Caracterización funcional y estructural de genes asociados a preeclampsia expresados en la placenta humana.
Resumen
Introducción: La preeclampsia continúa siendo la primera causa de morbimortalidad perinatal. El conocimiento sobre su etiología molecular se ha incrementado en los últimos años debido al avance en la aplicación de las ciencias “ómicas”. Ello ha llevado a identificar genes candidatos que participarían en su patogénesis
Objetivo: Identificar y caracterizar estructural y funcionalmente genes expresados en placenta que se asocian con preeclampsia.
Métodos: A partir de una revisión de literatura de los últimos diez años, se identificaron 16 genes cuya expresión en placenta estaba asociada con la patología. Se realizó la minería de datos incluyendo las siguientes variables: número de genes, tamaño de los genes, número de exones codificantes, islas CpG y las familias de los diferentes elementos repetidos en una ventana de 100Kbp. Mediante un análisis bioinformático, usando los diferentes recursos del NCBI (www.ncbi.nlm.nih.gov) y del Genome Browser de UCSC (http://genome.ucsc.edu/). Adicionalmente se usó el portal BioGPS (http://biogps.gnf.org/#goto=welcome), se determinaron los niveles de expresión de cada gen por tejidos
Resultados: Se registraron diferencias en la cromatina que contiene las familias de elementos no codificantes de los genes asociados en comparación con los controles (Prueba de Kruskall-Wallis, P= 0.0341824). Los genes LEP, EBI3, PROCR, FSTL3, HEXB, INHBA y ENG fueron los que registraron el mayor puntaje z en placentas preeclámpsicas.
Conclusión: La aplicación de las herramientas bioinformáticas se convierte en un instrumento potente para el análisis integrado de la expresión de genes y su papel en la patogénesis de la PE. Esto conllevaría a la identificación temprana de mujeres afectadas.
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Referencias bibliográficas
Herrera JA, Herrera-Miranda R, Herrera-Escobar JP, Nieto-Díaz A. Reducción de la mortalidad materna por preeclampsia en Colombia - un análisis de series de tiempo interrumpido. Colombia Médica. 2014; 45:25-31.
Sircar M, Thadhani R, Karumanchi SA. Pathogenesis of preeclampsia. Curr Opin Nephrol Hypertens. 2015; 24:131-138.http://dx.doi.org/10.1097/MNH.0000000000000105
Mol BW, Roberts CT, Thangaratinam S, Magee LA, de Groot CJ, Hofmeyr GJ. Pre-eclampsia. Lancet. 2015; pii: S0140-6736.
Cohen JM, Beddaoui M, Kramer MS, Platt RW, Basso O, Kahn SR. Maternal Antioxidant Levels in Pregnancy and Risk of Preeclampsia and Small for Gestational Age Birth: A Systematic Review and Meta-Analysis. PLoS One. 2015; 10(8):e0135192.http://dx.doi.org/10.1371/journal.pone.0135192
Dekker GA. Management of preeclampsia. Pregnancy Hypertens. 2014;4(3):246-247.http://dx.doi.org/10.1016/j.preghy.2014.04.021
Said J, G. Dekker G. Pre-eclamsia and trombophilia. Best Practice & Research Clinical Obstetrics & Gynaecology 2003;17(3): 441-458.http://dx.doi.org/10.1016/S1521-6934(03)00008-7
Gillon TE, Pels A, von Dadelszen P, MacDonell K, Magee LA. Hypertensive disorders of pregnancy: a systematic review of international clinical practice guidelines. PLoS One. 2014;9(12):e113715.http://dx.doi.org/10.1371/journal.pone.0113715
Kajii T, Ohama K. Androgenetic origin of hydatidiform mole. Nature 1977; 268(5621): 633-634.http://dx.doi.org/10.1038/268633a0
Hansson SR, Chen Y, Brodszki J, Chen M, Hernandez-Andrade E, Inman JM, et. al. Gene expression profiling of human placentas from preeclamptic and normotensive pregnancies. Mol Hum Reproduction. 2006; 12: 169-179.http://dx.doi.org/10.1093/molehr/gal011
Lyall F. The human placental bed revisited. Placenta 2002; 23: 555-562.http://dx.doi.org/10.1053/plac.2002.0850
Lyall F. Development of the utero-placental circulation: the role of carbon monoxide and nitric oxide in trophoblast invasion and spiral artery transformation. Microscopy Res Technique. 2003; 60(4): 402-411.http://dx.doi.org/10.1002/jemt.10278
Garoby-Salom S, Vayssiere C, Salvayre R, Parant O, Negre-Salvayre A. Oxidative stress and preeclampsia: A review. Gynecol Obstet Fertility. 2015; pii: S1297-9589.
Gram M, Dolberg Anderson U, Johansson ME, Edström-Hägerwall A, Larsson I, Jälmby M, Hansson SR, Åkerström B. The Human Endogenous Protection System against Cell-Free Hemoglobin and Heme Is Overwhelmed in Preeclampsia and Provides Potential Biomarkers and Clinical Indicators. PLoS One. 2015; http://dx.doi.org/10.1371/journal.pone.0138111
Vanwijk MJ, Kublickiene K, Boer K, Vanbavel E. Vascular function in preeclampsia. Cardiovascular Research. 2000; 47(1): 38-48.http://dx.doi.org/10.1016/S0008-6363(00)00087-0
Nishizawa H, Pryor-Koishi K, Kato T, Kowa H, Kurahashi H, Udagawa Y. Microarray Analysis of Differentially Expressed Fetal Genes in Placental Tissue Derived from Early and Late Onset Severe Pre-eclampsia. Placenta. 2007; 28: 487-497.http://dx.doi.org/10.1016/j.placenta.2006.05.010
Cox B, Leavey K, Nosi U, Wong F, Kingdom J. Placental transcriptome in development and pathology: expression, function, and methods of analysis. Am J Obstet Gynecol. 2015; 213 (Suppl):S138-151.http://dx.doi.org/10.1016/j.ajog.2015.07.046
Sõber S, Reiman M, Kikas T, Rull K, Inno R, Vaas P, Teesalu P, Marti JM, Mattila P, Laan M. Extensive shift in placental transcriptome profile in preeclampsia and placental origin of adverse pregnancy outcomes. Sci Rep. 2015; 5: 13336.ttp://dx.doi.org/10.1038/srep13336
Winn VD, Gormley M, Paquet AC, Kjaer-Sorensen K, Kramer A, Rumer KK, et al. Severe Preeclampsia-Related Changes in Gene Expression at the Maternal-Fetal Interface Include Sialic Acid-Binding Immunoglobulin-Like Lectin-6 and Pappalysin-2. Endocrinology. 2009; 150(1):452-462.http://dx.doi.org/10.1210/en.2008-0990
Enquobahrie DA, Meller M, Rice K, Psaty BM, Siscovick DS, Williams MA. Differential placental gene expression in preeclampsia. Am J Obst Gynecol. 2008; 199:566.e1-566.e11.http://dx.doi.org/10.1016/j.ajog.2008.04.020
Rajakumar A, Chua T, Handley DE, Bunce KD, Burke B, Hubel CA, et al. Maternal gene expression profiling during pregnancy and preeclampsia in human peripheral blood mononuclear cells. Placenta 2011; 32: 70-78.http://dx.doi.org/10.1016/j.placenta.2010.10.004
Su AI, Wiltshire T, Batalov S, Lapp H, Ching KA, Block D, et. al. A gene atlas of the mouse and human protein-encoding transcriptomes. Proc Natl Acad Sci USA. 2004; 101(16):6062-6067.http://dx.doi.org/10.1073/pnas.0400782101
Wu C, Orozco C, Boyer J, Leglise M, Goodale J, Batalov S, et al. BioGPS: an extensible and customizable portal for querying ang organizing gene annotation resources. Genome Biology 2009; 10(11): R130.http://dx.doi.org/10.1186/gb-2009-10-11-r130
Winn VD, Haimov-Kochman R, Paquet AC, Yang YJ, Madhusudhan MS, Gormley M, et. al. Gene expression profiling of the human maternal-fetal interface reveals dramatic changes between midgestation and term. Endocrinology 2007; 148:1059-1079.http://dx.doi.org/10.1210/en.2006-0683
Laresgoiti-Servitje E, Gomez-Lopez N. The pathophysiology of preeclampsia involves altered levels of angiogenic factors promoted by hypoxia and autoantibody-mediated mechanisms. Biol Reprod. 2012; 87(2):36.http://dx.doi.org/10.1095/biolreprod.112.099861
Jeha D, Usta I, Ghulmiyyah L, Nassar A. A review of the risks and consequences of adolescent pregnancy. J Neonatal Perinatal Med. 2015 Mar 12. [Epub ahead of print].http://dx.doi.org/10.3233/NPM-15814038
Martinussen MP, Bracken MB, Triche EW, Jacobsen GW, Risnes KR. Folic acid supplementation in early pregnancy and the risk of preeclampsia, small for gestational age offspring and preterm delivery. Eur J Obstet Gynecol Reprod Biol. 2015;195:94-99. http://dx.doi.org/10.1016/j.ejogrb.2015.09.022
Boeldt DS, Hankes AC, Alvarez RE, Khurshid N, Balistreri M, Grummer MA, Yi F, Bird IM. Pregnancy programming and preeclampsia: identifying a human endothelial model to study pregnancy-adapted endothelial function and endothelial adaptive failure in preeclamptic subjects. Adv Exp Med Biol. 2014; 814:27-47.http://dx.doi.org/10.1007/978-1-4939-1031-1_4
Murphy MS, Bytautiene E, Saade G, Smith GN. Alterations to the maternal circulating proteome after pre-eclampsia. Am J Obstet Gynecol. 2015 Oct 14. pii: S0002-9378(15)01271-5.
Monk D. Genomic imprinting in the human placenta. Am J Obstet Gynecol. 2015; 213(4 Suppl):S152-S162.http://dx.doi.org/10.1016/j.ajog.2015.06.032
Calicchio R, Doridot L, Miralles F, Méhats C, Vaiman D1. DNA methylation, an epigenetic mode of gene expression regulation in reproductive science. Curr Pharm Des. 2014; 20(11):1726-1750.http://dx.doi.org/10.2174/13816128113199990517
Ichiyanagi K, Okada N. Mobility Pathways for Vertebrate L1, L2, CR1, and RTE Clade Retrotransposons. Mol Biol Evol 2001; 25(6):1148-1157.http://dx.doi.org/10.1093/molbev/msn061
Khazina E, Weichenrieder O. Non-LTR retrotransposons encode noncanonical RRM domains in their first open reading frame. Proc Natl Acad Sci USA. 2009; 106:731-736.http://dx.doi.org/10.1073/pnas.0809964106
Schulz LC, Widmaier EP, Qiu J, Roberts RM. Effect of leptin on mouse trophoblast giant cells. Biol Reprod 2009; 80: 415-424.http://dx.doi.org/10.1095/biolreprod.108.073130
Cameo P, Bischof P, Calvo JC. Effect of leptin on progesterone, human chorionic gonadotropin, and interleukin-6 secretion by human term trophoblast cells in culture. Biol Reprod 2003; 68: 472-477.http://dx.doi.org/10.1095/biolreprod.102.006122
Schulz LC, Widmaier EP. The effect of leptin on mouse trophoblast cell invasion. Biol Reprod 2004; 71:1963-1967.http://dx.doi.org/10.1095/biolreprod.104.032722
Jansson N, Greenwood SL, Johansson BR, Powell TL, Jansson T. Leptin stimulates the activity of the system A amino acid transporter in human placental villous fragments. J Clin Endocrinol Metab 2003; 88: 1205-1211.http://dx.doi.org/10.1210/jc.2002-021332
Turgut A, Ozler A, Goruk NY, Tunç SY, Sak ME, Evsen MS, Evliyaoglu O, Gul T. Serum levels of the adipokines, free fatty acids, and oxidative stress markers in obese and non-obese preeclamptic patients. Clin Exp Obstet Gynecol. 2015; 42:473-479.
Henson MC, Castracane VD. Leptin in pregnancy: an update. Biology of Reproduction 2006; 74:218-229. http://dx.doi.org/10.1095/biolreprod.105.045120
Rahardjo B, Widjajanto E, Sujuti H, Keman K. Different levels of IL-1α, IL-6, TNF-α, NF-κB and PPAR-γ in monocyte cultures exposed by plasma preeclampsia and normotensive pregnancy. Pregnancy Hypertens. 2014; 4:187-193. http://dx.doi.org/10.1016/j.preghy.2014.03.001
Kaartokallio T, Cervera A, Kyllönen A, Laivuori K. Gene expression profiling of pre-eclamptic placentae by RNA sequencing.Adicionalmente. Sci Rep. 2015; 5:14107. http://dx.doi.org/10.1038/srep14107
Challier JC, Uzan S. The human placenta and its pathologies: focus on oxygen. Med Sci (Paris). 2003; 19(11):1111-1120. http://dx.doi.org/10.1051/medsci/200319111111
Louwen F, Muschol-Steinmetz C, Reinhard J, Reitter A, Yuan J. A lesson for cancer research: placental microarray gene analysis in Preeclampsia. Oncotarget. 2012; 3(8): 759-773. http://dx.doi.org/10.18632/oncotarget.595
Redman C. The six stages of pre-eclampsia. Pregnancy Hypertens. 2014; 4(3):246. http://dx.doi.org/10.1016/j.preghy.2014.04.020
Torrado J, Farro I, Zócalo Y, Farro F, Sosa C, Scasso S, Alonso J, Bia D. Preeclampsia Is Associated with Increased Central Aortic Pressure, Elastic Arteries Stiffness and Wave Reflections, and Resting and Recruitable Endothelial Dysfunction. Int J Hypertens. 2015; 2015:720683. http://dx.doi.org/10.1155/2015/720683
Reyna-Villasmil E, Brice-o-Pérez C, Torres-Cepeda D. Inmunología, inflamación y Preeclampsia. Revista de Obstetricia y Ginecología de Venezuela. 2009; 69(2): 97-110.
Devergne O, Coulomb-L'Herminé A, Capel F, Moussa M, Capron, F. Expression of the Epstein-Barr virus-induced gene 3, an interleukin-12 p40-related molecule, throughout human pregnancy: involvement of syncytiotrophoblasts and extravillous trophoblasts. The American Journal of Pathology. 2001; 159(5): 1763-1776. http://dx.doi.org/10.1016/S0002-9440(10)63023-4
Van Der Hoorn ML, Keijser R, Ris-Stalpers C, Afink G, Claas FH, Van Der Post JA et al. Increased EBI3 expression in placentas of preeclamptic patients. Journal of Reproductive Immunology. 2010; 81: 1-61. http://dx.doi.org/10.1016/j.jri.2010.06.129
Guo J, Tian T, Lu D, Xia G, Wang H, Dong M. Alterations of maternal serum and placental follistatin-like 3 and myostatin in pre-eclampsia. Journal of Obstetrics and Gynecology Research. 2012; 38(7): 988-996. http://dx.doi.org/10.1111/j.1447-0756.2011.01823.x
Kleinrouweler CE, Van Uitert M, Moerland PD, Ris-Stalpers C, Van der Post JAM, Afink GB. Differentially expressed genes in the Pre-eclamptic placenta: A systematic review and meta-analysis. PLoS ONE. 2013; 8(7): e68991. http://dx.doi.org/10.1371/journal.pone.0068991
Dijke PT, Arthur HM. Extracellular control of TGF_ signaling in vascular development and disease. Nature Reviews. 2007; 8: 857-869. http://dx.doi.org/10.1038/nrm2262
Lowe SA, Bowyer L, Lust K, McMahon LP, Morton M, North RA, Paech M, Said JM. SOMANZ guidelines for the management of hypertensive disorders of pregnancy 2014. Aust N Z J Obstet Gynaecol. 2015; 55(5):e1-e29. http://dx.doi.org/10.1111/ajo.12399
Enquobahrie DA, Meller M, Rice K, Psaty BM, Siscovick DS, Williams MA. Differential placental gene expression in preeclampsia. American J Obstetrics & Gynecology 2008; 199:566.e1-566.e11. http://dx.doi.org/10.1016/j.ajog.2008.04.020