Un análisis combinado de enlaces, microarrays y exomas sugiere que el MAP3K11 es un gen candidato para la hipertrofia ventricular izquierda.

Claudia Tamar Silva, Irina V. Zorkoltseva, Maartje N. Niemeijer, Marten E. Van Den Berg, Najaf Amin, Ayşe Demirkan, Elisa Van Leeuwen, Adriana I. Iglesias, Laura B. Piñeros-Hernández, Carlos M. Restrepo, Jan A. Kors, Anatoly V. Kirichenko, Rob Willemsen, Ben A. Oostra, Bruno H. Stricker, André G. Uitterlinden, Tatiana I. Axenovich, Cornelia M. Van Duijn, Aaron Isaacs

Resultado de la investigación: Contribución a RevistaArtículo

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Resumen

ANTECEDENTES: Las medidas electrocardiográficas de la hipertrofia ventricular izquierda (HLV) se utilizan como predictores del riesgo cardiovascular. Combinamos los análisis de vinculación y asociación para descubrir nuevas variantes genéticas raras implicadas en tres de estas medidas y dos componentes principales derivados de ellas. MÉTODOS: El estudio se llevó a cabo entre participantes del Erasmus Rucphen Family Study (ERF), una muestra de familias holandesas del suroeste de los Países Bajos. Los análisis de enlace de los componentes de varianza se realizaron utilizando Merlin. Las regiones de interés (LOD > 1.9) fueron mapeadas usando datos de microarrays y secuencias de exomas. RESULTADOS: Se observó una puntuación LOD significativa para el segundo componente principal del cromosoma 15 (puntuación LOD = 3,01) y 12 puntuaciones LOD sugestivas. Varios loci contenían variantes identificadas en GWAS para estos rasgos; sin embargo, estos no explicaban los picos de vinculación, ni tampoco otras variantes comunes. Los datos de la secuencia del exoma identificaron dos variantes asociadas después de aplicar múltiples correcciones de prueba. CONCLUSIONES: No se encontraron SNPs comunes que expliquen estas señales de enlace. La secuenciación del exoma descubrió una variante relativamente rara en el MAPK3K11 en el cromosoma 11 (MAF = 0,01) que ayudó a explicar el pico de sugestión observado para el primer componente principal. El análisis condicional reveló una caída en el LOD de 2.01 a 0.88 para el MAP3K11, sugiriendo que esta variante podría explicar parcialmente la señal de enlace en esta localización cromosómica. El MAP3K11 está relacionado con la vía JNK y es una cinasa pro-apoptótica que juega un papel importante en la inducción de la apoptosis cardiomiocitaria en varias patologías, incluyendo la HBV.
Título traducido de la contribuciónUn análisis combinado de enlaces, microarrays y exomas sugiere que el MAP3K11 es un gen candidato para la hipertrofia ventricular izquierda.
IdiomaEnglish (US)
Número de artículo22
PublicaciónBMC Medical Genomics
Volumen11
Número de edición1
DOI
EstadoPublished - mar 5 2018
Publicado de forma externa

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Citar esto

Silva, C. T., Zorkoltseva, I. V., Niemeijer, M. N., Van Den Berg, M. E., Amin, N., Demirkan, A., ... Isaacs, A. (2018). A combined linkage, microarray and exome analysis suggests MAP3K11 as a candidate gene for left ventricular hypertrophy. BMC Medical Genomics, 11(1), [22]. https://doi.org/10.1186/s12920-018-0339-9
Silva, Claudia Tamar ; Zorkoltseva, Irina V. ; Niemeijer, Maartje N. ; Van Den Berg, Marten E. ; Amin, Najaf ; Demirkan, Ayşe ; Van Leeuwen, Elisa ; Iglesias, Adriana I. ; Piñeros-Hernández, Laura B. ; Restrepo, Carlos M. ; Kors, Jan A. ; Kirichenko, Anatoly V. ; Willemsen, Rob ; Oostra, Ben A. ; Stricker, Bruno H. ; Uitterlinden, André G. ; Axenovich, Tatiana I. ; Van Duijn, Cornelia M. ; Isaacs, Aaron. / A combined linkage, microarray and exome analysis suggests MAP3K11 as a candidate gene for left ventricular hypertrophy. En: BMC Medical Genomics. 2018 ; Vol. 11, N.º 1.
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title = "A combined linkage, microarray and exome analysis suggests MAP3K11 as a candidate gene for left ventricular hypertrophy",
abstract = "Background: Electrocardiographic measures of left ventricular hypertrophy (LVH) are used as predictors of cardiovascular risk. We combined linkage and association analyses to discover novel rare genetic variants involved in three such measures and two principal components derived from them. Methods: The study was conducted among participants from the Erasmus Rucphen Family Study (ERF), a Dutch family-based sample from the southwestern Netherlands. Variance components linkage analyses were performed using Merlin. Regions of interest (LOD > 1.9) were fine-mapped using microarray and exome sequence data. Results: We observed one significant LOD score for the second principal component on chromosome 15 (LOD score = 3.01) and 12 suggestive LOD scores. Several loci contained variants identified in GWAS for these traits; however, these did not explain the linkage peaks, nor did other common variants. Exome sequence data identified two associated variants after multiple testing corrections were applied. Conclusions: We did not find common SNPs explaining these linkage signals. Exome sequencing uncovered a relatively rare variant in MAPK3K11 on chromosome 11 (MAF = 0.01) that helped account for the suggestive linkage peak observed for the first principal component. Conditional analysis revealed a drop in LOD from 2.01 to 0.88 for MAP3K11, suggesting that this variant may partially explain the linkage signal at this chromosomal location. MAP3K11 is related to the JNK pathway and is a pro-apoptotic kinase that plays an important role in the induction of cardiomyocyte apoptosis in various pathologies, including LVH.",
author = "Silva, {Claudia Tamar} and Zorkoltseva, {Irina V.} and Niemeijer, {Maartje N.} and {Van Den Berg}, {Marten E.} and Najaf Amin and Ayşe Demirkan and {Van Leeuwen}, Elisa and Iglesias, {Adriana I.} and Pi{\~n}eros-Hern{\'a}ndez, {Laura B.} and Restrepo, {Carlos M.} and Kors, {Jan A.} and Kirichenko, {Anatoly V.} and Rob Willemsen and Oostra, {Ben A.} and Stricker, {Bruno H.} and Uitterlinden, {Andr{\'e} G.} and Axenovich, {Tatiana I.} and {Van Duijn}, {Cornelia M.} and Aaron Isaacs",
year = "2018",
month = "3",
day = "5",
doi = "10.1186/s12920-018-0339-9",
language = "English (US)",
volume = "11",
journal = "BMC Medical Genomics",
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Silva, CT, Zorkoltseva, IV, Niemeijer, MN, Van Den Berg, ME, Amin, N, Demirkan, A, Van Leeuwen, E, Iglesias, AI, Piñeros-Hernández, LB, Restrepo, CM, Kors, JA, Kirichenko, AV, Willemsen, R, Oostra, BA, Stricker, BH, Uitterlinden, AG, Axenovich, TI, Van Duijn, CM & Isaacs, A 2018, 'A combined linkage, microarray and exome analysis suggests MAP3K11 as a candidate gene for left ventricular hypertrophy' BMC Medical Genomics, vol. 11, n.º 1, 22. https://doi.org/10.1186/s12920-018-0339-9

A combined linkage, microarray and exome analysis suggests MAP3K11 as a candidate gene for left ventricular hypertrophy. / Silva, Claudia Tamar; Zorkoltseva, Irina V.; Niemeijer, Maartje N.; Van Den Berg, Marten E.; Amin, Najaf; Demirkan, Ayşe; Van Leeuwen, Elisa; Iglesias, Adriana I.; Piñeros-Hernández, Laura B.; Restrepo, Carlos M.; Kors, Jan A.; Kirichenko, Anatoly V.; Willemsen, Rob; Oostra, Ben A.; Stricker, Bruno H.; Uitterlinden, André G.; Axenovich, Tatiana I.; Van Duijn, Cornelia M.; Isaacs, Aaron.

En: BMC Medical Genomics, Vol. 11, N.º 1, 22, 05.03.2018.

Resultado de la investigación: Contribución a RevistaArtículo

TY - JOUR

T1 - A combined linkage, microarray and exome analysis suggests MAP3K11 as a candidate gene for left ventricular hypertrophy

AU - Silva, Claudia Tamar

AU - Zorkoltseva, Irina V.

AU - Niemeijer, Maartje N.

AU - Van Den Berg, Marten E.

AU - Amin, Najaf

AU - Demirkan, Ayşe

AU - Van Leeuwen, Elisa

AU - Iglesias, Adriana I.

AU - Piñeros-Hernández, Laura B.

AU - Restrepo, Carlos M.

AU - Kors, Jan A.

AU - Kirichenko, Anatoly V.

AU - Willemsen, Rob

AU - Oostra, Ben A.

AU - Stricker, Bruno H.

AU - Uitterlinden, André G.

AU - Axenovich, Tatiana I.

AU - Van Duijn, Cornelia M.

AU - Isaacs, Aaron

PY - 2018/3/5

Y1 - 2018/3/5

N2 - Background: Electrocardiographic measures of left ventricular hypertrophy (LVH) are used as predictors of cardiovascular risk. We combined linkage and association analyses to discover novel rare genetic variants involved in three such measures and two principal components derived from them. Methods: The study was conducted among participants from the Erasmus Rucphen Family Study (ERF), a Dutch family-based sample from the southwestern Netherlands. Variance components linkage analyses were performed using Merlin. Regions of interest (LOD > 1.9) were fine-mapped using microarray and exome sequence data. Results: We observed one significant LOD score for the second principal component on chromosome 15 (LOD score = 3.01) and 12 suggestive LOD scores. Several loci contained variants identified in GWAS for these traits; however, these did not explain the linkage peaks, nor did other common variants. Exome sequence data identified two associated variants after multiple testing corrections were applied. Conclusions: We did not find common SNPs explaining these linkage signals. Exome sequencing uncovered a relatively rare variant in MAPK3K11 on chromosome 11 (MAF = 0.01) that helped account for the suggestive linkage peak observed for the first principal component. Conditional analysis revealed a drop in LOD from 2.01 to 0.88 for MAP3K11, suggesting that this variant may partially explain the linkage signal at this chromosomal location. MAP3K11 is related to the JNK pathway and is a pro-apoptotic kinase that plays an important role in the induction of cardiomyocyte apoptosis in various pathologies, including LVH.

AB - Background: Electrocardiographic measures of left ventricular hypertrophy (LVH) are used as predictors of cardiovascular risk. We combined linkage and association analyses to discover novel rare genetic variants involved in three such measures and two principal components derived from them. Methods: The study was conducted among participants from the Erasmus Rucphen Family Study (ERF), a Dutch family-based sample from the southwestern Netherlands. Variance components linkage analyses were performed using Merlin. Regions of interest (LOD > 1.9) were fine-mapped using microarray and exome sequence data. Results: We observed one significant LOD score for the second principal component on chromosome 15 (LOD score = 3.01) and 12 suggestive LOD scores. Several loci contained variants identified in GWAS for these traits; however, these did not explain the linkage peaks, nor did other common variants. Exome sequence data identified two associated variants after multiple testing corrections were applied. Conclusions: We did not find common SNPs explaining these linkage signals. Exome sequencing uncovered a relatively rare variant in MAPK3K11 on chromosome 11 (MAF = 0.01) that helped account for the suggestive linkage peak observed for the first principal component. Conditional analysis revealed a drop in LOD from 2.01 to 0.88 for MAP3K11, suggesting that this variant may partially explain the linkage signal at this chromosomal location. MAP3K11 is related to the JNK pathway and is a pro-apoptotic kinase that plays an important role in the induction of cardiomyocyte apoptosis in various pathologies, including LVH.

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U2 - 10.1186/s12920-018-0339-9

DO - 10.1186/s12920-018-0339-9

M3 - Article

VL - 11

JO - BMC Medical Genomics

T2 - BMC Medical Genomics

JF - BMC Medical Genomics

SN - 1755-8794

IS - 1

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