An intronic SNP in a RUNX1 binding site of SLC22A4, encoding an organic cation transporter, is associated with rheumatoid arthritis

Rheumatoid arthritis is a common inflammatory disease with complex genetic components. We investigated the genetic contribution of the cytokine gene cluster in chromosome 5q31 to susceptibility to rheumatoid arthritis in the Japanese population by case-control linkage disequilibrium (LD) mapping using single nucleotide polymorphisms (SNPs). Here we report that there is significant association between rheumatoid arthritis and the organic cation transporter gene SLC22A4 (P = 0.000034). We show that expression of SLC22A4 is specific to hematological and immunological tissues and that SLC22A4 is also highly expressed in the inflammatory joints of mice with collagen-induced arthritis. A SNP affects the transcriptional efficiency of SLC22A4 in vitro, owing to an allelic difference in affinity to Runt-related transcription factor 1 (RUNX1), a transcriptional regulator in the hematopoietic system. A SNP in RUNX1 is also strongly associated with rheumatoid arthritis (P = 0.00035). Our data indicate that the regulation of SLC22A4 expression by RUNX1 is associated with susceptibility to rheumatoid arthritis, which may represent an example of an epistatic effect of two genes on this disorder.

[1]  Hiroshi Sato,et al.  Functional SNPs in the lymphotoxin-α gene that are associated with susceptibility to myocardial infarction , 2002, Nature Genetics.

[2]  S. Kawamoto,et al.  Transcriptional Regulation of the Human Nonmuscle Myosin II Heavy Chain-A Gene , 1998, The Journal of Biological Chemistry.

[3]  Yusuke Nakamura,et al.  Functional haplotypes of PADI 4 , encoding citrullinating enzyme peptidylarginine deiminase 4 , are associated with rheumatoid arthritis , 2003 .

[4]  Yusuke Nakamura,et al.  Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis , 2003, Nature Genetics.

[5]  K. Miyazawa,et al.  Transcriptional Roles of CCAAT/Enhancer Binding Protein-β, Nuclear Factor-κB, and C-promoter Binding Factor 1 in Interleukin (IL)-1β-induced IL-6 Synthesis by Human Rheumatoid Fibroblast-like Synoviocytes* , 1998, The Journal of Biological Chemistry.

[6]  C. Deighton,et al.  The contribution of H LA to rheumatoid arthritis , 1989 .

[7]  T. Heinemeyer,et al.  Databases on transcriptional regulation: TRANSFAC, TRRD and COMPEL , 1998, Nucleic Acids Res..

[8]  Yusuke Nakamura,et al.  A high-throughput SNP typing system for genome-wide association studies , 2001, Journal of Human Genetics.

[9]  N. Risch,et al.  A comparison of linkage disequilibrium measures for fine-scale mapping. , 1995, Genomics.

[10]  D. F. Roberts,et al.  The contribution of HLA to rheumatoid arthritis. , 1989, Clinical genetics.

[11]  N. Kamatani,et al.  Identification of the gene loci that predispose to rheumatoid arthritis. , 1998, International immunology.

[12]  K. Lindblad-Toh,et al.  A second-generation association study of the 5q31 cytokine gene cluster and the interleukin-4 receptor in asthma. , 2001, Genomics.

[13]  P. Gregersen,et al.  The genetics revolution and the assault on rheumatoid arthritis. , 1999, Arthritis and rheumatism.

[14]  M. Liang,et al.  The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. , 1988, Arthritis and rheumatism.

[15]  D. Housman,et al.  Detection of two tissue-specific DNA-binding proteins with affinity for sites in the mouse beta-globin intervening sequence 2 , 1988, Molecular and cellular biology.

[16]  J. Nezu,et al.  Novel membrane transporter OCTN1 mediates multispecific, bidirectional, and pH-dependent transport of organic cations. , 1999, The Journal of pharmacology and experimental therapeutics.

[17]  M. Maruyama,et al.  Positive and Negative Regulation of Granulocyte-Macrophage Colony-Stimulating Factor Promoter Activity by AMLI-Related Transcription Factor , PEBP 2 , 2000 .

[18]  Jens Holmberg,et al.  Positional identification of Ncf1 as a gene that regulates arthritis severity in rats , 2003, Nature Genetics.

[19]  L. Ala‐Kokko,et al.  Regulation of human COL2A1 gene expression in chondrocytes. Identification of C-Krox-responsive elements and modulation by phenotype alteration. , 2000, The Journal of biological chemistry.

[20]  H. Cordell.  Epistasis: what it means, what it doesn't mean, and statistical methods to detect it in humans. , 2002, Human molecular genetics.

[21]  V. Ganapathy,et al.  Identity of the Organic Cation Transporter OCT3 as the Extraneuronal Monoamine Transporter (uptake2) and Evidence for the Expression of the Transporter in the Brain* , 1998, The Journal of Biological Chemistry.

[22]  Sinead B. O'Leary,et al.  Genetic variation in the 5q31 cytokine gene cluster confers susceptibility to Crohn disease , 2001, Nature Genetics.

[23]  H. Schumacher,et al.  Rheumatoid arthritis associated autoantibodies in patients with synovitis of recent onset , 2000, Arthritis research.

[24]  J Ott,et al.  Counting methods (EM algorithm) in human pedigree analysis: Linkage and segregation analysis , 1977, Annals of human genetics.

[25]  A. Markham,et al.  Association study of asthma and atopy traits and chromosome 5q cytokine cluster markers , 1998, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[26]  Yusuke Nakamura,et al.  Gene-based SNP discovery as part of the Japanese Millennium Genome Project: identification of 190 562 genetic variations in the human genome , 2002, Journal of Human Genetics.

[27]  Timothy C. Cox,et al.  Identification and Characterization of a Conserved Erythroid-specific Enhancer Located in Intron 8 of the Human 5-Aminolevulinate Synthase 2 Gene* , 1998, The Journal of Biological Chemistry.

[28]  F. Arnett.  Revised criteria for the classification of rheumatoid arthritis. , 1990, Orthopedic nursing.

[29]  M. Ehm,et al.  Detecting marker-disease association by testing for Hardy-Weinberg disequilibrium at a marker locus. , 1998, American journal of human genetics.

[30]  R. Maki,et al.  The proto-oncogene PU.1 regulates expression of the myeloid-specific CD11b promoter. , 1993, The Journal of biological chemistry.

[31]  R. Myers,et al.  Candidate-gene approaches for studying complex genetic traits: practical considerations , 2002, Nature Reviews Genetics.

[32]  S. Hiebert,et al.  Role of the transcription factor AML-1 in acute leukemia and hematopoietic differentiation. , 2000, Gene.

[33]  G. Nepom.  Major histocompatibility complex-directed susceptibility to rheumatoid arthritis. , 1998, Advances in immunology.

[34]  L. Kruglyak,et al.  Patterns of linkage disequilibrium in the human genome , 2002, Nature Reviews Genetics.

[35]  M. Rutherford,et al.  Genome-wide multilocus analysis for immune-mediated complex diseases. , 2002, Biochemical and biophysical research communications.

[36]  Hideyuki Saito,et al.  Gene expression levels and immunolocalization of organic ion transporters in the human kidney. , 2002, Journal of the American Society of Nephrology : JASN.

[37]  G. Gyapay,et al.  New susceptibility locus for rheumatoid arthritis suggested by a genome-wide linkage study. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[38]  J. Zhang,et al.  AML1A and AML1B can transactivate the human IL-3 promoter. , 1997, Journal of immunology.

[39]  K. Arai,et al.  Positive and negative regulation of granulocyte-macrophage colony-stimulating factor promoter activity by AML1-related transcription factor, PEBP2. , 1995, Blood.

[40]  Paul Wordsworth,et al.  Whole-genome linkage analysis of rheumatoid arthritis susceptibility loci in 252 affected sibling pairs in the United Kingdom. , 2002, Arthritis and rheumatism.

[41]  A. Sekine,et al.  Catalog of 238 variations among six human genes encoding solute carriers (hSLCs) in the Japanese population , 2002, Journal of Human Genetics.

[42]  Xiangli Xiao,et al.  Screening the genome for rheumatoid arthritis susceptibility genes: a replication study and combined analysis of 512 multicase families. , 2003, Arthritis and rheumatism.

[43]  C I Amos,et al.  A genomewide screen in multiplex rheumatoid arthritis families suggests genetic overlap with other autoimmune diseases. , 2001, American journal of human genetics.

[44]  R. Jonsson,et al.  A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans , 2002, Nature Genetics.

[45]  D B Corry,et al.  Requirement for IL-13 independently of IL-4 in experimental asthma. , 1998, Science.

[46]  M. Ohki,et al.  t(8;21) breakpoints on chromosome 21 in acute myeloid leukemia are clustered within a limited region of a single gene, AML1. , 1991, Proceedings of the National Academy of Sciences of the United States of America.