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Determinantes genéticos comunes de la insuficiencia de vitamina D: un estudio de asociación de todo el genoma
Thomas J Wang1, Feng Zhang, J Brent Richards
1Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. tjwang@partners.org
Lancet (London, England)
|June 15, 2010
Resumen
Las variantes genéticas impactan significativamente los niveles de vitamina D y aumentan el riesgo de insuficiencia de vitamina D. Este estudio identificó los loci genéticos clave que influyen en el estado de la vitamina D en una gran población europea.
Área de la Ciencia:
- Genética Humana Genética Humana.
- Bioquímica nutricional y nutrición.
- Epidemiología molecular y epidemiología molecular.
Sus antecedentes:
- La vitamina D es esencial para la salud ósea y juega un papel en los tejidos extraesqueléticos.
- Las concentraciones circulantes de 25-hidroxivitamina D están influenciadas por la exposición al sol, la dieta y la genética.
- Se sugiere que los factores genéticos contribuyen significativamente al estado de la vitamina D debido a su alta heredabilidad.
Objetivo del estudio:
- Identificar las variantes genéticas comunes asociadas con las concentraciones circulantes de 25-hidroxivitamina D.
- Investigar la relación entre las variantes genéticas identificadas y el riesgo de insuficiencia de vitamina D.
- Aprovechar los estudios de asociación de todo el genoma (GWAS) para el descubrimiento genético integral.
Principales métodos:
- Estudio de asociación de todo el genoma (GWAS) realizado en 33.996 individuos de ascendencia europea en 15 cohortes.
- Utilizó el descubrimiento, la replicación in silico y las cohortes de replicación de novo para una validación robusta.
- Se midieron las concentraciones de 25-hidroxivitamina D utilizando varios ensayos (radioinmunoensayo, ELISA, espectrometría de masas) y se definieron los umbrales de insuficiencia (75 nmol/L o 50 nmol/L).
- Empleó un metaanálisis ponderado por puntaje Z para resultados combinados y puntajes de genotipos construidos para variantes confirmadas.
Principales resultados:
- Se identificaron variantes significativas en tres loci (4p12 cerca de GC, 11q12 cerca de DHCR7, 11p15 cerca de CYP2R1) asociadas con las concentraciones de 25-hidroxivitamina D.
- Un locus adicional (20q13 cerca de CYP24A1) alcanzó la significación de todo el genoma en la muestra agrupada.
- Los individuos en el cuartil más alto de una puntuación de genotipo combinado mostraron un riesgo significativamente mayor de insuficiencia de vitamina D (OR 2,47 para <75 nmol/L, O 1,92 para <50 nmol/L).
Conclusiones:
- Las variantes genéticas cerca de los genes involucrados en la síntesis del colesterol, la hidroxilación y el transporte de vitamina D influyen en el estado de la vitamina D.
- Estos loci genéticos identificados son cruciales para comprender el metabolismo y el estado de la vitamina D.
- La variación genética en estos loci identifica efectivamente a las personas con un riesgo sustancialmente mayor de insuficiencia de vitamina D.
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