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SLC22A4 and RUNX1: identification of RA susceptible genes

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Abstract

Recently we reported that SLC22A4 and RUNX1 are associated with rheumatoid arthritis (RA). SLC22A4 is an organic cation transporter with unknown physiological function, and RUNX1 is a hematological transcriptional regulator that has been shown to be responsible for acute myelogenic leukemia. It is suggested that the association of RUNX1 with RA is due to its regulation of expression of SLC22A4. Because the physiological function of SLC22A4 is still unclear, further investigation is needed into how SLC22A4 affects RA susceptibility. Although the association of RUNX1 with RA was identified as a regulatory factor of SLC22A4, it is possible that RUNX1 is a key molecule in autoimmunity, as it has been reported to be associated with systemic lupus erythematosus and psoriasis, two other autoimmune diseases.

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Abbreviations

CBF :

Core-binding factor

IL :

Interleukin

IRF :

Interferon regulatory factor

LD :

Linkage disequilibrium

NCF :

Neutrophil cytosolic factor

OCT :

Organic cation transporter

PADI :

Peptidylarginine deiminase

RA :

Rheumatoid arthritis

SLE :

Systemic lupus erythematosus

SNP :

Single nucleotide polymorphism

References

  1. Seldin MF, Amos CI, Ward R, Gregersen PK (1999) The genetics revolution and the assault on rheumatoid arthritis. Arthritis Rheum 42:1071–1079

    CAS  PubMed  Google Scholar 

  2. Goldbach-Mansky R et al. (2000) Rheumatoid arthritis associated autoantibodies in patients with synovitis of recent onset. Arthritis Res 2:236–243

    CAS  PubMed  Google Scholar 

  3. Risch N, Merikangas K (1996) The future of genetic studies of complex human diseases. Science 273:1516–1517

    CAS  PubMed  Google Scholar 

  4. Tokuhiro S et al. (2003) An intronic SNP in a RUNX1 binding site of SLC22A4, encoding an organic cation transporter, is associated with rheumatoid arthritis. Nat Genet 35:341–348

    Article  CAS  PubMed  Google Scholar 

  5. Aho K, Koskenvuo M, Tuominen J, Kaprio J (1986) Occurrence of rheumatoid arthritis in a nationwide series of twins. J Rheumatol 13:899–902

    CAS  PubMed  Google Scholar 

  6. Silman AJ et al. (1993) Twin concordance rates for rheumatoid arthritis: results from a nationwide study. Br J Rheumatol 32:903–907

    CAS  PubMed  Google Scholar 

  7. Jarvinen P, Aho K (1994) Twin studies in rheumatic diseases. Semin Arthritis Rheum 24:19–28

    Google Scholar 

  8. Wolfe F, Kleinheksel SM, Khan MA (1988) Familial vs sporadic rheumatoid arthritis: a comparison of the demographic and clinical characteristics of 956 patients. J Rheumatol 15:400–404

    CAS  PubMed  Google Scholar 

  9. Deighton CM, Walker DJ, Griffiths ID, Roberts DF (1989) The contribution of HLA to rheumatoid arthritis. Clin Genet 36:178–182

    CAS  PubMed  Google Scholar 

  10. Hasstedt SJ, Clegg DO, Ingles L, Ward RH (1994) HLA-linked rheumatoid arthritis. Am J Hum Genet 55:738–746

    CAS  PubMed  Google Scholar 

  11. Nepom GT (1998) Major histocompatibility complex-directed susceptibility to rheumatoid arthritis. Adv Immunol 68:315–332

    CAS  PubMed  Google Scholar 

  12. Reveille JD (1998) The genetic contribution to the pathogenesis of rheumatoid arthritis. Curr Opin Rheumatol 10:187–200

    CAS  PubMed  Google Scholar 

  13. Cornelis F et al. (1998) New susceptibility locus for rheumatoid arthritis suggested by a genome-wide linkage study. Proc Natl Acad Sci USA 95:10746–10750

    Article  CAS  PubMed  Google Scholar 

  14. Shiozawa S et al. (1998) Identification of the gene loci that predispose to rheumatoid arthritis. Int Immunol 10:1891–1895

    CAS  PubMed  Google Scholar 

  15. Jawaheer D et al. (2001) A genomewide screen in multiplex rheumatoid arthritis families suggests genetic overlap with other autoimmune diseases. Am J Hum Genet 68:927–936

    CAS  PubMed  Google Scholar 

  16. MacKay K et al. (2002) Whole-genome linkage analysis of rheumatoid arthritis susceptibility loci in 252 affected sibling pairs in the United Kingdom. Arthritis Rheum 46:632–639

    CAS  PubMed  Google Scholar 

  17. Ohnishi Y et al. (2001) A high-throughput SNP typing system for genome-wide association studies. J Hum Genet 46:471–477

    CAS  PubMed  Google Scholar 

  18. Ozaki K et al. (2002) Functional SNPs in the lymphotoxin-alpha gene that are associated with susceptibility to myocardial infarction. Nat Genet 32:650–654

    Article  CAS  PubMed  Google Scholar 

  19. Suzuki A et al. (2003) Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat Genet 34:395–402

    Article  CAS  PubMed  Google Scholar 

  20. Yamada R, Suzuki A, Chang X, Yamamoto K (2003) Peptidylarginine deiminase type 4: identification of a rheumatoid arthritis-susceptible gene. Trends Mol Med 9:503–508

    Google Scholar 

  21. Grunig G et al. (1998) Requirement for IL-13 independently of IL-4 in experimental asthma. Science 282:2261–2263

    Article  PubMed  Google Scholar 

  22. Rioux JD et al. (2001) Genetic variation in the 5q31 cytokine gene cluster confers susceptibility to Crohn disease. Nat Genet 29:223–228

    Article  CAS  PubMed  Google Scholar 

  23. Mansur AH, Bishop DT, Markham AF, Britton J, Morrison JF (1998) Association study of asthma and atopy traits and chromosome 5q cytokine cluster markers. Clin Exp Allergy 28:141–150

    Article  CAS  Google Scholar 

  24. Kauppi P. et al. (2001) A second-generation association study of the 5q31 cytokine gene cluster and the interleukin-4 receptor in asthma. Genomics 77:35–42

    Article  CAS  PubMed  Google Scholar 

  25. Lee JK, Park C, Kimm K, Rutherford MS (2002) Genome-wide multilocus analysis for immune-mediated complex diseases. Biochem Biophys Res Commun 295:771–773

    Article  CAS  PubMed  Google Scholar 

  26. Giallourakis C et al. (2003) IBD5 is a general risk factor for inflammatory bowel disease: replication of association with Crohn disease and identification of a novel association with ulcerative colitis. Am J Hum Genet 73:205–211

    Article  CAS  PubMed  Google Scholar 

  27. Nezu K et al. (1999) Thoracoscopic lung volume reduction surgery for emphysema. Evaluation using ventilation-perfusion scintigraphy. Jpn J Thorac Cardiovasc Surg 47:267–272

    CAS  PubMed  Google Scholar 

  28. Tamai I et al. (2000) Molecular and functional characterization of organic cation/carnitine transporter family in mice. J Biol Chem 275:40064–40072

    Article  CAS  PubMed  Google Scholar 

  29. Tamai I et al. (2001) Na (+)-coupled transport of L-carnitine via high-affinity carnitine transporter OCTN2 and its subcellular localization in kidney. Biochim Biophys Acta 1512:273–284

    Article  CAS  PubMed  Google Scholar 

  30. Nezu J et al. (1999) Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium ion-dependent carnitine transporter. Nat Genet 21:91–94

    CAS  PubMed  Google Scholar 

  31. Tamai I et al. (1997) Cloning and characterization of a novel human pH-dependent organic cation transporter, OCTN1. FEBS Lett 419:107–111

    CAS  PubMed  Google Scholar 

  32. Yabuuchi H et al. (1999) Novel membrane transporter OCTN1 mediates multispecific, bidirectional, and pH-dependent transport of organic cations. J Pharmacol Exp Ther 289:768–773

    CAS  PubMed  Google Scholar 

  33. Motohashi H et al. (2002) Gene expression levels and immunolocalization of organic ion transporters in the human kidney. J Am Soc Nephrol 13:866–874

    CAS  PubMed  Google Scholar 

  34. Wu X, et al. (1998) Identity of the organic cation transporter OCT3 as the extraneuronal monoamine transporter (uptake2) and evidence for the expression of the transporter in the brain. J Biol Chem 273:32776–32786

    CAS  PubMed  Google Scholar 

  35. Roumier C et al. (2003) New mechanisms of AML1 gene alteration in hematological malignancies. Leukemia 17:9–16

    Article  CAS  PubMed  Google Scholar 

  36. Downing JR (2001) AML1/CBFbeta transcription complex: its role in normal hematopoiesis and leukemia. Leukemia 15:664–665

    Article  CAS  PubMed  Google Scholar 

  37. Coffman JA (2003) Runx transcription factors and the developmental balance between cell proliferation and differentiation. Cell Biol Int 27:315–324

    Article  CAS  PubMed  Google Scholar 

  38. Nucifora G, Rowley JD (1995) AML1 and the 8;21 and 3;21 translocations in acute and chronic myeloid leukemia. Blood 86:1–14

    CAS  PubMed  Google Scholar 

  39. Romana SP et al. (1995) High frequency of t(12;21) in childhood B-lineage acute lymphoblastic leukemia. Blood 86:4263–4269

    CAS  PubMed  Google Scholar 

  40. Osato M et al. (1999) Biallelic and heterozygous point mutations in the runt domain of the AML1/PEBP2alphaB gene associated with myeloblastic leukemias. Blood 93:1817–1824

    CAS  PubMed  Google Scholar 

  41. Niini T, Kanerva J, Vettenranta K, Saarinen-Pihkala UM, Knuutila S (2000) AML1 gene amplification: a novel finding in childhood acute lymphoblastic leukemia. Haematologica 85:362–366

    CAS  PubMed  Google Scholar 

  42. Song WJ. et al. (1999) Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Nat Genet 23:166–175

    Article  CAS  PubMed  Google Scholar 

  43. Prokunina L et al. (2002) A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans. Nat Genet 32:666–669

    Article  CAS  PubMed  Google Scholar 

  44. Helms C et al. (2003) A putative RUNX1 binding site variant between SLC9A3R1 and NAT9 is associated with susceptibility to psoriasis. Nat Genet 35:349–356

    Article  CAS  PubMed  Google Scholar 

  45. Surinya KH, Cox TC, May BK (1998) Identification and characterization of a conserved erythroid-specific enhancer located in intron 8 of the human 5-aminolevulinate synthase 2 gene. J Biol Chem 273:16798–16809

    Article  CAS  PubMed  Google Scholar 

  46. Ghayor C et al. (2000) Regulation of human COL2A1 gene expression in chondrocytes. Identification of C-Krox-responsive elements and modulation by phenotype alteration. J Biol Chem 275:27421–27438

    CAS  PubMed  Google Scholar 

  47. Beohar N, Kawamoto S (1998) Transcriptional regulation of the human nonmuscle myosin II heavy chain-A gene. Identification of three clustered cis-elements in intron-1 which modulate transcription in a cell type- and differentiation state-dependent manner. J Biol Chem 273:9168–9178

    Article  CAS  PubMed  Google Scholar 

  48. Lutterbach B, Hiebert SW (2000) Role of the transcription factor AML-1 in acute leukemia and hematopoietic differentiation. Gene 245:223–235

    Article  CAS  PubMed  Google Scholar 

  49. Olofsson P et al. (2003) Positional identification of Ncf1 as a gene that regulates arthritis severity in rats. Nat Genet 33:25–32

    Article  CAS  PubMed  Google Scholar 

  50. Peltekova VD, Wintle RF, Rubin LA et al. (2004) Functional variants of OCTN cation transporter genes are associated with Crohn disease. Nat Genet 36:471–475

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Laboratory for Rheumatic Diseases, SNP Research Center, Institute of Physical and Chemical Research, 1-7-22 Suehiro-cho, Tsurumi-ku, 230-0045, Yokohama, Kanagawa, Japan

    Ryo Yamada, Shinya Tokuhiro, Xiotian Chang & Kazuhiko Yamamoto

Authors
  1. Ryo Yamada
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  2. Shinya Tokuhiro
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  3. Xiotian Chang
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  4. Kazuhiko Yamamoto
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Correspondence to Ryo Yamada.

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Yamada, R., Tokuhiro, S., Chang, X. et al. SLC22A4 and RUNX1: identification of RA susceptible genes. J Mol Med 82, 558–564 (2004). https://doi.org/10.1007/s00109-004-0547-y

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  • DOI: https://doi.org/10.1007/s00109-004-0547-y

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