Patrón de metilación en ADN de sujetos hipertrigliceridémicos / DNA methylation pattern of hypertriglyceridemic subjects

ANTECEDENTES:Las quilomicronemias generalmente se diagnostican genéticamente mediante secuenciación genómica o cribado de mutaciones en genes causales con un gran efecto fenotípico. Esta estrategia ha permitido mejorar la caracterización de estos pacientes, pero aún tenemos un 30% de ellos sin un diagnóstico genético concluyente. Es por esto que hipotetizamos que añadiendo el componente epigenético podemos mejorar el diagnóstico genético y para ello hemos explorado el grado de metilación en el ADN de pacientes hipertrigliceridémicos. METODOLOGÍA: El ADN de células sanguíneas fue obtenido de 16 pacientes hipertrigliceridémicos y de 16 sujetos control emparejados por edad y sexo. El grado de metilación en el ADN de todo el genoma fue determinado mediante el Illumina® Infinium MethylationEPIC Array Analysis. RESULTADOS: Identificamos 31 citosinas diferencialmente metiladas al comparar los patrones de metilación que presentaban los pacientes hipertrigliceridémicos vs. los sujetos control. La cg03636183 en el gen F2RL3 estaba un 10% hipometilada en los pacientes hipertrigliceridémicos, y ha sido previamente asociada a un mayor riesgo cardiovascular. La cg13824500 está un 10% hipometilada en pacientes hipertrigliceridémicos y se localiza en VTI1A, que es un gen limitante en el tránsito de los quilomicrones en el enterocito a través del retículo endoplásmico y el aparato de Golgi. La cg26468118 en el gen RAB20 (13% hipometilada) y la cg21560722 en el gen SBF2 (33% hipermetilada) están implicadas en la regulación de vesículas del aparato de Golgi. CONCLUSIONES: Nuestros resultados evidencian que existen regiones diferencialmente metiladas relacionadas con la formación de los quilomicrones en pacientes hipertrigliceridémicos.

BACKGROUND: Chylomicronemias are generally diagnosed genetically by genomic sequencing or screening for mutations in causal genes with a large phenotypic effect. This strategy has allowed to improve the characterization of these patients, but we still have 30% of the patients without a conclusive genetic diagnosis. This is why we hypothesize that by adding the epigenetic component we can improve the genetic diagnosis, and for this we have explored the degree of methylation in the DNA of hypertriglyceridemic patients. METHODOLOGY: Blood cell DNA was obtained from 16 hypertriglyceridemic patients and from 16 age- and sex-matched control subjects. The degree of methylation in genome-wide DNA was determined using the Illumina® Infinium Methylation EPIC Array Analysis. RESULTS: We identified 31 differentially methylated cytosines by comparing the methylation patterns presented by hypertriglyceridemic patients vs. control subjects. The cg03636183 in the F2RL3 gene was 10% hypomethylated in hypertriglyceridemic patients, and has previously been associated with an increased cardiovascular risk. Cg13824500 is 10% hypomethylated in hypertriglyceridemic patients and is located in VTI1A, which is a limiting gene in the transit of chylomicrons in the enterocyte through the endoplasmic reticulum and the Golgi apparatus. Cg26468118 in the RAB20 gene (13% hypomethylated) and cg21560722 in the SBF2 gene (33% hypermethylated) are involved in the regulation of Golgi apparatus vesicles. CONCLUSIONS: Our results suggest that there are differentially methylated regions related to the formation of chylomicrons in hypertriglyceridemic patients.

DNA methylation pattern of hypertriglyceridemic subjects. / Patrón de metilación en ADN de sujetos hipertrigliceridémicos.

BACKGROUND: Chylomicronemias are generally diagnosed genetically by genomic sequencing or screening for mutations in causal genes with a large phenotypic effect. This strategy has allowed to improve the characterization of these patients, but we still have 30% of the patients without a conclusive genetic diagnosis. This is why we hypothesize that by adding the epigenetic component we can improve the genetic diagnosis, and for this we have explored the degree of methylation in the DNA of hypertriglyceridemic patients. METHODOLOGY: Blood cell DNA was obtained from 16 hypertriglyceridemic patients and from 16 age- and sex-matched control subjects. The degree of methylation in genome-wide DNA was determined using the Illumina® Infinium Methylation EPIC Array Analysis. RESULTS: We identified 31 differentially methylated cytosines by comparing the methylation patterns presented by hypertriglyceridemic patients vs. control subjects. The cg03636183 in the F2RL3 gene was 10% hypomethylated in hypertriglyceridemic patients, and has previously been associated with an increased cardiovascular risk. Cg13824500 is 10% hypomethylated in hypertriglyceridemic patients and is located in VTI1A, which is a limiting gene in the transit of chylomicrons in the enterocyte through the endoplasmic reticulum and the Golgi apparatus. Cg26468118 in the RAB20 gene (13% hypomethylated) and cg21560722 in the SBF2 gene (33% hypermethylated) are involved in the regulation of Golgi apparatus vesicles. CONCLUSIONS: Our results suggest that there are differentially methylated regions related to the formation of chylomicrons in hypertriglyceridemic patients.

Epigenetic changes in headache.

INTRODUCTION: Multiple factors, including both genetic and environmental mechanisms, appear to play a role in the aetiology of headache. An interesting area of study is the possible involvement of epigenetic mechanisms in headache development and the transformation to chronic headache, and the potential role of these factors as a therapeutic target. METHODS: We performed a literature review of the involvement of different epigenetic mechanisms in headache, mainly using the Medline/PubMed database. To this end, we used the following English search terms: headache, migraine, epigenetics, DNA methylation, histones, non-coding RNA, and miRNA. RESULTS: A total of 15 English-language publications related to the above terms were obtained. CONCLUSION: There is limited but consistent evidence of the relationship between epigenetics and headache; it is therefore essential to continue research of epigenetic changes in headache. This may help to understand the pathophysiology of headache and even to identify candidate biomarkers and new, more effective, therapeutic targets.

Modificaciones epigenéticas en las cefaleas / Epigenetic changes in headache

Introducción: En las cefaleas parece existir una influencia multifactorial, tanto de mecanismos genéticos como ambientales, siendo interesante el estudio de la posible participación de mecanismos epigenéticos en su desarrollo, cronificación y potencial papel como diana terapéutica.MétodosHemos llevado a cabo una revisión bibliográfica, principalmente a través de la base de datos Medline/PubMed, de la implicación de los distintos mecanismos epigenéticos en las cefaleas. Para ello hemos utilizado los términos de búsqueda en inglés: headache, migraine, epigenetics, DNA methylation, histones, non-coding RNA y miRNA.ResultadosSe obtuvieron un total de 15 publicaciones en idioma inglés relacionadas con los términos anteriores.ConclusionesExisten indicios de la relación entre la epigenética y las cefaleas, siendo imprescindible, debido al reducido número de estudios, continuar con la investigación de las modificaciones epigenéticas en las cefaleas. Esto podría ayudar a comprender la fisiopatología de las cefaleas e incluso identificar biomarcadores y nuevas dianas terapéuticas más eficaces. (AU)

Introduction: Multiple factors, including both genetic and environmental mechanisms, appear to play a role in the aetiology of headache. An interesting area of study is the possible involvement of epigenetic mechanisms in headache development and the transformation to chronic headache, and the potential role of these factors as a therapeutic target.MethodsWe performed a literature review of the involvement of different epigenetic mechanisms in headache, mainly using the Medline/PubMed database. To this end, we used the following English search terms: headache, migraine, epigenetics, DNA methylation, histones, non-coding RNA, and miRNA.ResultsA total of 15 English-language publications related to the above terms were obtained.ConclusionThere is limited but consistent evidence of the relationship between epigenetics and headache; it is therefore essential to continue research of epigenetic changes in headache. This may help to understand the pathophysiology of headache and even to identify candidate biomarkers and new, more effective, therapeutic targets. (AU)

Epigenética y síndrome metabólico / Epigenetics and Metabolic Syndrome

La epigenética puede definirse como los cambios estables y heredables en la expresión génica, que no son producidos por cambios en la secuencia del ADN. Las modificaciones epigenéticas más estudiadas son la metilación del ADN y las modificaciones postraduccionales de histonas. Estas podrían explicar cómo factores ambientales, nutricionales y otros, contribuyen a la modulación de la expresión de genes y al desarrollo de distintas enfermedades. El síndrome metabólico está definido por la presencia de obesidad, fundamentalmente central, hipertensión, diabetes, dislipemia, y un estado protrombótico y proinflamatorio, que son factores de riesgo de enfermedad cardiovascular. La genética de estas enfermedades es compleja, y es sabido que tanto factores genéticos de susceptibilidad o resistencia, como factores ambientales contribuyen al desarrollo de este síndrome. Nuestro grupo ha estudiado la participación de las modificaciones epigenéticas en la fisio­patología del síndrome metabólico. Ellas podrían tener un rol importante no solo en el desarrollo de estas enfermedades en la vida adulta, sino predisponer al individuo desde desarrollo prenatal. En esta revisión describimos las principales modificaciones epigenéticas, y a través de nuestros hallazgos cómo sería su papel en el desarrollo del síndrome metabólico. Conocer cómo participarían las modificaciones epigenéticas en estas enfermedades, no solo permitirá mejorar el tratamiento de las mismas, sino establecer medidas preventivas desde la gestación. Rev Argent Endocrinol Metab 52:35-44, 2015 Los autores declaran no poseer conflictos de interés.

Epigenetics can be defined as stable and heritable changes in gene expression that are not produced by changes in DNA sequence. The most studied epigenetic modifications are DNA methylation and histone post-translational modifications. Epigenetic modifications might explain how environmental, nutritional and others factors contribute to the modulation of gene expression and the development of different diseases. Metabolic syndrome is defined by the presence of mainly central obesity, hypertension, diabetes, dyslipidemia, and a prothrombotic and proinflammatory state, which are risk factors for cardiovascular disease. The genetic factors of these diseases are complex, and it is known that genetic susceptibility or resistance backgrounds as well as environmental factors contribute to the development of this syndrome. We have studied the in­volvement of epigenetic modifications in the pathophysiology of metabolic syndrome. These modifications might play an important role in the development of these diseases in adulthood, and according to our results, they might also predispose an individual from prenatal life. In this review, we describe the main epigenetic modifications, and which could be their role in the development of metabolic syndrome. Understanding how epigenetic modifications act in these diseases could not only help to identify new avenues of treatment but also to establish preventive measures from gestation. Rev Argent Endocrinol Metab 52:35-44, 2015 No financial conflicts of interest exist.

Epigenética y síndrome metabólico / Epigenetics and Metabolic Syndrome

La epigenética puede definirse como los cambios estables y heredables en la expresión génica, que no son producidos por cambios en la secuencia del ADN. Las modificaciones epigenéticas más estudiadas son la metilación del ADN y las modificaciones postraduccionales de histonas. Estas podrían explicar cómo factores ambientales, nutricionales y otros, contribuyen a la modulación de la expresión de genes y al desarrollo de distintas enfermedades. El síndrome metabólico está definido por la presencia de obesidad, fundamentalmente central, hipertensión, diabetes, dislipemia, y un estado protrombótico y proinflamatorio, que son factores de riesgo de enfermedad cardiovascular. La genética de estas enfermedades es compleja, y es sabido que tanto factores genéticos de susceptibilidad o resistencia, como factores ambientales contribuyen al desarrollo de este síndrome. Nuestro grupo ha estudiado la participación de las modificaciones epigenéticas en la fisio¡patología del síndrome metabólico. Ellas podrían tener un rol importante no solo en el desarrollo de estas enfermedades en la vida adulta, sino predisponer al individuo desde desarrollo prenatal. En esta revisión describimos las principales modificaciones epigenéticas, y a través de nuestros hallazgos cómo sería su papel en el desarrollo del síndrome metabólico. Conocer cómo participarían las modificaciones epigenéticas en estas enfermedades, no solo permitirá mejorar el tratamiento de las mismas, sino establecer medidas preventivas desde la gestación. Rev Argent Endocrinol Metab 52:35-44, 2015 Los autores declaran no poseer conflictos de interés.(AU)

Epigenetics can be defined as stable and heritable changes in gene expression that are not produced by changes in DNA sequence. The most studied epigenetic modifications are DNA methylation and histone post-translational modifications. Epigenetic modifications might explain how environmental, nutritional and others factors contribute to the modulation of gene expression and the development of different diseases. Metabolic syndrome is defined by the presence of mainly central obesity, hypertension, diabetes, dyslipidemia, and a prothrombotic and proinflammatory state, which are risk factors for cardiovascular disease. The genetic factors of these diseases are complex, and it is known that genetic susceptibility or resistance backgrounds as well as environmental factors contribute to the development of this syndrome. We have studied the in¡volvement of epigenetic modifications in the pathophysiology of metabolic syndrome. These modifications might play an important role in the development of these diseases in adulthood, and according to our results, they might also predispose an individual from prenatal life. In this review, we describe the main epigenetic modifications, and which could be their role in the development of metabolic syndrome. Understanding how epigenetic modifications act in these diseases could not only help to identify new avenues of treatment but also to establish preventive measures from gestation. Rev Argent Endocrinol Metab 52:35-44, 2015 No financial conflicts of interest exist.(AU)