Article information
Resumen
El estudio genético de las enfermedades autoinmunes de base poligénica (artritis reumatoide, enfermedad inflamatoria intestinal, etc) ha evolucionado desde la identificación, mediante estudios de ligamiento, de regiones del genoma implicadas en la susceptibilidad, a la identificación dentro de esas zonas, mediante estudios de asociación, de las variantes concretas en genes específicos que están molecularmente relacionadas con la predisposición incrementada a la enfermedad. Una de las regiones que ha atraído más interés es 5q31, ligada a enfermedad inflamatoria intestinal y enfermedades alérgicas, puesto que en dicha región se encuentran los genes de importantes citocinas como IL4, IL5 e IL13. Un resultado sorprendente de los estudios de asociación que se hicieron a continuación, es que tanto en la enfermedad de Crohn como en la artritis reumatoide, los genes responsables presentes en la región resultaron ser, no esos genes de citocinas, sino dos transportadores de cationes orgánicos, OCTN1 y OCTN2, codificados por los genes SLC22A4 y SLC22A5, respectivamente, y para los que nadie había anticipado una función relevante en el sistema inmune. En los últimos dos años ha existido un animado debate en la literatura inmunogenética acerca de si realmente esos genes son los auténticamente responsables de la enfermedad, o si simplemente son arrastrados pasivamente en el cromosoma 5, por desequilibrio de ligamiento, con la variante etiológica, que aún permanecería por identificar. En la presente revisión, pretendemos dar un breve panorama del estado de la cuestión.
Palabras clave:
OCTN1
SLC22A4
OCTN2
SLC22A5
Susceptibilidad genética
Polimorfismo de Nucleótido Único
Artritis Reumatoide
Enfermedad de Crohn
Abstract
Genetic studies in polygenic autoimmune diseases (Rheumatoid arthritis, inflammatory bowel disease, etc) have moved from identifying by linkage studies those genomic regions involved in susceptibility, to the precise ascertainment of specific variants molecularly related to the disease by association studies. One of the regions which attracted more attention is 5q31, linked to inflammatory bowel and allergic diseases because it harbours the cytokine-cluster comprising IL4, IL5 and IL13, among others. A surprising result of subsequent association studies, both in Crohn's disease and in rheumatoid arthritis, was that the susceptibility genes in that region turned out to be, not any of the cytokine genes, but two organic cation transporters, OCTN1 and OCTN2 coded by the SLC22A4 and SLC22A5 genes respectively, not previously anticipated as relevant for the immune response. During the last two years there has been a lively debate in the immunogenetic literature on whether these genes are truly responsible of the increased susceptibility to the disease, or they are simply passively carried on chromosome 5q31 by linkage disequilibrium with an as-yet-unknown etiologic variant. In the present review, we aim at offering a brief glance of the current status in this field.
Key words:
OCTN1
SLC22A4
OCTN2
SLC22A5
Genetic susceptibility
Single Nucleotide Polymorphism
Rheumatoid Arthritis
Crohn's disease
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Nat Genet, 29 (2001), pp. 229-232
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An intronic SNP in a RUNX1 binding site of SLC22A4, encoding an organic cation transporter, is associated with rheumatoid arthritis.
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Nat Genet, 35 (2003), pp. 349-356
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A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans.
Nat Genet, 32 (2002), pp. 666-669
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Nat Genet, 36 (2004), pp. 471-475
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Association analysis of SLC22A4 SLC22A5 and DLG5 in Japanese patients with Crohn disease.
J Hum Genet, 49 (2004), pp. 664-668
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A. Martinez, A. Valdivia, D. Pascual-Salcedo, A. Balsa, B. Fernandez- Gutierrez, E. De la Concha, et al.
Role of SLC22A4, SLC22A5, and RUNX1 genes in rheumatoid arthritis.
J Rheumatol, 33 (2006), pp. 842-846
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M. Tosa, K. Negoro, Y. Kinouchi, H. Abe, E. Nomura, S. Takagi, et al.
Lack of association between IBD5 and Crohn's disease in Japanese patients demonstrates population-specific differences in inflammatory bowel disease.
Scand J Gastroenterol, 41 (2006), pp. 48-53
[75.]
K. Negoro, D.P. McGovern, Y. Kinouchi, S. Takahashi, N.J. Lench, T. Shimosegawa, et al.
Analysis of the IBD5 locus and potential gene-gene interactions in Crohn's disease.
Gut, 52 (2003), pp. 541-546
[76.]
T. Watanabe, A. Kitani, W. Strober.
NOD2 regulation of Toll-like receptor responses and the pathogenesis of Crohn's disease.
Gut, 54 (2005), pp. 1515-1518
[77.]
Y. Ogura, D.K. Bonen, N. Inohara, D.L. Nicolae, F.F. Chen, R. Ramos, et al.
A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease.
Nature, 411 (2001), pp. 603-606
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J.P. Hugot, M. Chamaillard, H. Zouali, S. Lesage, J.P. Cezard, J. Belaiche, et al.
Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease.
Nature, 411 (2001), pp. 599-603
[79.]
A.M. Lamhonwah, C. Ackerley, R. Onizuka, A. Tilups, D. Lamhonwah, C. Chung, et al.
Epitope shared by functional variant of organic cation/carnitine transporter, OCTN1 Campylobacter jejuni and Mycobacterium paratuberculosis may underlie susceptibility to Crohn's disease at 5q31.
Biochem Biophys Res Commun, 337 (2005), pp. 1165-1175
[80.]
D. Grundemann, S. Harlfinger, S. Golz, A. Geerts, A. Lazar, R. Berkels, et al.
Discovery of the ergothioneine transporter.
Proc Natl Acad Sci U S A, 102 (2005), pp. 5256-5261
[81.]
D. Taubert, A. Lazar, G. Grimberg, N. Jung, A. Rubbert, K.S. Delank, et al.
Association of rheumatoid arthritis with ergothioneine levels in red blood cells: a case control study.
J Rheumatol, 33 (2006), pp. 2139-2145
[82.]
D. Taubert, G. Grimberg, N. Jung, A. Rubbert, E. Schomig.
Functional role of the 503F variant of the organic cation transporter OCTN1 in Crohn's disease.
Gut, 54 (2005), pp. 1505-1506
[83.]
B. Newman, R.F. Wintle, M. van Oene, M. Yazdanpanah, J. Owen, B. Johnson, et al.
SLC22A4 polymorphisms implicated in rheumatoid arthritis and Crohn's disease are not associated with rheumatoid arthritis in a Canadian Caucasian population.
Arthritis Rheum, 52 (2005), pp. 425-429
[84.]
A. Barton, S. Eyre, J. Bowes, P. Ho, S. John, J. Worthington.
Investigation of the SLC22A4 gene (associated with rheumatoid arthritis in a Japanese population) in a United Kingdom population of rheumatoid arthritis patients.
Arthritis Rheum, 52 (2005), pp. 752-758
[85.]
G. Orozco, E. Sanchez, M.A. Gonzalez-Gay, M.A. Lopez-Nevot, B. Torres, D. Pascual-Salcedo, et al.
SLC22A4 RUNX1, and SUMO4 polymorphisms are not associated with rheumatoid arthritis: a case-control study in a Spanish population.
J Rheumatol, 33 (2006), pp. 1235-1239
[86.]
B. Newman, X. Gu, R. Wintle, D. Cescon, M. Yazdanpanah, X. Liu, et al.
A risk haplotype in the Solute Carrier Family 22A4/22A5 gene cluster influences phenotypic expression of Crohn's disease.
Gastroenterology, 128 (2005), pp. 260-269
[87.]
F. Zhong, C.C. McCombs, J.M. Olson, R.C. Elston, F.M. Stevens, C.F. McCarthy, et al.
An autosomal screen for genes that predispose to celiac disease in the western counties of Ireland.
Nat Genet, 14 (1996), pp. 329-333
[88.]
L. Greco, G. Corazza, M.C. Babron, F. Clot, M.C. Fulchignoni-Lataud, S. Percopo, et al.
Genome search in celiac disease.
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