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Genomewide Association between GLCCI1 and Response to Glucocorticoid Therapy in Asthma

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Jorge Valencia Rico
Daniel Vélez Díaz

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Genomewide Association between GLCCI1 and Response to Glucocorticoid Therapy in Asthma

  1. 1. Genomewide Association between GLCCI1 and Response to Glucocorticoid Therapy in Asthma Kelan G. Tantisira, M.D., Jessica Lasky-Su, Sc.D., Michishige Harada, Ph.D., Amy Murphy, Ph.D., Augusto A. Litonjua, M.D., Blanca E. Himes, Ph.D., Christoph Lange, Ph.D., Ross Lazarus, M.B., B.S., Jody Sylvia, B.S., Barbara Klanderman, Ph.D., Qing Ling Duan, Ph.D., Weiliang Qiu, Ph.D., Tomomitsu Hirota, Ph.D., Fernando D. Martinez, M.D., David Mauger, Ph.D., Christine Sorkness, Pharm.D., Stanley Szefler, M.D., Stephen C. Lazarus, M.D., Robert F. Lemanske, Jr., M.D., Stephen P. Peters, M.D., Ph.D., John J. Lima, Pharm.D., Yusuke Nakamura, M.D., Ph.D., Mayumi Tamari, M.D., Ph.D., and Scott T. Weiss, M.D. Jorge Valencia Rico Daniel Vélez Díaz Universidad Pontificia Bolivariana School of Health Sciences February / 2012
  2. 2. INTRODUCTION
  3. 3. INTRODUCTION The key treatments for most people with asthma are glucocorticoid and other anti-inflammatory drugs. Not only do steroids and anti-inflammatory drugs help people gain better asthma control, but these asthma drugs help to prevent asthma attacks. INHALER- ASTHMA http://www1.imperial.ac.uk/nhli/respiratory/pharmacologytoxicology/pharmacology/ ASTHMA PATIENT http://abcnews.go.com/topics/lifestyle/health/albuterol.htm
  4. 4. INTRODUCTION The response to treatment for asthma is characterized by wide interindividual variability, with a significant number of patients who have no response. They think that a genomewide association study would reveal pharmacogenetic determinants of the response to inhaled glucocorticoids. ASTHMA http://www.infoenfermedades.com/asma/
  5. 5. INTRODUCTION Asthma is a chronic disease that affects your airways. If you have asthma, the inside walls of your airways become sore and swollen. That makes them very sensitive, and they may react strongly to things that you are allergic to or find irritating. When your airways react, they get narrower and your lungs get less air. This can cause wheezing, coughing, chest tightness and trouble breathing, especially early in the morning or at night. ASTHMA IN LUNGS http://medicine.med.nyu.edu/pulmonary/node/673 ASTHMA
  6. 6. INTRODUCTION Corticosteroids are drugs closely related to cortisol, a hormone which is naturally produced in the adrenal cortex (the outer layer of the adrenal gland). Corticosteroids act on the immune system by blocking the production of substances that trigger allergic and inflammatory actions, such as prostaglandins. CORTICOSTEROIDS http://corticosteroides.blogspot.com/2010/03/los-corticosteroides.html CORTICOSTEROIDS
  7. 7. INTRODUCTION Glucocorticoid-induced transcript 1 protein is a protein that in humans is encoded by the GLCCI1 gene. Its expression is associated with the use of glucocorticoids, therefore this study included a good number of participants and observed its response and its relationship with FEV1. GENES http://radioamericahn.net/identifican-un-gen-que-produce-envejecimiento-acelerado-hereditario/ GLCCI1
  8. 8. INTRODUCTION Asthma is a complex genetic syndrome that affects 300 million people and the problem is that treatment response is also genetically complex and variable. Up to 40% of asthma patients no response to treatment. Glucocorticoids increase the expression of GLLC1 and it is interesting that the functional SNP rs37973 (single nucleotide polymorphisms), which down-regulates expression GLCCI1 ASTHMA PUMPS http://www.yourstuffwork.com/2011/11/what-is-asthma.html RELATION
  9. 9. GENERAL OBJECTIVE
  10. 10. GENERAL OBJECTIVE A genomewide association study will identify novel variants associated with the response to inhaled glucocorticoids for asthma. ASTHMATIC KIDS http://www.allergizer.com/50226711/asthmatic_kids_with_food_allergies_need_second_dose_of_epinephrine.php
  11. 11. MATERIALES Y MÉTODOS
  12. 12. MATERIALES Y MÉTODOS La Figura 1 proporciona una visión general del diseño del estudio.  DISEÑO DEL ESTUDIO Y DETECCIÓN Y LA REPLICACIÓN COHORTE .
  13. 13. MATERIALES Y MÉTODOS En el CAMP (Programa de Manejo del Asma  Infantil) un estudio aleatorizado, controlado, se estudiaron 1041 niños con asma que tenían entre 5 a 12 años de edad y que recibieron tratamiento de la ONU durante un periodo medio de 4,6 años. A los niños se les asignó al azar tratamiento con budesonida inhalada, nedocromil sodio, o un placebo. A partir de este estudio, se seleccionaron 422 blancos, no hispanos y sus padres para determinar el genotipo de la BeadChip HumanHap550 v3 (Illumina). De este grupo, 118 tríos fueron asignados al azar con budesonida. En estos tríos se evaluó la respuesta de glucocorticoides de terapia.
  14. 14. MATERIALES Y MÉTODOS La Tabla 1 muestra las características de las poblaciones y por escrito se hizo el consentimiento informado para participar en el estudio.
  15. 15. RESPUESTAS A LOS FÁRMACOS Y LOS RESULTADOS En CAMP, las mayores diferencias en el FEV1 de que se le atribuyeron a la budesonida se observaron durante la los primeros 16 meses de tratamiento. Calcularon el cambio en el FEV1 como la diferencia entre el FEV1 al inicio y durante las cinco visitas de seguimiento que se llevó a cabo dentro de los 16 meses después de la aleatorización (FEV1treatment-FEV1baseline).  MATERIALES Y MÉTODOS ASMA http://gmmsalud.ucoz.es/index/0-24
  16. 16. MATERIALES Y MÉTODOS Los datos fueron limpiados, y 547.645 marcadores (97,54%) pasaron el control de calidad métrica. La genotipificación fue un éxito en 1169 participantes CAMP. El promedio tasa de terminación de la genotipificación por participante en el estudio era del 99,75%. Trece SNPs que reunió los criterios se genotipó con el uso de Sequenom en las cohortes de replicación, el funcional rs37973 SNP se genotipó con el uso de TaqMan (AppliedBiosystems). Las tasas promedio de terminación fueron superiores al 95%. GENOTIPIFICACIÓN Y CONTROL DE CALIDAD GENÓMICA GEN http://www.blogodisea.com/2011/genetica-molecular/ciencia/
  17. 17. MATERIALES Y MÉTODOS Los perfiles de expresión de GLCCI1 en las células linfoblásticas Se correlacionaron rs37972 rs37973 con los cambios mediados por dexametasona en la expresión de de un gen (GLCCI1) en las líneas celulares linfoblásticas en 147 probandos blancos CAMP. Las Asociaciones de la expresión de GLCCI con el genotipo se determinaron por medio del análisis lineal de regresión. El Gen GLCCI1 resultó estar altamente implicado en pulmón y tejidos linfoides. VALIDACIÓN FUNCIONAL
  18. 18. MATERIALES Y MÉTODOS Ensayo de la luciferasa Se construyeron plásmidos reportero de luciferasa por clonación de fragmentos de ADN amplificados humanos mediante la reacción en cadena de la polimerasa. Los productos para potenciar el ensayo que contienen la secuencia de tipo salvaje, la rs37972 o rs37973, o el haplotipo rs37972-rs37973 fueron clonados en la región superior del vector de la luciferasa pGL4.23- (Promega). ENSAYO DE LA LUCIFERASA
  19. 19. Se confirmó las diferencias alélicas en la actividad del promotor en la células B humanas línea Raji con el uso del vector pGL3-base. Las células se transfectaron con el reportero y con el vectorPRL-TK Renillaluciferase como un control de la normalización con el uso del FuGENE 6 transfección reactivo. MATERIALES Y MÉTODOS ENSAYO DE LA LUCIFERASA LUCIFERASA http://es.wikipedia.org/wiki/Luciferasa
  20. 20. MATERIALES Y MÉTODOS El cambio de la movilidad electroforética se llevó a cabo con el uso de sistemas de gel de cambio (Promega) de acuerdo con las instrucciones del fabricante. ENSAYO DE CAMBIO DE LA MOVILIDAD ELECTROFORÉTICA Los oligonucleotidos de la doble cadena rs37973 fueron marcados en el extremo con [γ-32P] ATP con el uso de la T4 polinucleótido quinasa, se mezclaron con extractos nucleares de Jurkat, Raji y células humanas monociticasleucemicas (THP-1). EQUIPO DE ELECTROFORESIS http://www.cepazahar.org/recursos/
  21. 21. RESULTADOS
  22. 22. RESULTADOS ESTUDIO INICIAL DE ASOCIACIÓN GENÓMICA Y ANÁLISIS DE REPLICACIÓN Comparando con las otras 3 poblaciones, las personas del CAMP and CARE eran más jóvenes y predominantemente eran hombres con una mejor función pulmonar. En cada ensayo, el VEF1 aumentó significativamente después de la administración de glucocorticoides. Después de la selección, los 100 SNPs de mayor potencia fueron evaluados para la asociación. Cada SNP se encontraba en equilibrio de Hardy-Weinberg.  
  23. 23. RESULTADOS
  24. 24. RESULTADOS Un SNP, rs37972, se asoció con elcambio en el VEF1 en tres de las cuatro poblaciones de replicación con un valor de p canónica de: P= 0,05 en CAMP P = 0,04 en CARE. P = 0,03 en SOCS y SLIC y prueba LOCCS, P = 0,08 en el Estudio para Adultos. Valor de p ajustado siguió siendo significativa (p = 0,0085).
  25. 25. RESULTADOS <ul><li>La otra variante del GLCCI1, el rs37973( modula la act transcripcional), esta en desequilibrio con el rs37972. </li></ul><ul><li>La expresión del GLCCI1 se midió en un panel de tejidos humanos por medio de una transcriptasa inversa con G3PDH. </li></ul><ul><li>GLCCI1 tuvo una alta expresión en pulmones, células B,T y natural Killer. (En asmáticos tratados con glucorticoides) </li></ul>CARACTERIZACIÓN FUNCIONAL
  26. 26. RESULTADOS <ul><li>En CAMP, la dexametasona incrementó la expresión. </li></ul><ul><li>Para saber que SNP afecta GLCCI1 se construyeron los plásmidos reporteros de luciferasa que contenían fragmentos de rs 37972 y rs 37973 o ambos </li></ul><ul><li>El rs 37972T- rs37973G (minor)= Menor transcripción </li></ul><ul><li>El rs 37972C- rs37973A (major)= Mayor transcripción en las 3 lineas celulares estudiadas. </li></ul>CARACTERIZACIÓN FUNCIONAL
  27. 27. RESULTADOS
  28. 28. RESULTADOS CARACTERIZACIÓN FUNCIONAL <ul><li>Se genotipó el rs 37973 funcional y se realizó un análisis con el cambio del VEF1 después de la terapia con los glucocorticoides inhalados. </li></ul><ul><li>Se concluyó que el SNP rs 37973 disminuía el VEF1 y que éste valor aumentaba en pacientes que eran homocigotos para el tipo salvaje en comparación con los que eran homocigotos para el tipo mutante </li></ul>
  29. 29. DISCUSSION
  30. 30. DISCUSSION AUTHOR OPINION AGREEMENT DISAGREEMENT CHAPMAN GLCCI1 may be an early marker of glucocorticoid-induced apoptosis. X HO Apoptosis is a key mechanism through which glucocorticoids resolve lymphocytic and eosinophilic inflammation in asthma. X
  31. 31. DISCUSSION AUTHOR OPINION AGREEMENT DISAGREEMENT LANGE The statistical power was further enhanced by the use of repeated measures of the outcome variable during FBAT screening of the CAMP population. X CHAPMAN Identified several differentially expressed sequenced tags in glucocorticoid-sensitive and glucocorticoid-resistant thymoma- derived cell lines after the administration of dexamethasone. X
  32. 32. CONCLUSIONS
  33. 33. CONCLUSIONS ASTHMA http://www.georgecoller.pwp.blueyonder.co.uk/asthma-facts.html One of the main challenges talking about asthma for medicine is to eliminate the many barriers to control the disease, in that field this article is important to recognize some of that barriers that generated decrements in the response to inhaled glucocorticoids in patients with asthma. Patients treated with Triamcinolone have smalls changes in FEV 1 because their have a low bioavailability that reduce their systemic effects and they suffer the first pass metabolism in the liver, then little drug reach the systemic circulation. In that cases is better uses other glucocorticoids like bludesonide or fluticasone.
  34. 34. CONCLUSIONS The number of functions that glucocorticoids have open a large field of research to find new solutions to diseases that occur in much of the population. Many patients come to treatment with inhaled glucocorticoids and the misfortune that the effect on their bodies is minimal or zero due to the great variability presented by each individual. For this reason it is right and necessary to delve into topics such as these in order to improve the quality of life of patients. ASTHMA http://www.mdnews.com/media/901187/boyholdinginhaler_250.jpg
  35. 35. BIBLIOGRAPHY
  36. 36. BIBLIOGRAPHY The New England Journal of Medicine. Genowide Association between GLCCI1 and Response to Glucocorticoid Theraphy in Asthma. September 29, 2011. Zubiria de Salgado E. , ASMA BRONQUIAL, Segunda Edición. Editorial Médica Panamericana , capítulo 28, páginas 457-454 Brasó J, Martínez G. &quot;Manual de alergia clinica&quot;. Masson. URL disponible en :  www.books.google.com
  37. 37. MAPAS CONCEPTUALES
  38. 38. JORGE VALENCIA RICO
  39. 39. DANIEL VÉLEZ DÍAZ
  40. 41. THANKS…

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