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The genetics of systemic lupus erythematosus: understanding how SNPs confer disease susceptibility

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Abstract

The identification of genes for autoimmune diseases is just the first step towards our understanding of disease pathogenesis. In investigating how mutations, deletions or other types of polymorphic defects occur, it is important to determine the pathways and the mechanisms through which susceptibility leads to disease. In this review I touch on three examples of studies that have attempted to understand the mechanisms of genetic susceptibility in three genes identified recently for systemic lupus erythematosus: PDCD1, PTPN22 and IRF5. We are just beginning to comprehend and much needs to be done.

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References

  1. Sachidanandam R, Weissman D, Schmidt SC, Kakol JM, Stein LD, Marth G, Sherry S, Mullikin JC, Mortimore BJ, Willey DL, Hunt SE, Cole CG, Coggill PC, Rice CM, Ning Z, Rogers J, Bentley DR, Kwok PY, Mardis ER, Yeh RT, Schultz B, Cook L, Davenport R, Dante M, Fulton L, Hillier L, Waterston RH, McPherson JD, Gilman B, Schaffner S, Van Etten WJ, Reich D, Higgins J, Daly MJ, Blumenstiel B, Baldwin J, Stange-Thomann N, Zody MC, Linton L, Lander ES, Altshuler D (2001) A map of human genome sequence variation containing 142 million single nucleotide polymorphisms. Nature 409:928–933

    PubMed  CAS  Google Scholar 

  2. Pastinen T, Ge B, Gurd S, Gaudin T, Dore C, Lemire M, Lepage P, Harmsen E, Hudson TJ (2005) Mapping common regulatory variants to human haplotypes. Hum Mol Genet 14:3963–3971

    PubMed  CAS  Google Scholar 

  3. Cheung VG, Spielman RS, Ewens KG, Weber TM, Morley M, Burdick JT (2005) Mapping determinants of human gene expression by regional and genome-wide association. Nature 437:1365–1369

    PubMed  CAS  Google Scholar 

  4. Pastinen T, Ge B, Hudson TJ (2006) Influence of human genome polymorphism on gene expression. Hum Mol Genet 15(Suppl 1):R9–R16

    PubMed  CAS  Google Scholar 

  5. Stranger BE, Forrest MS, Clark AG, Minichiello MJ, Deutsch S, Lyle R, Hunt S, Kahl B, Antonarakis SE, Tavare S, Deloukas P, Dermitzakis ET (2005) Genome-wide associations of gene expression variation in humans. PLoS Genet 1:e78

    PubMed  Google Scholar 

  6. Schmidt CW (2003) HapMap: building a database with blocks. EHP Toxicogenomics. EHP Toxicogenomics 111:A16

    PubMed  Google Scholar 

  7. McVean G, Spencer CC, Chaix R (2005) Perspectives on human genetic variation from the HapMap project. PLoS Genet 1:e54

    PubMed  Google Scholar 

  8. Kruglyak L (2005) Power tools for human genetics. Nat Genet 37:1299-1300

    PubMed  CAS  Google Scholar 

  9. Altshuler D, Brooks LD, Chakravarti A, Collins FS, Daly MJ, Donnelly P (2005) A haplotype map of the human genome. Nature 437:1299–1320

    Google Scholar 

  10. Zeggini E, Rayner W, Morris AP, Hattersley AT, Walker M, Hitman GA, Deloukas P, Cardon LR, McCarthy MI (2005) An evaluation of HapMap sample size and tagging SNP performance in large-scale empirical and simulated data sets. Nat Genet 37:1299–1300

    Google Scholar 

  11. Alarcon-Segovia D, Alarcon-Riquelme ME (2003) Etiopathogenesis of systemic lupus erythematosus. In: Lahita RG (ed) Systemic lupus erythematosus. Academic, San Diego, CA

    Google Scholar 

  12. Alarcon-Riquelme ME (2005) The genetics of systemic lupus erythematosus. J Autoimmun 25(Suppl):46–48

    PubMed  CAS  Google Scholar 

  13. Davies JL, Kawaguchi Y, Bennett ST, Copeman JB, Cordell HJ, Pritchard LE, Reed PW, Gough SC, Jenkins SC, Palmer SM et al (1994) A genome-wide search for human type 1 diabetes susceptibility genes. Nature 371:130–136

    PubMed  CAS  Google Scholar 

  14. Gaffney PM, Kearns GM, Shark KB, Ortmann WA, Selby SA, Malmgren ML, Rohlf KE, Ockenden TC, Messner RP, King RA, Rich SS, Behrens TW (1998) A genome-wide search for susceptibility genes in human systemic lupus erythematosus sib-pair families. Proc Natl Acad Sci USA 95:14875–14879

    PubMed  CAS  Google Scholar 

  15. Moser KL, Neas BR, Salmon JE, Yu H, Gray-McGuire C, Asundi N, Bruner GR, Fox J, Kelly J, Henshall S, Bacino D, Dietz M, Hogue R, Koelsch G, Nightingale L, Shaver T, Abdou NI, Albert DA, Carson C, Petri M, Treadwell EL, James JA, Harley JB (1998) Genome scan of human systemic lupus erythematosus: evidence for linkage on chromosome 1q in African-American pedigrees. Proc Natl Acad Sci USA 95:14869–14874

    PubMed  CAS  Google Scholar 

  16. Lindqvist AK, Steinsson K, Johanneson B, Kristjansdottir H, Arnasson A, Grondal G, Jonasson I, Magnusson V, Sturfelt G, Truedsson L, Svenungsson E, Lundberg I, Terwilliger JD, Gyllensten UB, Alarcon-Riquelme ME (2000) A susceptibility locus for human systemic lupus erythematosus (hSLE1) on chromosome 2q. J Autoimmun 14:169–178

    PubMed  CAS  Google Scholar 

  17. Shai R, Quismorio FP Jr, Li L, Kwon OJ, Morrison J, Wallace DJ, Neuwelt CM, Brautbar C, Gauderman WJ, Jacob CO (1999) Genome-wide screen for systemic lupus erythematosus susceptibility genes in multiplex families. Hum Mol Genet 8:639–644

    PubMed  CAS  Google Scholar 

  18. Kono DH, Burlingame RW, Owens DG, Kuramochi A, Balderas RS, Balomenos D, Theofilopoulos AN (1994) Lupus susceptibility loci in New Zealand mice. Proc Natl Acad Sci USA 91:10168–10172

    PubMed  CAS  Google Scholar 

  19. Morel L, Rudofsky UH, Longmate JA, Schiffenbauer J, Wakeland EK (1994) Polygenic control of susceptibility to murine systemic lupus erythematosus. Immunity 1:219–229

    PubMed  CAS  Google Scholar 

  20. Drake CG, Rozzo SJ, Vyse TJ, Palmer E, Kotzin BL (1995) Genetic contributions to lupus-like disease in (NZB × NZW)F1 mice. Immunol Rev 144:51–74

    PubMed  CAS  Google Scholar 

  21. Cardon LR, Bell JI (2001) Association study designs for complex diseases. Nat Rev Genet 2:91–99

    PubMed  CAS  Google Scholar 

  22. Pritchard JK, Rosenberg NA (1999) Use of unlinked genetic markers to detect population stratification in association studies. Am J Hum Genet 65:220–228

    PubMed  CAS  Google Scholar 

  23. Pritchard JK, Donnelly P (2001) Case-control studies of association in structured or admixed populations. Theor Popul Biol 60:227–237

    PubMed  CAS  Google Scholar 

  24. Cardon LR, Palmer LJ (2003) Population stratification and spurious allelic association. Lancet 361:598–604

    PubMed  Google Scholar 

  25. Magnusson V, Lindqvist AK, Castillejo-Lopez C, Kristjansdottir H, Steinsson K, Grondal G, Sturfelt G, Truedsson L, Svenungsson E, Lundberg I, Gunnarsson I, Bolstad AI, Haga HJ, Jonsson R, Klareskog L, Alcocer-Varela J, Alarcon-Segovia D, Terwilliger JD, Gyllensten UB, Alarcon-Riquelme ME (2000) Fine mapping of the SLEB2 locus involved in susceptibility to systemic lupus erythematosus. Genomics 70:307–314

    PubMed  CAS  Google Scholar 

  26. Shinohara T, Taniwaki M, Ishida Y, Kawaichi M, Honjo T (1994) Structure and chromosomal localization of the human PD-1 gene (PDCD1). Genomics 23:704–706

    PubMed  CAS  Google Scholar 

  27. Agata Y, Kawasaki A, Nishimura H, Ishida Y, Tsubata T, Yagita H, Honjo T (1996) Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int Immunol 8:765–772

    PubMed  CAS  Google Scholar 

  28. Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, Fitz LJ, Malenkovich N, Okazaki T, Byrne MC, Horton HF, Fouser L, Carter L, Ling V, Bowman MR, Carreno BM, Collins M, Wood CR, Honjo T (2000) Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 192:1027–1034

    PubMed  CAS  Google Scholar 

  29. Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T (2001) PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci USA 98:13866–13871

    PubMed  CAS  Google Scholar 

  30. Cai G, Karni A, Oliveira EM, Weiner HL, Hafler DA, Freeman GJ (2004) PD-1 ligands, negative regulators for activation of naive, memory, and recently activated human CD4+ T cells. Cell Immunol 230:89–98

    PubMed  CAS  Google Scholar 

  31. Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I, Iwai Y, Long AJ, Brown JA, Nunes R, Greenfield EA, Bourque K, Boussiotis VA, Carter LL, Carreno BM, Malenkovich N, Nishimura H, Okazaki T, Honjo T, Sharpe AH, Freeman GJ (2001) PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol 2:261–268

    PubMed  CAS  Google Scholar 

  32. Carter L, Fouser LA, Jussif J, Fitz L, Deng B, Wood CR, Collins M, Honjo T, Freeman GJ, Carreno BM (2002) PD-1:PD-L inhibitory pathway affects both CD4(+) and CD8(+) T cells and is overcome by IL-2. Eur J Immunol 32:634–643

    PubMed  CAS  Google Scholar 

  33. Nishimura H, Okazaki T, Tanaka Y, Nakatani K, Hara M, Matsumori A, Sasayama S, Mizoguchi A, Hiai H, Minato N, Honjo T (2001) Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science 291:319–322

    PubMed  CAS  Google Scholar 

  34. Nishimura H, Nose M, Hiai H, Minato N, Honjo T (1999) Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 11:141–151

    PubMed  CAS  Google Scholar 

  35. Wang J, Yoshida T, Nakaki F, Hiai H, Okazaki T, Honjo T (2005) Establishment of NOD-Pdcd1−/− mice as an efficient animal model of type I diabetes. Proc Natl Acad Sci USA 102:11823–11828

    PubMed  CAS  Google Scholar 

  36. Hogarth MB, Slingsby JH, Allen PJ, Thompson EM, Chandler P, Davies KA, Simpson E, Morley BJ, Walport MJ (1998) Multiple lupus susceptibility loci map to chromosome 1 in BXSB mice. J Immunol 161:2753–2761

    PubMed  CAS  Google Scholar 

  37. Haywood ME, Hogarth MB, Slingsby JH, Rose SJ, Allen PJ, Thompson EM, Maibaum MA, Chandler P, Davies KA, Simpson E, Walpor MJ, Morley BJ (2000) Identification of intervals on chromosomes 1, 3, and 13 linked to the development of lupus in BXSB mice. Arthritis Rheum 43:349–355

    PubMed  CAS  Google Scholar 

  38. Haywood ME, Rose SJ, Horswell S, Lees MJ, Fu G, Walport MJ, Morley BJ (2006) Overlapping BXSB congenic intervals, in combination with microarray gene expression, reveal novel lupus candidate genes. Genes Immun 7:250–263

    PubMed  CAS  Google Scholar 

  39. Prokunina L, Castillejo-Lopez C, Oberg F, Gunnarsson I, Berg L, Magnusson V, Brookes AJ, Tentler D, Kristjansdottir H, Grondal G, Bolstad AI, Svenungsson E, Lundberg I, Sturfelt G, Jonssen A, Truedsson L, Lima G, Alcocer-Varela J, Jonsson R, Gyllensten UB, Harley JB, Alarcon-Segovia D, Steinsson K, Alarcon-Riquelme ME (2002) A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans. Nat Genet 32:666–669

    PubMed  CAS  Google Scholar 

  40. Ferreiros-Vidal I, Gomez-Reino JJ, Barros F, Carracedo A, Carreira P, Gonzalez-Escribano F, Liz M, Martin J, Ordi J, Vicario JL, Gonzalez A (2004) Association of PDCD1 with susceptibility to systemic lupus erythematosus: evidence of population-specific effects. Arthritis Rheum 50:2590–2597

    PubMed  CAS  Google Scholar 

  41. Nielsen C, Laustrup H, Voss A, Junker P, Husby S, Lillevang ST (2004) A putative regulatory polymorphism in PD-1 is associated with nephropathy in a population-based cohort of systemic lupus erythematosus patients. Lupus 13:510–516

    Article  PubMed  CAS  Google Scholar 

  42. Johansson M, Arlestig L, Moller B, Rantapaa-Dahlqvist S (2005) Association of a PDCD1 polymorphism with renal manifestations in systemic lupus erythematosus. Arthritis Rheum 52:1665–1669

    PubMed  CAS  Google Scholar 

  43. Sanghera DK, Manzi S, Bontempo F, Nestlerode C, Kamboh MY (2004) Role of an intronic polymorphism in the PDCD1 gene with the risk of sporadic systemic lupus erythematosus and the occurrence of antiphospholipid antibodies. Hum Genet 115:393–398

    PubMed  CAS  Google Scholar 

  44. Kroner A, Mehling M, Hemmer B, Rieckmann P, Toyka KV, Maurer M, Wiendl H (2005) A PD-1 polymorphism is associated with disease progression in multiple sclerosis. Ann Neurol 58:50–57

    PubMed  CAS  Google Scholar 

  45. Prokunina L, Padyukov L, Bennet A, de Faire U, Wiman B, Prince J, Alfredsson L, Klareskog L, Alarcon-Riquelme M (2004) Association of the PD-1.3A allele of the PDCD1 gene in patients with rheumatoid arthritis negative for rheumatoid factor and the shared epitope. Arthritis Rheum 50:1770–1773

    PubMed  CAS  Google Scholar 

  46. Nielsen C, Hansen D, Husby S, Jacobsen BB, Lillevang ST (2003) Association of a putative regulatory polymorphism in the PD-1 gene with susceptibility to type 1 diabetes. Tissue Antigens 62:492–497

    PubMed  CAS  Google Scholar 

  47. Kong EK, Prokunina-Olsson L, Wong WH, Lau CS, Chan TM, Alarcon-Riquelme M, Lau YL (2005) A new haplotype of PDCD1 is associated with rheumatoid arthritis in Hong Kong Chinese. Arthritis Rheum 52:1058–1062

    PubMed  CAS  Google Scholar 

  48. Lin SC, Yen JH, Tsai JJ, Tsai WC, Ou TT, Liu HW, Chen CJ (2004) Association of a programmed death 1 gene polymorphism with the development of rheumatoid arthritis, but not systemic lupus erythematosus. Arthritis Rheum 50:770–775

    PubMed  CAS  Google Scholar 

  49. Otto F, Lubbert M, Stock M (2003) Upstream and downstream targets of RUNX proteins. J Cell Biochem 89:9–18

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  51. Nishimura H, Honjo T, Minato N (2000) Facilitation of beta selection and modification of positive selection in the thymus of PD-1-deficient mice. J Exp Med 191:891–898

    PubMed  CAS  Google Scholar 

  52. Waltzer L, Ferjoux G, Bataille L, Haenlin M (2003) Cooperation between the GATA and RUNX factors Serpent and Lozenge during Drosophila hematopoiesis. EMBO J 22:6516–6525

    PubMed  CAS  Google Scholar 

  53. Fossett N, Hyman K, Gajewski K, Orkin SH, Schulz RA (2003) Combinatorial interactions of serpent, lozenge, and U-shaped regulate crystal cell lineage commitment during Drosophila hematopoiesis. Proc Natl Acad Sci USA 100:11451–11456

    PubMed  CAS  Google Scholar 

  54. Rennert J, Coffman JA, Mushegian AR, Robertson AJ (2003) The evolution of Runx genes I. A comparative study of sequences from phylogenetically diverse model organisms. BMC Evol Biol 3:4

    PubMed  Google Scholar 

  55. Burns CE, DeBlasio T, Zhou Y, Zhang J, Zon L, Nimer SD (2002) Isolation and characterization of runxa and runxb, zebrafish members of the runt family of transcriptional regulators. Exp Hematol 30:1381–1389

    PubMed  CAS  Google Scholar 

  56. Banerjee C, McCabe LR, Choi JY, Hiebert SW, Stein JL, Stein GS, Lian JB (1997) Runt homology domain proteins in osteoblast differentiation: AML3/CBFA1 is a major component of a bone-specific complex. J Cell Biochem 66:1–8

    PubMed  CAS  Google Scholar 

  57. McCarthy TL, Ji C, Chen Y, Kim KK, Imagawa M, Ito Y, Centrella M (2000) Runt domain factor (Runx)-dependent effects on CCAAT/ enhancer-binding protein delta expression and activity in osteoblasts. J Biol Chem 275:21746–21753

    PubMed  CAS  Google Scholar 

  58. Banerjee C, Javed A, Choi JY, Green J, Rosen V, van Wijnen AJ, Stein JL, Lian JB, Stein GS (2001) Differential regulation of the two principal Runx2/Cbfa1 n-terminal isoforms in response to bone morphogenetic protein-2 during development of the osteoblast phenotype. Endocrinology 142:4026–4039

    PubMed  CAS  Google Scholar 

  59. Leboy P, Grasso-Knight G, D’Angelo M, Volk SW, Lian JV, Drissi H, Stein GS, Adams SL (2001) Smad–Runx interactions during chondrocyte maturation. J Bone Joint Surg Am 83-A(Suppl 1):S15–S22

    PubMed  Google Scholar 

  60. Zhang YW, Yasui N, Ito K, Huang G, Fujii M, Hanai J, Nogami H, Ochi T, Miyazono K, Ito Y (2000) A RUNX2/PEBP2alpha A/CBFA1 mutation displaying impaired transactivation and Smad interaction in cleidocranial dysplasia. Proc Natl Acad Sci USA 97:10549–10554

    PubMed  CAS  Google Scholar 

  61. Bergwitz C, Prochnau A, Mayr B, Kramer FJ, Rittierodt M, Berten HL, Hausamen JE, Brabant G (2001) Identification of novel CBFA1/RUNX2 mutations causing cleidocranial dysplasia. J Inherit Metab Dis 24:648–656

    PubMed  CAS  Google Scholar 

  62. Zhang YW, Bae SC, Takahashi E, Ito Y (1997) The cDNA cloning of the transcripts of human PEBP2alphaA/CBFA1 mapped to 6p12.3–p21.1, the locus for cleidocranial dysplasia. Oncogene 15:367–371

    PubMed  CAS  Google Scholar 

  63. Levanon D, Bettoun D, Harris-Cerruti C, Woolf E, Negreanu V, Eilam R, Bernstein Y, Goldenberg D, Xiao C, Fliegauf M, Kremer E, Otto F, Brenner O, Lev-Tov A, Groner Y (2002) The Runx3 transcription factor regulates development and survival of TrkC dorsal root ganglia neurons. EMBO J 21:3454–3463

    PubMed  CAS  Google Scholar 

  64. Komine O, Hayashi K, Natsume W, Watanabe T, Seki Y, Seki N, Yagi R, Sukzuki W, Tamauchi H, Hozumi K, Habu S, Kubo M, Satake M (2003) The Runx1 transcription factor inhibits the differentiation of naive CD4+ T cells into the Th2 lineage by repressing GATA3 expression. J Exp Med 198:51–61

    PubMed  CAS  Google Scholar 

  65. Taniuchi I, Osato M, Egawa T, Sunshine MJ, Bae SC, Komori T, Ito Y, Littman DR (2002) Differential requirements for Runx proteins in CD4 repression and epigenetic silencing during T lymphocyte development. Cell 111:621–633

    PubMed  CAS  Google Scholar 

  66. Woolf E, Xiao C, Fainaru O, Lotem J, Rosen D, Negreanu V, Bernstein Y, Goldenberg D, Brenner O, Berke G, Levanon D, Groner Y (2003) Runx3 and Runx1 are required for CD8 T cell development during thymopoiesis. Proc Natl Acad Sci USA 100:7731–7736

    PubMed  CAS  Google Scholar 

  67. Telfer JC, Hedblom EE, Anderson MK, Laurent MN, Rothenberg EV (2004) Localization of the domains in Runx transcription factors required for the repression of CD4 in thymocytes. J Immunol 172:4359–4370

    PubMed  CAS  Google Scholar 

  68. Grueter B, Petter M, Egawa T, Laule-Kilian K, Aldrian CJ, Wuerch A, Ludwig Y, Fukuyama H, Wardemann H, Waldschuetz R, Moroy T, Taniuchi I, Steimle V, Littman DR, Ehlers M (2005) Runx3 regulates integrin alpha E/CD103 and CD4 expression during development of CD4-/CD8+ T cells. J Immunol 175:1694

    PubMed  CAS  Google Scholar 

  69. Fainaru O, Woolf E, Lotem J, Yarmus M, Brenner O, Goldenberg D, Negreanu V, Bernstein Y, Levanon D, Jung S, Groner Y (2004) Runx3 regulates mouse TGF-beta-mediated dendritic cell function and its absence results in airway inflammation. EMBO J 23:969–979

    PubMed  CAS  Google Scholar 

  70. Miyazono K, Maeda S, Imamura T (2004) Coordinate regulation of cell growth and differentiation by TGF-beta superfamily and Runx proteins. Oncogene 23:4232–4237

    PubMed  CAS  Google Scholar 

  71. Fainaru O, Shseyov D, Hantisteanu S, Groner Y (2005) Accelerated chemokine receptor 7-mediated dendritic cell migration in Runx3 knockout mice and the spontaneous development of asthma-like disease. Proc Natl Acad Sci USA 102:10598–10603

    PubMed  CAS  Google Scholar 

  72. Brenner O, Levanon D, Negreanu V, Golubkov O, Fainaru O, Woolf E, Groner Y (2004) Loss of Runx3 function in leukocytes is associated with spontaneously developed colitis and gastric mucosal hyperplasia. Proc Natl Acad Sci USA 101:16016–16021

    PubMed  CAS  Google Scholar 

  73. Yamada R, Tokuhiro S, Chang X, Yamamoto K (2004) SLC22A4 and RUNX1: identification of RA susceptible genes. J Mol Med 82:558–564

    PubMed  CAS  Google Scholar 

  74. Alarcon-Riquelme ME (2003) A RUNX trio with a taste for autoimmunity. Nat Genet 35:299–300

    PubMed  CAS  Google Scholar 

  75. Alarcon-Riquelme ME (2004) Role of RUNX in autoimmune diseases linking rheumatoid arthritis, psoriasis and lupus. Arthritis Res Ther 6:169–173

    PubMed  CAS  Google Scholar 

  76. Bottini N, Musumeci L, Alonso A, Rahmouni S, Nika K, Rostamkhani M, MacMurray J, Meloni GF, Lucarelli P, Pellecchia M, Eisenbarth GS, Comings D, Mustelin T (2004) A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat Genet 36:337–338

    PubMed  CAS  Google Scholar 

  77. Begovich AB, Carlton VE, Honigberg LA, Schrodi SJ, Chokkalingam AP, Alexander HC, Ardlie KG, Huang Q, Smith AM, Spoerke JM, Conn MT, Chang M, Chang SY, Saiki RK, Catanese JJ, Leong DU, Garcia VE, McAllister LB, Jeffery DA, Lee AT, Batliwalla F, Remmers E, Criswell LA, Seldin MF, Kastner DL, Amos CI, Sninsky JJ, Gregersen PK (2004) A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am J Hum Genet 75:330–337

    PubMed  CAS  Google Scholar 

  78. Kyogoku C, Langefeld CD, Ortmann WA, Lee A, Selby S, Carlton VE, Chang M, Ramos P, Baechler EC, Batliwalla FM, Novitzke J, Williams AH, Gillett C, Rodine P, Graham RR, Ardlie KG, Gaffney PM, Moser KL, Petri M, Begovich AB, Gregersen PK, Behrens TW (2004) Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE. Am J Hum Genet 75:504–507

    PubMed  CAS  Google Scholar 

  79. Orozco G, Sanchez E, Gonzalez-Gay MA, Lopez-Nevot MA, Torres B, Caliz R, Ortego-Centeno N, Jimenez-Alonso J, Pascual-Salcedo D, Balsa A, de Pablo R, Nunez-Roldan A, Gonzalez-Escribano MF, Martin J (2005) Association of a functional single-nucleotide polymorphism of PTPN22, encoding lymphoid protein phosphatase, with rheumatoid arthritis and systemic lupus erythematosus. Arthritis Rheum 52:219–224

    PubMed  CAS  Google Scholar 

  80. Reddy MV, Johansson M, Sturfelt G, Jonsen A, Gunnarsson I, Svenungsson E, Rantapaa-Dahlqvist S, Alarcon-Riquelme ME (2005) The R620W C/T polymorphism of the gene PTPN22 is associated with SLE independently of the associationof PDCD1. Genes Immun 6:658–662

    PubMed  CAS  Google Scholar 

  81. Wu H, Cantor RM, Graham DS, Lingren CM, Farwell L, Jager PL, Bottini N, Grossman JM, Wallace DJ, Hahn BH, Julkunen H, Hebert LA, Rovin BH, Birmingham DJ, Rioux JD, Yu CY, Kere J, Vyse TJ, Tsao BP (2005) Association analysis of the R620W polymorphism of protein tyrosine phosphatase PTPN22 in systemic lupus erythematosus families: increased T allele frequency in systemic lupus erythematosus patients with autoimmune thyroid disease. Arthritis Rheum 52:2396–2402

    PubMed  CAS  Google Scholar 

  82. Zheng W, She JX (2005) Genetic association between a lymphoid tyrosine phosphatase (PTPN22) and type 1 diabetes. Diabetes 54:906–908

    PubMed  CAS  Google Scholar 

  83. Viken MK, Amundsen SS, Kvien TK, Boberg KM, Gilboe IM, Lilleby V, Sollid LM, Forre OT, Thorsby E, Smerdel A, Lie BA (2005) Association analysis of the 1858C>T polymorphism in the PTPN22 gene in juvenile idiopathic arthritis and other autoimmune diseases. Genes Immun 6:271–273

    PubMed  CAS  Google Scholar 

  84. Velaga MR, Wilson V, Jennings CE, Owen CJ, Herington S, Donaldson PT, Ball SG, James RA, Quinton R, Perros P, Pearce SH (2004) The codon 620 tryptophan allele of the lymphoid tyrosine phosphatase (LYP) gene is a major determinant of Graves’ disease. J Clin Endocrinol Metab 89:5862–5865

    PubMed  CAS  Google Scholar 

  85. Smyth D, Cooper JD, Collins JE, Heward JM, Franklyn JA, Howson JM, Vella A, Nutland S, Rance HE, Maier L, Barratt BJ, Guja C, Ionescu-Tirgoviste C, Savage DA, Dunger DB, Widmer B, Strachan DP, Ring SM, Walker N, Clayton DG, Twells RC, Gough SC, Todd JA (2004) Replication of an association between the lymphoid tyrosine phosphatase locus (LYP/PTPN22) with type 1 diabetes, and evidence for its role as a general autoimmunity locus. Diabetes 53:3020–3023

    PubMed  CAS  Google Scholar 

  86. Qu H, Tessier MC, Hudson TJ, Polychronakos C (2005) Confirmation of the association of the R620W polymorphism in the protein tyrosine phosphatase PTPN22 with type 1 diabetes in a family based study. J Med Genet 42:266–270

    PubMed  CAS  Google Scholar 

  87. Plenge RM, Padyukov L, Remmers EF, Purcell S, Lee AT, Karlson EW, Wolfe F, Kastner DL, Alfredsson L, Altshuler D, Gregersen PK, Klareskog L, Rioux JD (2005) Replication of putative candidate-gene associations with rheumatoid arthritis in >4,000 samples from North America and Sweden: association of susceptibility with PTPN22, CTLA4, and PADI4. Am J Hum Genet 77:1044–1060

    PubMed  CAS  Google Scholar 

  88. Onengut-Gumuscu S, Ewens KG, Spielman RS, Concannon P (2004) A functional polymorphism (1858C/T) in the PTPN22 gene is linked and associated with type I diabetes in multiplex families. Genes Immun 5:678–680

    PubMed  CAS  Google Scholar 

  89. Ladner MB, Bottini N, Valdes AM, Noble JA (2005) Association of the single nucleotide polymorphism C1858T of the PTPN22 gene with type 1 diabetes. Hum Immunol 66:60–64

    PubMed  CAS  Google Scholar 

  90. Criswell LA, Pfeiffer KA, Lum RF, Gonzales B, Novitzke J, Kern M, Moser KL, Begovich AB, Carlton VE, Li W, Lee AT, Ortmann W, Behrens TW, Gregersen PK (2005) Analysis of families in the multiple autoimmune disease genetics consortium (MADGC) collection: the PTPN22 620W allele associates with multiple autoimmune phenotypes. Am J Hum Genet 76:561–571

    PubMed  CAS  Google Scholar 

  91. Begovich AB, Caillier SJ, Alexander HC, Penko JM, Hauser SL, Barcellos LF, Oksenberg JR (2005) The R620W polymorphism of the protein tyrosine phosphatase PTPN22 is not associated with multiple sclerosis. Am J Hum Genet 76:184–187

    PubMed  CAS  Google Scholar 

  92. Matesanz F, Rueda B, Orozco G, Fernandez O, Leyva L, Alcina A, Martin J (2005) Protein tyrosine phosphatase gene (PTPN22) polymorphism in multiple sclerosis. J Neurol 258:994–996

    Google Scholar 

  93. Gregersen PK (2005) Gaining insight into PTPN22 and autoimmunity. Nat Genet 37:1300–1302

    PubMed  CAS  Google Scholar 

  94. Vang T, Congia M, Macis MD, Musumeci L, Orru V, Zavattari P, Nika K, Tautz L, Tasken K, Cucca F, Mustelin T, Bottini N (2005) Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant. Nat Genet 37:1317–1319

    PubMed  CAS  Google Scholar 

  95. Alcocer-Varela J, Alarcon-Segovia D (1982) Decreased production of and response to interleukin-2 by cultured lymphocytes from patients with systemic lupus erythematosus. J Clin Invest 69:1388–1392

    Article  PubMed  CAS  Google Scholar 

  96. Linker-Israeli M, Bakke AC, Kitridou RC, Gendler S, Gillis S, Horwitz DA (1983) Defective production of interleukin 1 and interleukin 2 in patients with systemic lupus erythematosus (SLE). J Immunol 130:2651–2655

    PubMed  CAS  Google Scholar 

  97. Miyara M, Amoura Z, Parizot C, Badoual C, Dorgham K, Trad S, Nochy D, Debre P, Piette JC, Gorochov G (2005) Global natural regulatory T cell depletion in active systemic lupus erythematosus. J Immunol 175:8392–8400

    PubMed  CAS  Google Scholar 

  98. Bensinger SJ, Walsh PT, Zhang J, Carroll M, Parsons R, Rathmell JC, Thompson CB, Burchill MA, Farrar MA, Turka LA (2004) Distinct IL-2 receptor signaling pattern in CD4+CD25+ regulatory T cells. J Immunol 172:5287–5296

    PubMed  CAS  Google Scholar 

  99. Ronnblom L, Alm GV (2001) An etiopathogenic role for the type I IFN system in SLE. Trends Immunol 22:427–431

    PubMed  CAS  Google Scholar 

  100. Ronnblom L, Alm GV (2002) The natural interferon-alpha producing cells in systemic lupus erythematosus. Hum Immunol 63:1181–1193

    PubMed  CAS  Google Scholar 

  101. Crow MK, Kirou KA, Wohlgemuth J (2003) Microarray analysis of interferon-regulated genes in SLE. Autoimmunity 36:481–490

    PubMed  CAS  Google Scholar 

  102. Bennett L, Palucka AK, Arce E, Cantrell V, Borvak J, Banchereau J, Pascual V (2003) Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J Exp Med 197:711–723

    PubMed  CAS  Google Scholar 

  103. Kirou KA, Lee C, George S, Louca K, Papagiannis IG, Peterson MG, Ly N, Woodward RN, Fry KE, Lau AY, Prentice JG, Wohlgemuth JG, Crow MK (2004) Coordinate overexpression of interferon-alpha-induced genes in systemic lupus erythematosus. Arthritis Rheum 50:3958–3967

    PubMed  CAS  Google Scholar 

  104. Baechler EC, Batliwalla FM, Karypis G, Gaffney PM, Ortmann WA, Espe KJ, Shark KB, Grande WJ, Hughes KM, Kapur V, Gregersen PK, Behrens TW (2003) Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci USA 100:2610–2615

    PubMed  CAS  Google Scholar 

  105. Zhuang H, Kosboth M, Lee P, Rice A, Driscoll DJ, Zori R, Narain S, Lyons R, Satoh M, Sobel E, Reeves WH (2006) Lupus-like disease and high interferon levels corresponding to trisomy of the type I interferon cluster on chromosome 9p. Arthritis Rheum 54:1573–1579

    PubMed  CAS  Google Scholar 

  106. Feuk L, Marshall CR, Wintle RF, Scherer SW (2006) Structural variants: changing the landscape of chromosomes and design of disease studies. Hum Mol Genet 15(Spec No 1):R57–R66

    PubMed  CAS  Google Scholar 

  107. Sigurdsson S, Nordmark G, Goring HH, Lindroos K, Wiman AC, Sturfelt G, Jonsen A, Rantapaa-Dahlqvist S, Moller B, Kere J, Koskenmies S, Widen E, Eloranta ML, Julkunen H, Kristjansdottir H, Steinsson K, Alm G, Ronnblom L, Syvanen AC (2005) Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus. Am J Hum Genet 76:528–537

    PubMed  CAS  Google Scholar 

  108. Graham RR, Kozyrev SV, Baechler EC, Reddy MV, Plenge RM, Bauer JW, Ortmann WA, Koeuth T, Escribano MF, Pons-Estel B, Petri M, Daly M, Gregersen PK, Martin J, Altshuler D, Behrens TW, Alarcon-Riquelme ME, T.A. Collaborative Groups (2006) A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus. Nat Genet 38:550–555

    PubMed  CAS  Google Scholar 

  109. Takaoka A, Yanai H, Kondo S, Duncan G, Negishi H, Mizutani T, Kano S, Honda K, Ohba Y, Mak TW, Taniguchi T (2005) Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors. Nature 434:243–249

    PubMed  CAS  Google Scholar 

  110. Mancl ME, Hu G, Sangster-Guity N, Olshalsky SL, Hoops K, Fitzgerald-Bocarsly P, Pitha PM, Pinder K, Barnes BJ (2005) Two discrete promoters regulate the alternatively spliced human interferon regulatory factor-5 isoforms. Multiple isoforms with distinct cell type-specific expression, localization, regulation, and function. J Biol Chem 280:21078–21090

    PubMed  CAS  Google Scholar 

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Acknowledgments

The work described in this study has been supported by the Swedish Research Council, the Swedish Association Against Rheumatism, the Marcus Borgströms Foundation, the Gustaf V:e80-års Fond, and the Alliance For Lupus Research.

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  1. Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Dag Hammarskjölds väg 20, 751 85, Uppsala, Sweden

    Marta E. Alarcón-Riquelme

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Correspondence to Marta E. Alarcón-Riquelme.

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Alarcón-Riquelme, M.E. The genetics of systemic lupus erythematosus: understanding how SNPs confer disease susceptibility. Springer Semin Immun 28, 109–117 (2006). https://doi.org/10.1007/s00281-006-0033-4

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