Polimorfismos de la región promotora del gen de la IL-10 y artritis reumatoide en una población colombiana
Palabras clave:
interleucinas, interleucina-10, polimorfismo genético, artritis reumatoide, polimorfismo de nucleótido simple
Resumen
Introducción. La artritis reumatoide es una enfermedad inflamatoria con un predominio de la actividad de las células TH1 CD4+. La interleucina-10, presente en altas concentraciones en suero y líquido sinovial de pacientes con artritis reumatoide, tiene una marcada actividad antinflamatoria, al mismo tiempo que estimula las células B y la generación de autoanticuerpos. La producción de la interleucina-10 está bajo control genético.
Objetivo. En este estudio analizamos los polimorfismos de la región promotora de la interleucina-10 -1082, -819 y -592 en pacientes con artritis reumatoide y en una población control, y su asociación con edad de inicio de la enfermedad, presencia y títulos de factor reumatoideo e historia de reemplazo articular.
Materiales y métodos. Se estudiaron 102 pacientes con artritis reumatoide y 102 controles. La genotipificación se realizó por reacción en cadena de la polimerasa, iniciador específico de secuencia. Los tres polimorfismos están en marcado desequilibrio de unión y forman tres haplotipos -1082A/-819C/-592C, -1082A/-819T/-592A y -1082G/-819C/-592C.
Resultados. No se encontró asociación de la artritis reumatoide con las diferentes variaciones alélicas, haplotípicas ni genotípicas del promotor de la interleucina-10. Tampoco se encontraron diferencias significativas con inicio de la enfermedad, presencia y títulos de factor reumatoideo e historia de reemplazo articular.
Conclusiones. La interleucina-10 es uno de los principales reguladores de la respuesta inmune y por lo tanto podría jugar un papel importante en la patogénesis de la artritis reumatoide; sin embargo, nuestros resultados no dan evidencia de una asociación genética entre los polimorfismos estudiados y el desarrollo o gravedad de la artritis reumatoide.
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Referencias bibliográficas
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18. Panayi GS, Corrigall VM, Pitzalis C. Patogenesis de la artritis reumatoide. El papel de las células T y otras bestias. Rheum Dis Clin North Am (Edición Española) 2001;3:55-76.
19. Van Roon JA, Wijngaarden S, Labefer FP, Damen C, Van der Winkel JG, Bulsma JW. Interleukin 10 treatment of patients with rheumatoid arthritis enhances Fcg receptor expression on monocytes and responsiveness to immune complex stimulation. J Rheumatol 2003;30:648-51.
20. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31:315-24.
21. Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucl Acids Res 1988;16:1215.
22. Mullighan CG, Marshall SE, Bunce M, Welsh KI. Variation in immunoregulatory genes determines the clinical phenotype of common variable immunodeficiency. Genes Immun 1999;1:137-48.
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24. Schneider S, Roessli D, Excoffier L. Arlequin version 2000. A software for population genetics data analysis. Genetics and Biometry Laboratory. Geneva: University of Geneva; 2000.
25. Hartl DL, Clark AG. Principles of population genetics. 2nd ed. Sinauer Sunderland-Massachsetts: Associate Inc Publishers; 1989. p.293-8.
26. Houssiau FA, Lefebre C, van den Berghe M, Lambert M, Devogelaer JP, Reanuld JC. Serum interleukin 10 titers in systemic lupus erythematosus reflect disease activity. Lupus 1995;4:393-5.
27. Llorente L, Richaud-Patin Y, Fior R, Alcocer-Varela J, Wijdenes J, Fourrier BM et al. In vivo production of interleukin-10 by non-T cells in rheumatoid arthritis, Sjogren's Syndrome and systemic lupus erythematosus: A potential mechanism of B lymphocyte hyperactivity and autoimmunity. Arthritis Rheum 1994;37:1647-55.
28. Anaya JM, Correa PA, Herrera M, Eskdale J, Gallagher G. IL-10 influences autoimmune response in primary Sjögren's syndrome and is linked to IL-10 gene polymorphism. J Rheumatol 2002;29:1874-6.
29. Fortis C, Foppoli M, Gianotti L, Galle L, Citterio G, Consogno G et al. Increased Interleukin-10 serum levels in patients with solid tumors. Cancer Lett 1996;104:1-5.
30. Westendorp RD, Langermans JA, Huizinga TW, Verweij CL, Sturk A. Genetic influence on cytokine production in meningococcal disease. Lancet 1997;349:1912-3.
31. Koss K, Satsangi J, Fanning GC, Welsh KI, Jewell DP. Cytokine (TNFa, LTa and IL-10) polymorphisms in inflammatory bowel diseases and normal controls: differential effects on production and allele frequencies. Genes Immun 2000;1:185-90.
32. Reich K, Garbe C, Blaschke V, Maurer C, Middel P, Westphal G et al. Response of psoriasis to interleukin- 10 associated with suppression of cutaneous type 1 inflammation, downregulation of the epidermal interleukin 8/CXCR2 pathway and normalization of keratinocyte maturation. J Invest Dermatol 2001;116:319-29.
33. Lim S, Crawley E, Woo P, Barnes PJ. Haplotype associated with low interleukin 10 production in patients with severe asthma. Lancet 1998;352:113.
34. Schulze-Koops H, Davis LS, Kavanaugh AF, Lipsky PE. Elevated cytokine messenger RNA levels in the peripheral blood of patients with rheumatoid arthritis suggest different degrees of myeloid cell activation. Arthritis Rheum 1997;40:639-47.
35. Isomäki P, Luukkainen R, Saario R, Toivanen P, Punnonen J. Interleukin-10 functions as an antiinflammatory cytokine in rheumatoid synovium. Arthritis Rheum 1996;39:386-95.
36. Perez L, Orte J, Brieva JA. Terminal differentiation of spontaneous rheumatoid factor-secreting B cells from rheumatoid arthritis patients depends on endogenous interleukin-10. Arthritis Rheum 1995;38:1771-6.
37. Reparon-Schuijt CC, van Esch WE, van Kooten C, Levarht EW, Breedveld FC, Verweij CL. Functional analysis of rheumatoid factor producing B cells from the synovial fluid of rheumatoid arthritis patients. Arthritis Rheum 1998;41:2211-20.
38. Hoffmann SC, Stanley ER, Cox ED, Craighead N, DiMercurio BS, Koziol DE et al. Association of cytokine polymorphic inheritance and in vitro cytokine production in anti CD3/CD28- stimulated peripheral blood lymphocytes. Transplantation 2001;72:1444-50.
39. Huizinga TW, Keijsers V, Yanni G, Hall M, Ramage W, Lanchbury J et al. Are differences in interleukin 10 production associated with joint damage? Rheumatology (Oxford) 2000;39:1180-8.
40. Coakley G, Mok CC, Hajeer AH, Ollier WER, Turner D, Sinnott PJ. Interleukin-10 promoter polymorphisms in rheumatoid arthritis and Felty's syndrome. Br J Rheumatol 1998;37:988-91.
41. Cantagrel A, Navaux F, Loubet-lescoulié P, Nourhasehemi F, Enault G, Abbal M et al. Interleukin- 1â, interleukin-1 receptor antagonist, interleukin-4 and interleukin-10 gene polymorphisms. Arthritis Rheum 1999;42:1093-100.
42. Martínez A, Pascual M, Pascual-Salcedo D, Balsa A, Martin J, de la Concha EG. Genetic polymorphisms in Spanish rheumatoid arthritis patients: an association and linkage study. Genes Immun 2003;4:117-21.
43. Padyukov L, Hytönen AM, Smolnikova M, Hahn-Zoric M, Nilsson N, Hanson LA et al. Polymorphism in promoter region of IL-10 gene is associated with rheumatoid arthritis in women. J Rheumatol 2004;31:422-5.
44. Hajeer AH, Lazarus M, Turner D, Mageed RA, Vencovsky J, Sinnott P et al. IL-10 gene promoter polymorphisms in rheumatoid arthritis. Scan J Rheumatol 1998;27:142-5.
45. Pawlik A, Kurzawski M, Szlarz BG, Hercynska M, Drozdzik M. Interleukin-10 promoter polymorphism in patients with rheumatoid arthritis. Clin Rheumatol 2005;24:480-4.
46. Eskdale J, McNicholl J, Wordsworth P, Jonas B, Huizinga T, Field M et al. Interleukin-10 microsatellite polymorphisms and IL-10 locus alleles in rheumatoid arthritis susceptibility (letter). Lancet 1998;352:1282-3.
47. MacKay K, Milicic A, Lee D, Tikly M, Laval S, Shatford J et al. Rheumatoid arthritis susceptibility and interleukin-10. Rheumatology 2003;42:149-53.
48. Lard LR, van Gaalen FA, Schonkeren JJ, Pieterman EI, Toeken G, Kos K et al. Association of the -2849 interleukin-10 promoter polymorphism with autoantibody production and joint destruction in rheumatoid arthritis. Arthritis Rheum 2003;48:1841-8.
49. Mörmann M, Rieth H, Hua TD, Assohou C, Roupelieva M, Hu SL et al. Mosaics of gene variations in the Interleukin-10 gene promoter affect interleukin-10 production depending on the stimulation used. Genes Immun 2004;5:246-55.
50. Mok CC, Lanchbury JS, Chan DW, Lau CS. Interleukin-10 promoter polymorphisms in southern Chinese patients with systemic lupus erythematosus. Arthritis Rheum 1998;41:1090-5.
51. Reynard MP, Turner D, Navarrete CV. Allele frequencies of polymorphisms of the tumor necrosis factor-a, interleukin-10, interferon-g and interleukin -2 genes in a North European Caucasoid group from the UK. Eur J Immunogenet 2000;27:241-9.
52. Origuchi, Kawasaki E, Ide A, Kamachi M, Tanaka F, Ida H et al. Correlation between interleukin 10 promoter region polymorphisms and clinical manifestations in Japanese patients with Sjogren's syndrome. Ann Rheum Dis 2003;62:1117-8.
53. Anaya JM, Correa PA, Herrera M, Eskdale, Gallagher G. Interleukin 10 (IL-10) influences autoinmmune response in primary Sjögrens´s syndrome and is linked to IL-10 gene polymorphisms. J Rheumatol 2002;29:1874-6
54. Henao MI, Montes C, París SC, García LF. Cytokines ene polymorphisms in Colombian patients with different clinical presentations of tuberculosis. Tuberculosis2006;86:11-9
55. Larcombe L, Rempel JD, Dembinski I, Tinckam K, Rigatto C, Nickerson P. Differential cytokine genotype frequencies among Canadian aboriginal and Caucasian populations. Genes Immun 2005;6:140-4.
56. Torkildsen O, Utsi E, Harbo HF, Mellgren SI, Vedeler CA, Myhr KM. Ethnic variations of IL-10 polymorphisms in a Sami and Norwegian population. Scan J Immunol 2005;62:71-4.
2. Newton JL, Harney SM, Wordsworth BP, Brown MA. A review of the MHC genetics of rheumatoid arthritis. Genes Immun 2004;5:151-7.
3. Deighton CM, Walter DJ, Griffiths ID, Robertos DF. The contribution of HLA to rheumatoid arthritis. Clin Genet 1989; 36:178-82.
4. Camargo JF, Correa PA, Vélez S, Anaya JM. Citocinas en artritis reumatoide. En: Ramírez LA, Anaya JM, editores. Artritis Reumatoide. 2ª edición. Bogotá: Editorial Edimeco S.A.; 2004. p.53-80.
5. Choy EH, Panayi GS. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med 2001;344:907-16.
6. Szekannez Z, Koch AE. Cytokines. In: Ruddy S, Harris ED, Sledge CB, Budd RC, Sergent JS. Textbook of Rheumatology. 6ª Ed. Philadelphia: W.B. Saunders Company; 2001. p.275-87.
7. Arend WP, Gabay C. Cytokines in the rheumatic diseases. Rheum Dis Clin North Am 2004;30:41-67.
8. Moore KW, de Waal Malefyt R, Coffman RL, O'Garra A. Interleukin-10 and the interleukin -10 Receptor. Annu Rev Immunol 2001;19:683-765.
9. Van Roon JA, Lafeber FP, Bijlsma JW. Synergistic activity of interleukin-4 and interleukin-10 in suppression of inflammation and joint destruction in rheumatoid arthritis. Arthritis Rheum 2001;44:3-12.
10. Katsikis PD, Chu CO, Brennan FM, Maini RN, Feldman M. Immunoregulatory role of interleukin 10 in rheumatoid arthritis. J Exp Med 1994;179:1517-27.
11. Cush JJ, Splawski JB, Thomas R, McFarlin JE, Schulza-Koops H, Davis LS et al. Elevated interleukin 10 levels in patients with rheumatoid arthritis. Arthritis Rheum 1995;38:96-104.
12. Rousset G, Garcia E, Defrance T, Peronne C, Vezzio N, Hsu DH et al. Interleukin-10 is a potent growth and differentiation factor for activated human B lymphocytes. Proc Natl Acad Sc USA 1992;89:1890-3.
13. Westendorp RGJ, Langermans JA, Huizinga TWJ, Elouali AH, Verweij CL, Boomsma DI et al. Genetic influence on cytokine production and fatal meningococcal disease. Lancet 1997;349:170-3.
14. Turner DM, Williams DM, Sankarán D, Lazarus M, Sinnott PJ, Hutchinson IV. An investigation of polymorphism in the interleukin-10 gene promoter. Eur J Inmunogenet 1997;24:1-8.
15. Asadullah K, Sterry W, Volk HD. Interleukin-10 therapy. Review of a new approach. Pharmacol Rev 2003;55:241-69.
16. Westendorp RG, van Dunne G FM, Kirkwood TB, Helmerhorst FM, Huizinga TW. Optimizing human fertility and survival (letter). Nat Med 2002;7:873.
17. Suárez A, Castro P, Alonso R, Mozo L, Gutiérrez C. Interindividual variations in constitutive interleukin-10 messenger RNA and protein levels and their association with genetic polymorphisms. Transplantation 2003;75:711-7.
18. Panayi GS, Corrigall VM, Pitzalis C. Patogenesis de la artritis reumatoide. El papel de las células T y otras bestias. Rheum Dis Clin North Am (Edición Española) 2001;3:55-76.
19. Van Roon JA, Wijngaarden S, Labefer FP, Damen C, Van der Winkel JG, Bulsma JW. Interleukin 10 treatment of patients with rheumatoid arthritis enhances Fcg receptor expression on monocytes and responsiveness to immune complex stimulation. J Rheumatol 2003;30:648-51.
20. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31:315-24.
21. Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucl Acids Res 1988;16:1215.
22. Mullighan CG, Marshall SE, Bunce M, Welsh KI. Variation in immunoregulatory genes determines the clinical phenotype of common variable immunodeficiency. Genes Immun 1999;1:137-48.
23. Daniel WW. Bioestadística. Base para el análisis de las ciencias de la salud. 4ª edición. México D.F: Edit. Limusa Wiley; 2002. p.571-657.
24. Schneider S, Roessli D, Excoffier L. Arlequin version 2000. A software for population genetics data analysis. Genetics and Biometry Laboratory. Geneva: University of Geneva; 2000.
25. Hartl DL, Clark AG. Principles of population genetics. 2nd ed. Sinauer Sunderland-Massachsetts: Associate Inc Publishers; 1989. p.293-8.
26. Houssiau FA, Lefebre C, van den Berghe M, Lambert M, Devogelaer JP, Reanuld JC. Serum interleukin 10 titers in systemic lupus erythematosus reflect disease activity. Lupus 1995;4:393-5.
27. Llorente L, Richaud-Patin Y, Fior R, Alcocer-Varela J, Wijdenes J, Fourrier BM et al. In vivo production of interleukin-10 by non-T cells in rheumatoid arthritis, Sjogren's Syndrome and systemic lupus erythematosus: A potential mechanism of B lymphocyte hyperactivity and autoimmunity. Arthritis Rheum 1994;37:1647-55.
28. Anaya JM, Correa PA, Herrera M, Eskdale J, Gallagher G. IL-10 influences autoimmune response in primary Sjögren's syndrome and is linked to IL-10 gene polymorphism. J Rheumatol 2002;29:1874-6.
29. Fortis C, Foppoli M, Gianotti L, Galle L, Citterio G, Consogno G et al. Increased Interleukin-10 serum levels in patients with solid tumors. Cancer Lett 1996;104:1-5.
30. Westendorp RD, Langermans JA, Huizinga TW, Verweij CL, Sturk A. Genetic influence on cytokine production in meningococcal disease. Lancet 1997;349:1912-3.
31. Koss K, Satsangi J, Fanning GC, Welsh KI, Jewell DP. Cytokine (TNFa, LTa and IL-10) polymorphisms in inflammatory bowel diseases and normal controls: differential effects on production and allele frequencies. Genes Immun 2000;1:185-90.
32. Reich K, Garbe C, Blaschke V, Maurer C, Middel P, Westphal G et al. Response of psoriasis to interleukin- 10 associated with suppression of cutaneous type 1 inflammation, downregulation of the epidermal interleukin 8/CXCR2 pathway and normalization of keratinocyte maturation. J Invest Dermatol 2001;116:319-29.
33. Lim S, Crawley E, Woo P, Barnes PJ. Haplotype associated with low interleukin 10 production in patients with severe asthma. Lancet 1998;352:113.
34. Schulze-Koops H, Davis LS, Kavanaugh AF, Lipsky PE. Elevated cytokine messenger RNA levels in the peripheral blood of patients with rheumatoid arthritis suggest different degrees of myeloid cell activation. Arthritis Rheum 1997;40:639-47.
35. Isomäki P, Luukkainen R, Saario R, Toivanen P, Punnonen J. Interleukin-10 functions as an antiinflammatory cytokine in rheumatoid synovium. Arthritis Rheum 1996;39:386-95.
36. Perez L, Orte J, Brieva JA. Terminal differentiation of spontaneous rheumatoid factor-secreting B cells from rheumatoid arthritis patients depends on endogenous interleukin-10. Arthritis Rheum 1995;38:1771-6.
37. Reparon-Schuijt CC, van Esch WE, van Kooten C, Levarht EW, Breedveld FC, Verweij CL. Functional analysis of rheumatoid factor producing B cells from the synovial fluid of rheumatoid arthritis patients. Arthritis Rheum 1998;41:2211-20.
38. Hoffmann SC, Stanley ER, Cox ED, Craighead N, DiMercurio BS, Koziol DE et al. Association of cytokine polymorphic inheritance and in vitro cytokine production in anti CD3/CD28- stimulated peripheral blood lymphocytes. Transplantation 2001;72:1444-50.
39. Huizinga TW, Keijsers V, Yanni G, Hall M, Ramage W, Lanchbury J et al. Are differences in interleukin 10 production associated with joint damage? Rheumatology (Oxford) 2000;39:1180-8.
40. Coakley G, Mok CC, Hajeer AH, Ollier WER, Turner D, Sinnott PJ. Interleukin-10 promoter polymorphisms in rheumatoid arthritis and Felty's syndrome. Br J Rheumatol 1998;37:988-91.
41. Cantagrel A, Navaux F, Loubet-lescoulié P, Nourhasehemi F, Enault G, Abbal M et al. Interleukin- 1â, interleukin-1 receptor antagonist, interleukin-4 and interleukin-10 gene polymorphisms. Arthritis Rheum 1999;42:1093-100.
42. Martínez A, Pascual M, Pascual-Salcedo D, Balsa A, Martin J, de la Concha EG. Genetic polymorphisms in Spanish rheumatoid arthritis patients: an association and linkage study. Genes Immun 2003;4:117-21.
43. Padyukov L, Hytönen AM, Smolnikova M, Hahn-Zoric M, Nilsson N, Hanson LA et al. Polymorphism in promoter region of IL-10 gene is associated with rheumatoid arthritis in women. J Rheumatol 2004;31:422-5.
44. Hajeer AH, Lazarus M, Turner D, Mageed RA, Vencovsky J, Sinnott P et al. IL-10 gene promoter polymorphisms in rheumatoid arthritis. Scan J Rheumatol 1998;27:142-5.
45. Pawlik A, Kurzawski M, Szlarz BG, Hercynska M, Drozdzik M. Interleukin-10 promoter polymorphism in patients with rheumatoid arthritis. Clin Rheumatol 2005;24:480-4.
46. Eskdale J, McNicholl J, Wordsworth P, Jonas B, Huizinga T, Field M et al. Interleukin-10 microsatellite polymorphisms and IL-10 locus alleles in rheumatoid arthritis susceptibility (letter). Lancet 1998;352:1282-3.
47. MacKay K, Milicic A, Lee D, Tikly M, Laval S, Shatford J et al. Rheumatoid arthritis susceptibility and interleukin-10. Rheumatology 2003;42:149-53.
48. Lard LR, van Gaalen FA, Schonkeren JJ, Pieterman EI, Toeken G, Kos K et al. Association of the -2849 interleukin-10 promoter polymorphism with autoantibody production and joint destruction in rheumatoid arthritis. Arthritis Rheum 2003;48:1841-8.
49. Mörmann M, Rieth H, Hua TD, Assohou C, Roupelieva M, Hu SL et al. Mosaics of gene variations in the Interleukin-10 gene promoter affect interleukin-10 production depending on the stimulation used. Genes Immun 2004;5:246-55.
50. Mok CC, Lanchbury JS, Chan DW, Lau CS. Interleukin-10 promoter polymorphisms in southern Chinese patients with systemic lupus erythematosus. Arthritis Rheum 1998;41:1090-5.
51. Reynard MP, Turner D, Navarrete CV. Allele frequencies of polymorphisms of the tumor necrosis factor-a, interleukin-10, interferon-g and interleukin -2 genes in a North European Caucasoid group from the UK. Eur J Immunogenet 2000;27:241-9.
52. Origuchi, Kawasaki E, Ide A, Kamachi M, Tanaka F, Ida H et al. Correlation between interleukin 10 promoter region polymorphisms and clinical manifestations in Japanese patients with Sjogren's syndrome. Ann Rheum Dis 2003;62:1117-8.
53. Anaya JM, Correa PA, Herrera M, Eskdale, Gallagher G. Interleukin 10 (IL-10) influences autoinmmune response in primary Sjögrens´s syndrome and is linked to IL-10 gene polymorphisms. J Rheumatol 2002;29:1874-6
54. Henao MI, Montes C, París SC, García LF. Cytokines ene polymorphisms in Colombian patients with different clinical presentations of tuberculosis. Tuberculosis2006;86:11-9
55. Larcombe L, Rempel JD, Dembinski I, Tinckam K, Rigatto C, Nickerson P. Differential cytokine genotype frequencies among Canadian aboriginal and Caucasian populations. Genes Immun 2005;6:140-4.
56. Torkildsen O, Utsi E, Harbo HF, Mellgren SI, Vedeler CA, Myhr KM. Ethnic variations of IL-10 polymorphisms in a Sami and Norwegian population. Scan J Immunol 2005;62:71-4.
Cómo citar
1.
Moreno OM, González CI, Saaibi DL, Otero W, Badillo R, Martín J, et al. Polimorfismos de la región promotora del gen de la IL-10 y artritis reumatoide en una población colombiana. biomedica [Internet]. 1 de marzo de 2007 [citado 15 de abril de 2024];27(1):56-65. Disponible en: https://revistabiomedica.org/index.php/biomedica/article/view/233
Publicado
2007-03-01
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