterone synthase (CYP11B2), the enzyme catalyzing the last steps of aldosterone biosynthesis. METHODS AND RESULTS: A Finnish population sample of 84 persons (44 women) aged 36 to 37 years was studied by M-mode and Doppler echocardiography to assess left ventricular size, mass, and function. Subjects were genotyped through the use of the polymerase chain reaction for two diallelic polymorphisms in CYP11B2: one in the transcriptional regulatory region (promoter) and the other in the second intron. In multiple regression analyses, the CYP11B2 promoter genotype predicted statistically significant variations in left ventricular end-diastolic diameter (beta=.40, P<.0001), end-systolic diameter (beta=.33, P=.0009), and mass (beta=.17, P=.023). These effects were independent of potentially confounding factors, including sex, body size, blood pressure, physical activity, smoking, and ethanol consumption. Genotype groups also differed in a measure of left ventricular diastolic function, the heart rate-adjusted atrial filling fraction (P=.018). Increased dietary salt, which is known to predict increased left ventricular mass, had this effect only in association with certain CYP11B2 genotypes (P<.001). CONCLUSIONS: Genetic variations in or near the aldosterone synthase (CYP11B2) gene strongly affect left ventricular size and mass in young adults free of clinical heart disease. These polymorphisms may also influence the response of the left ventricle to increases in dietary salt.