Skip to main content
SpringerLink
Log in

Genome Screening for Susceptibility Loci in Systemic Lupus Erythematosus

  • Genomics in Human Disease
  • Published:
American Journal of Pharmacogenomics

Abstract

Systemic lupus erythematosus (SLE) is a complex, multigenic autoimmune disease with a wide spectrum of clinical manifestations. Much of the pathology is attributed to deposition to various tissues of immune complexes continuously formed with autoantibodies; thus, the pathogenesis is related to dysregulation of self-reactive B cells. Recent family linkage studies and allele-sharing linkage analyses of affected sibling pairs have advanced genome screening for susceptibility loci in SLE, and a considerable number of chromosomal intervals with significant or suggestive linkage to SLE have been identified. However, there are still several inherent difficulties in precisely identifying loci and genes, as the complexity of polygenic inheritance of SLE phenotypes is considerable. One must note that each specific aspect of diverse SLE phenotypes (clinical manifestations and immunological abnormalities) is mostly controlled separately by a different set of susceptibility loci. Involvement of positive and negative epistatic gene interactions often puzzles genetic analyses. Studies on SLE using murine lupus models are ongoing to solve some of these difficulties. Comparative studies have identified several syntenic chromosomal intervals with susceptibility loci in both mouse models and humans. Thus, combining knowledge derived from both human and murine studies is vital. The ultimate identification of susceptibility genes and their functions will probably depend largely on studies using genetically manipulated mutant mice, including those with homologous recombination of potent polymorphic target genes. The up-coming completion of genomic sequences in mice and humans is predicted to limit the numbers of potent candidate genes in particular genomic intervals and accelerates this line of studies. Such knowledge will lead to elucidation of genetic and cellular mechanisms involved in the dysregulation of self-reactive lymphocytes in the pathogenesis of SLE. Prophylactic and therapeutic clinical approaches can then be better designed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1a
Fig. 1b
Fig. 2
Table I

Similar content being viewed by others

References

  1. Wallace DJ, Hahn BH, editors. Dubois’ lupus erythematosus. 5th ed. Baltimore (MD): Williams & Wilkins, 1997

    Google Scholar 

  2. Arnett FC. Genetic studies of human lupus in families. Int Rev Immunol 2000; 19: 289–95

    Article  Google Scholar 

  3. Arnett FC. The genetics of human lupus. In: Wallace DJ, Hahn BH, editors. Dubois’ lupus erythematosus. 5th ed. Baltimore (MD): Williams & Wilkins; 1997: 77–117

    Google Scholar 

  4. Shirai T, Hirose S. Genetics of SLE; a sine qua non for identification. Int Rev Immunol 2000; 19: 289–95

    Article  PubMed  CAS  Google Scholar 

  5. Hirose S, Jiang Y, Hamano Y, et al. Genetic aspects of inherent B-cell abnormalities associated with SLE and B-cell malignancy: lessons from New Zealand mouse models. Int Rev Immunol 2000; 19: 389–421

    Article  PubMed  CAS  Google Scholar 

  6. Tan EM, Cohen AS, Fries JF, et al. Special article: the 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982; 25: 1271–7

    Article  PubMed  CAS  Google Scholar 

  7. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997; 40: 1725

    Article  PubMed  CAS  Google Scholar 

  8. Shirai T. The genetic basis of autoimmunity in murine lupus. Immunol Today 1982; 3: 187–94

    Article  Google Scholar 

  9. Shur PH. Complement and systemic lupus erythematosus. In: Wallace DJ, Hahn BH, editors. Dubois’ lupus erythematosus. 5th ed. Baltimore (MD): Williams & Wilkins; 1997:245–61

    Google Scholar 

  10. Salmon JE. Abnormalities in immune complex clearance and Fcγ receptor function. In: Wallace DJ, Hahn BH, editors. Dubois’ lupus erythematosus. 5th ed. Baltimore (MD): Williams & Wilkins; 1997: 221–43

    Google Scholar 

  11. Tsao BP. Lupus susceptibility genes on human chromosome 1. Int Rev Immunol 2000; 19: 319–34

    Article  PubMed  CAS  Google Scholar 

  12. Tsao BP, Cantor RM, Kalunian KC, et al. Evidence for linkage of a candidate chromosome 1 region to human systemic lupus erythematosus. J Clin Invest 1997; 99: 725–31

    Article  PubMed  CAS  Google Scholar 

  13. Gaffney PM, Kearns GM, Shark KB, et al. A genome-wide search for susceptibility genes in human systemic lupus erythematosus sib-pair families. Proc Natl Acad Sci U S A 1998; 95: 14875–9

    Article  PubMed  CAS  Google Scholar 

  14. Moser KL, Neas BR, Salmon JE, et al. Genome scan of human systemic lupus erythematosus: evidence for linkage on chromosome 1q in African-American pedigrees. Proc Natl Acad Sci U S A 1998; 95: 14869–74

    Article  PubMed  CAS  Google Scholar 

  15. Shai R, Quismorio Jr FP, Li L, et al. Genome-wide screen for systemic lupus erythematosus susceptibility genes in multiplex families. Hum Mol Genet 1999; 8: 639–44

    Article  PubMed  CAS  Google Scholar 

  16. Gaffney PM, Ortmann WA, Selby SA, et al. Genome screening in human systemic lupus erythematosus: results from a second Minnesota cohort and combined analysis of 187 sib-pair families. Am J Hum Genet 2000; 66: 547–56

    Article  PubMed  CAS  Google Scholar 

  17. Lindqvist AK, Steinsson K, Johanneson B, et al. A susceptibility locus for human systemic lupus erythematosus (hSLE1) on chromosome 2q. J Autoimmun 2000; 14: 169–78

    Article  PubMed  CAS  Google Scholar 

  18. Gray-McGuire C, Moser KL, Gaffney PM, et al. Genome scan of human systemic lupus erythematosus by regression modeling. evidence of linkage and epistasis at 4pl6-15.2. Am J Hum Genet 2000; 67: 1460–9

    Article  PubMed  CAS  Google Scholar 

  19. Lander ES, Kruglyak L. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nature Genet 1995; 11: 241–7

    Article  PubMed  CAS  Google Scholar 

  20. Kono DH, Burlingame RW, Owens DG, et al. Lupus susceptibility loci in New Zealand mice. Proc Natl Acad Sci U S A 1994; 91: 10168–72

    Article  PubMed  CAS  Google Scholar 

  21. Morel L, Rudofsky UH, Longmate JA, et al. Polygenic control of susceptibility to murine systemic lupus erythematosus. Immunity 1994; 1: 219–29

    Article  PubMed  CAS  Google Scholar 

  22. Vyse TJ, Rozzo SJ, Drake CG, et al. Control of multiple autoantibodies linked with a lupus nephritis susceptibility locus in New Zealand black mice. J Immunol 1997; 158: 5566–74

    PubMed  CAS  Google Scholar 

  23. Jiang Y, Hirose S, Sanokawa-Akakura R, et al. Genetically determined aberrant down-regulation of FcγRIIB 1 in germinal center B cells associated with hyper-IgG and IgG autoantibodies in murine systemic lupus erythematosus. Int Immunol 1999; 11: 1685–91

    Article  PubMed  CAS  Google Scholar 

  24. Izui S, Ibnou-Zekri N, Fossati-Jimack L, et al. Genetics of SLE: lessons from BXSB and related mouse models. Int Rev Immunol 2000; 19: 447–72

    Article  PubMed  CAS  Google Scholar 

  25. Kono DH, Theofilopoulos AN. Genetics of systemic autoimmunity in mouse models of lupus. Int Rev Immunol 2000; 19: 367–87

    Article  PubMed  CAS  Google Scholar 

  26. Drake CG, Babcock SK, Palmer E, et al. Genetic analysis of the NZB contribution to lupus-like autoimmune disease in (NZB × NZW) F1 mice. Proc Natl Acad Sci U S A 1994; 91: 4062–6

    Article  PubMed  CAS  Google Scholar 

  27. Hirose S, Tsurui H, Nishimura H, et al. Mapping of a gene for hypergammaglobulinemia to the distal region on chromosome 4 in NZB mice and its contribution to systemic lupus erythematosus in (NZB × NZW) F1 mice. Int Immunol 1994; 6: 1857–64

    Article  PubMed  CAS  Google Scholar 

  28. Jiang Y, Hirose S, Hamano Y, et al. Mapping of a gene for the increased susceptibility of B1 cells to Mott cell formation in murine autoimmune disease. J Immunol 1997; 158: 992–7

    PubMed  CAS  Google Scholar 

  29. Ida A, Hirose S, Hamano Y, et al. Multigenic control of lupus-associated antiphospholipid syndrome in a model of (NZW × BXSB) F1 mice. Eur J Immunol 1998; 28: 2694–703

    Article  PubMed  CAS  Google Scholar 

  30. Ochiai K, Ozaki S, Tanino A, et al. Genetic regulation of anti-erythrocyte autoantibodies and splenomegaly in autoimmune hemolytic anemia-prone New Zealand black mice. Int Immunol 2000; 12: 1–8

    Article  PubMed  CAS  Google Scholar 

  31. Wheeler DL, Church DM, Lash AE, et al. Database resources of the National Center for Biotechnology Information. Nucleic Acids Res 2001; 29: 11–6

    Article  PubMed  CAS  Google Scholar 

  32. Pruitt KD, Maglott D. RefSeq and LocusLink: NCBI gene-centered resources. Nucleic Acids Res 2001; 29: 137–40

    Article  PubMed  CAS  Google Scholar 

  33. Knight GJ, Adams DD and Purves HD. The genetic contribution of the NZB mouse to the renal disease of the NZB × NZW hybrid. Clin Exp Immunol 1977; 28: 352–8

    PubMed  CAS  Google Scholar 

  34. Knight GJ, Adams DD. Three genes for lupus nephritis in NZB × NZW mice. J Exp Med 1978; 147: 1653–60

    Article  PubMed  CAS  Google Scholar 

  35. Yoshida H, Kohno A, Ohta K, et al. Genetic studies of autoimmunity in New Zealand mice III. Associations among anti-DNA antibodies, NTA, and renal disease in (NZB × NZW) F1 × NZW backcross mice. J Immunol 1981; 127: 433–7

    PubMed  CAS  Google Scholar 

  36. Hirose S, Nagasawa R, Sekikawa I, et al. Enhancing effect of H-2-linked NZW gene(s) on the autoimmune traits of (NZB × NZW) F1 mice. J Exp Med 1983; 158: 228–33

    Article  PubMed  CAS  Google Scholar 

  37. Maruyama N, Furukawa F, Nakai Y, et al. Genetic studies of autoimmunity in New Zealand mice IV. Contribution of NZB and NZW genes to the spontaneous occurrence of retroviral gp70 immune complexes in (NZB × NZW) Fl hybrid and the correlation to renal disease. J Immunol 1998; 130: 740–6

    Google Scholar 

  38. Hirose S, Sekigawa I, Ozaki S, et al. Genetic regulation oh hypergammaglobulinemia and the correlations to autoimmune traits in (NZB × NZW) F1 hybrid. Clin Exp Immunol 1984; 58: 694–702

    PubMed  CAS  Google Scholar 

  39. Watson ML, Rao JK, Gilson GS, et al. Genetic analysis of MRL-lpr mice: relationship of the Fas apoptosis gene to disease manifestation and renal disease-modifying loci. J Exp Med 1992; 176: 1645–56

    Article  PubMed  CAS  Google Scholar 

  40. Vyse TJ, Drake CG, Rozzo SJ, et al. Genetic linkage of IgG autoantibody production in relation to lupus nephritis in New Zealand mice. J Clin Invest 1996; 98:1762–72

    Article  PubMed  CAS  Google Scholar 

  41. Wang Y, Nose M, Kamoto T, et al. Host modifier genes affect mouse autoimmunity induced by the lpr gene. Am J Pathol 1997; 151: 1791–8

    PubMed  CAS  Google Scholar 

  42. Gu L, Weinreb A, Wang XP, et al. Genetic determinants of autoimmune disease and coronary vasculitis in the MRL-lpr/lpr mouse model of systemic lupus erythematosus. J Immunol 1998; 161: 6999–7006

    PubMed  CAS  Google Scholar 

  43. Vidal S, Kono DH and Theofilopoulos AN. Loci predisposing to autoimmunity in MRL-Faslpr and C57BL/6-Faslpr mice. J Clin Invest 1998; 101: 696–702

    Article  PubMed  CAS  Google Scholar 

  44. Santiago ML, Mart C, Parzy D, et al. Linkage of a major quantitative trait locus to Yaa gene-induced lupus-like nephritis in (NZW × C57BL/6) F1 mice. Eur J Immunol 1998; 28: 4257–67

    Article  PubMed  CAS  Google Scholar 

  45. Morel L, Mohan C, Yu Y, et al. Multiplex inheritance of component phenotypes in a murine model. Mamm Genome 1999; 10: 176–81

    Article  PubMed  CAS  Google Scholar 

  46. Haywood MK, Hogarth MB, Slingsby JH, et al. Identification of intervals on chromosome 1, 3, and 13 linked to the development of lupus in BXSB mice. Arthritis Rheum 2000; 43: 349–55

    Article  PubMed  CAS  Google Scholar 

  47. Hirose S, Tokushige K, Kinoshita K, et al. Contribution of the gene linked to the T cell receptor β chain gene complex of NZW mice to the autoimmunity of (NZB × NZW) F1 mice. Eur J Immunol 1991; 21: 823–6

    Article  PubMed  CAS  Google Scholar 

  48. Hirose S, Ueda G, Noguchi K, et al. Requirement of H-2 heterozygosity for autoimmunity in (NZB × NZW) F1 hybrid mice. Eur J Immunol 1986; 16: 1631–3

    Article  PubMed  CAS  Google Scholar 

  49. Morel L, Tian XH, Croker BP, et al. Epistatic modifiers of autoimmunity in a murine model of lupus nephritis. Immunity 1999; 11: 131–9

    Article  PubMed  CAS  Google Scholar 

  50. Falconer DS. Threshold characters. In: Introduction to quantitative genetics. 2nd ed. New York, Longman, 1981, 80

    Google Scholar 

  51. Khono A, Yoshida H, Sekita K, et al. Genetic regulation of the class conversion of dsDNA-specific antibodies in (NZB × NZW) F1 hybrid. Immunogenetics 1983; 18: 513–24

    Article  Google Scholar 

  52. Okada T, Takiura F, Tokushige K, et al. Major histocompatibility complex controls clonal proliferation of CD5+ B cells in H-2-congenic New Zealand mice: a model for B-cell chronic lymphocytic leukemia and autoimmune disease. Eur J Immunol 1991; 21: 2743–8

    Article  PubMed  CAS  Google Scholar 

  53. Hamano Y, Hirose S, Ida A, et al. Susceptibility alleles for aberrant B-1 cell proliferation involved in spontaneously occurring B cell chronic lymphocytic leukemia in a model of New Zealand white mice. Blood 1998; 92: 3772–9

    PubMed  CAS  Google Scholar 

  54. Hirose S, Kinoshita K, Nozawa S, et al. Effects of major histocompatibility complex on autoimmune disease of H-2-congenic New Zealand mice. Int Immunol 1990; 2: 1091–5

    Article  PubMed  CAS  Google Scholar 

  55. Harley JB, Moser KL, Gaffney PM, et al. The genetics of human systemic lupus erythematosus. Curr Opin Immunol 1998; 10: 690–6

    Article  PubMed  CAS  Google Scholar 

  56. Hirose S, Ogawa S, Nishimura H, et al. Association of HLA-DR2/DR4 heterozygosity with systemic lupus erythematosus in Japanese patients. J Rheumatol 1988; 15: 1489–92

    PubMed  CAS  Google Scholar 

  57. Howie JB, Helyer BJ. The immunology and pathology of NZB mice. Adv Immunol 1968; 9: 215–66

    Article  PubMed  CAS  Google Scholar 

  58. Theofilopoulos AN, Dixon FJ. Murine models of systemic lupus erythematosus. Adv Immunol 1985; 37: 269–390

    Article  PubMed  CAS  Google Scholar 

  59. Shirai T, Hirose S, Okada T, et al. Immunology and immunopathology of the autoimmune disease of NZB and related mouse strains. In: Rihova B, Vetvicka V, editors. Immunological disorders in mice. Boca Raton (FL): CRC Press, 1991: 96–136

    Google Scholar 

  60. Murphy ED, Roth JB. Autoimmunity and lymphoproliferation: induction by mutant gene lpr, and acceleration by a male-associated factor in strain BXSB mice. In: Rose NR, Bigazzi PE, Warner NL, editors. Genetic control of autoimmune disease. Amsterdam: Elsevier, 1978: 207–21

    Google Scholar 

  61. Lander ES, Botstein D. Mapping Mendelian factors underlying quantitative traits using RFLP linkage maps. Genetics 1989; 121: 185–99

    PubMed  CAS  Google Scholar 

  62. Nishimura H, Ozaki S. Practical approaches to determining disease-susceptibility loci in multigenic autoimmune models. Int Rev Immunol 2000; 19: 335–66

    Article  PubMed  CAS  Google Scholar 

  63. Bielschowsky M, Helyer BJ, Howie JB. Spontaneous haemolytic anemia in mice of the NZB/B1 strain. Proc Univ Otago Med Sch 1959; 37: 9–11

    Google Scholar 

  64. Helyer BJ, Howie JB. Renal disease associated with positive lupus erythematosus tests in a cross-bred strain of mice [letter]. Nature 1963; 197: 197

    Article  PubMed  CAS  Google Scholar 

  65. Burnet FM, Holmes MC. The natural history of the NZB/NZW Fl hybrid mouse: a laboratory model of systemic lupus erythematosus. Australas Ann Med 1965; 14: 185–91

    PubMed  CAS  Google Scholar 

  66. Morel L, Wakeland EK. Genetics of SLE: lessons from the NZM2410 model and related strains. Int Rev Immunol 2000; 19: 423–46

    Article  PubMed  CAS  Google Scholar 

  67. Vyse TJ, Kotzin BL. Genetic susceptibility to systemic lupus erythematosus. Annu Rev Immunol 1998; 16: 261–92

    Article  PubMed  CAS  Google Scholar 

  68. Rudofsky UH, Evans BD, Balaban SL, et al. Dissection in expression of lupus nephritis in New Zealand mixed H-2Z homozygous inbred strains of mice derived from New Zealand black and New Zealand white mice; origins and initial characterization. Lab Invest 1993; 68: 419–26

    PubMed  CAS  Google Scholar 

  69. Nose M, Nishihara M, Fujii H. Genetic basis of complex pathological manifestations of collagen disease: lessons from MRL/lpr and related mouse models. Int Rev Immunol 2000; 19: 473–98

    Article  PubMed  CAS  Google Scholar 

  70. Watanabe-Fukunaga R, Brannan CI, Copeland NG, et al. Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediate apoptosis. Nature 1992; 356: 314–7

    Article  PubMed  CAS  Google Scholar 

  71. Hughes GRV, Harris EN, Gharavi AE. The anticardiolipin syndrome. J Rheumatol 1986; 13: 486–9

    PubMed  CAS  Google Scholar 

  72. Koike T, Matsuura E. β2-glycoprotein I and antiphospholipid syndrome. Isr J Med Sci 1997; 33: 225–38

    PubMed  CAS  Google Scholar 

  73. Hang LM, Izui S, Dixon FJ. (NZW × BXSB) F1 hybrid; a model of acute lupus and coronary vascular disease with myocardial infarction. J Exp Med 1981; 154: 216–21

    Article  PubMed  CAS  Google Scholar 

  74. Oyaizu N, Yasumizu R, Miyama-Inaba M, et al. (NZW × BXSB) F1 mouse; a new animal model of idiopathic thrombocytopenic purpura. J Exp Med 1988; 167: 2017–22

    Article  PubMed  CAS  Google Scholar 

  75. Hashimoto Y, Kawamura M, Ichikawa K, et al. Anticardiolipin antibodies in NZW × BXSB F1 mice: a model of antiphospholipid syndrome. J Immunol 1992; 149: 1063–8

    PubMed  CAS  Google Scholar 

  76. Izui S, Kelley VE, Masuda K, et al. Induction of various autoantibodies by mutant gene lpr in several strains of mice. J Immunol 1984; 133: 227–33

    PubMed  CAS  Google Scholar 

  77. Hudgins CC, Steinberg RT, Klinman DM, et al. Studies of consomic mice bearing the Y chromosome of the BXSB mouse. J Immunol 1985; 134: 3849–54

    PubMed  CAS  Google Scholar 

  78. Rieux-Laucat F, Le Deist F, Hivroz C, et al. Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity. Science 1995; 268: 1347–9

    Article  PubMed  CAS  Google Scholar 

  79. Fisher GH, Rosenberg FJ, Straus SE, et al. Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell 1995; 81: 935–46

    Article  PubMed  CAS  Google Scholar 

  80. Ozaki S, Honda H, Maruyama N, et al. Genetic regulation of erythrocyte autoantibody production in New Zealand black mice. Immunogenetics 1983; 18: 241–54

    Article  PubMed  CAS  Google Scholar 

  81. Nishimura H, Okamoto H, Ogawa S, et al. MHC class II gene polymorphism of New Zealand mice and its possible contribution to autoimmunity. In: Yoshida TO, Wilson JM, editors. Molecular approaches to the study and treatment of human disease. Amsterdam: Elsevier Science Publishers. 1992: 315–22

    Google Scholar 

  82. Shirai J, Ida A, Jiang Y, et al. Genetic polymorphism of murine tissue plasminogen activator associated with antiphospholipid syndrome. Genes and Immun 1999; 1: 130–6

    Article  CAS  Google Scholar 

  83. Gavalchin J, Nicklas JA, Eastcott JW, et al. Lupus prone (NZB × SWR) F1 mice produce potentially nephritogenic autoantibodies inherited from the normal SWR parent. J Immunol 1985; 134: 885–94

    PubMed  CAS  Google Scholar 

  84. Warner NL. Genetic aspects of immunological abnormalities in New Zealand mouse strains. Arthritis Rheum 1978; 21: S106–12

    Article  PubMed  CAS  Google Scholar 

  85. Okada T, Abe M, Takiura F, et al. Distinct surface phenotypes of B cells responsible for spontaneous production of IgM and IgG anti-DNA antibodies in autoimmune-prone NZB × NZW F1 mice. Autoimmunity 1990; 7: 109–20

    Article  PubMed  CAS  Google Scholar 

  86. Hasegawa K, Abe M, Okada T, et al. Are Ly1 B cells responsible for the IL 2-hyperresponsiveness of B cells in autoimmune-prone NZB × NZW F1 mice? Int Immunol 1989; 1: 99–103

    Article  PubMed  CAS  Google Scholar 

  87. Abe M, Okada T, Matsumoto Y, et al. The novel murine B cell differentiation antigen Lp-3. Int Immunol 1989; 1: 576–81

    Article  PubMed  CAS  Google Scholar 

  88. Kanno K, Okada T, Abe M, et al. Differential sensitivity to interleukins of CD5+ and CD5− anti-DNA antibody-producing B cells in murine lupus. Autoimmunity 1993; 14: 205–14

    Article  PubMed  CAS  Google Scholar 

  89. Shirai T, Okada T, Hirose S. Genetic regulation of CD5+ B cells in autoimmune disease and in chronic lymphocytic leukemia. Ann N Y Acad Sci 1992; 651: 509–26

    Article  PubMed  CAS  Google Scholar 

  90. Herzenberg LA, Stall AM, Lalor PA, et al. The LY-1 B cell lineage. Immunol Rev 1986; 93: 81–102

    Article  PubMed  CAS  Google Scholar 

  91. Hardy RR, Hayakawa K. CD5 cells, a fetal B cell lineage. Adv Immunol 1994; 55: 297–339

    Article  PubMed  CAS  Google Scholar 

  92. Okamoto H, Nishimura H, Shinozaki A, et al. H-2Z homozygous New Zealand mice as a model for B-cell chronic lymphocytic leukemia: elevated bcl-2 expression in CD5 B cells at premalignant stages. Jpn J Cancer Res 1993; 84: 1273–8

    Article  PubMed  CAS  Google Scholar 

  93. Taki S, Hirose S, Kinoshita K, et al. Somatically mutated IgG anti-DNA antibody clonally related to germ-line encoded IgM anti-DNA antibody. Eur J Immunol 1992; 22: 987–92

    Article  PubMed  CAS  Google Scholar 

  94. Hirose S, Wakiya M, Kawano-Nishi Y, et al. Somatic diversification and affinity maturation of IgM and IgG anti-DNA antibodies in murine lupus. Eur J Immunol 1993; 23: 2813–20

    Article  PubMed  CAS  Google Scholar 

  95. Coggeshall KM. Inhibitory signaling by B cell FcγRIIb. Curr Opin Immunol 1998; 10: 306–12

    Article  PubMed  CAS  Google Scholar 

  96. Gessner JE, Heiken H, Tamm A, et al. The IgG Fc receptor family. Ann Hematol 1998; 76: 231–48

    Article  PubMed  CAS  Google Scholar 

  97. Bolland S and Ravetch JV. Spontaneous autoimmune disease in FcγRIIB-deficient mice results from strain-specific epistasis. Immunity 2000; 13: 277–85

    Article  PubMed  CAS  Google Scholar 

  98. Jiang Y, Hirose S, Abe M, et al. Polymorphisms in IgG Fc receptor IIB regulatory regions associated with autoimmune susceptibility. Immunogenetics 2000; 51: 429–35

    Article  PubMed  CAS  Google Scholar 

  99. Morel L, Blenman KR, Croker BP, et al. The major murine systemic lupus erythematosus susceptibility locus, Sle1, is a cluster of functionally related genes. Proc Natl Acad Sci U S A 2001; 98: 1787–92

    Article  PubMed  CAS  Google Scholar 

  100. Rosso SJ, Allard JD, Choubey D, et al. Evidence for an interferon-inducible gene, Ifi202, in the susceptibility to systemic lupus erythematosus. Immunity 2001; 15: 435–43

    Article  Google Scholar 

  101. Jongeneel CV, Acha-Orbea H, Blankenstein T. A polymorphic microsatellite in the tumor necrosis factor α promoter identifies an allele unique to the NZW mouse strain. J Exp Med 1990; 171: 2141–6

    Article  PubMed  CAS  Google Scholar 

  102. Jacob CO, Hwang F, Lewis GD, et al. Tumor necrosis factor alpha in murine systemic lupus erythematosus disease models: implications for genetic predisposition and immune regulation. Cytokine 1991; 3: 551–61

    Article  PubMed  CAS  Google Scholar 

  103. Jacob CO, McDevitt HO. Tumor necrosis factor-α in murine autoimmune ‘lupus’ nephritis. Nature 1988; 331: 356–8

    Article  PubMed  CAS  Google Scholar 

  104. Strasser A, Whittingham S, Vaux DL, et al. Enforced BCL2 expression in B-lymphoid cells prolongs antibody responses and elicits autoimmune disease. Proc Natl Acad Sci U S A 1991; 88: 8661–5

    Article  PubMed  CAS  Google Scholar 

  105. Zhang L, Eddy A, Teng YT, et al. An immunological renal disease in transgenic mice that overexpress Fli-1, a member of the ets family of transcription factor genes. Mol Cell Biol 1995; 15: 6961–70

    PubMed  CAS  Google Scholar 

  106. Sato S, Ono N, Steeber DA, et al. CD19 regulates B lymphocyte signaling thresholds critical for the development of B-1 lineage cells and autoimmunity. J Immunol 1996; 157: 4371–8

    PubMed  CAS  Google Scholar 

  107. Erb KJ, Ruger B, von Brevern M, et al. Constitutive expression of interleukin (IL)-4 in vivo cause autoimmune-type disorders in mice. J Exp Med 1997; 185: 329–39

    Article  PubMed  CAS  Google Scholar 

  108. Seery JP, Carroll JM, Cattell V, et al. Anti-nuclear autoantibodies and lupus nephritis in transgenic mice expressing interferon gamma in the epidermis. J Exp Med 1997; 186: 1455–9

    Article  Google Scholar 

  109. Gross JA, Johnston J, Mudri S, et al. TACI and BCMA are receptors for a TNF homologue implicated in B-cell autoimmune disease. Nature 2000; 404: 995–9

    Article  PubMed  CAS  Google Scholar 

  110. Dang H, Geiser AG, Letterio JJ, et al. SLE-like autoantibodies and Sjögren’s syndrome-like lymphoproliferation in TGF-beta knockout mice. J Immunol 1994; 155: 3205–12

    Google Scholar 

  111. Sadlack B, Lohler J, Schorle H, et al. Generalized autoimmune disease in inter-leukin-2-deficient mice is triggered by an uncontrolled activation and proliferation of CD4+ T cells. Eur J Immunol 1995; 25(11): 3053–9

    Article  PubMed  CAS  Google Scholar 

  112. Willerford DM, Chen J, Ferry JA, et al. Interleukin-2 receptor α chain regulates the size and content of the peripheral lymphoid compartment. Immunity 1995; 3: 521–30

    Article  PubMed  CAS  Google Scholar 

  113. Suzuki H, Kundig TM, Furlonger C, et al. Deregulated T cell activation and autoimmunity in mice lacking interleukin-2 receptor β. Science 1995; 268: 1472–6

    Article  PubMed  CAS  Google Scholar 

  114. Nishizumi H, Taniuchi I, Yamanashi Y, et al. Impaired proliferation of peripheral B cells and indication of autoimmune disease in lyn-deficient mice. Immunity 1995; 3: 549–60

    Article  PubMed  CAS  Google Scholar 

  115. Hibbs ML, Tarlinton DM, Armes J, et al. Multiple defects in the immune system of Lyn-deficient mice, culminating in autoimmune disease. Cell 1995; 83: 301–11

    Article  PubMed  CAS  Google Scholar 

  116. O’Keefe TL, Williams GT, Davies SL, et al. Hyperresponsive B cells in CD22-deficient mice. Science 1996; 274: 798–801

    Article  PubMed  Google Scholar 

  117. Botto M, Dell’Agnola C, Bygrave AE, et al. Homozygous Clq deficiency caused glomerulonephritis associated with multiple apoptotic bodies. Nat Genet 1998; 19: 56–9

    Article  PubMed  CAS  Google Scholar 

  118. Wang JH, Avitahl N, Cariappa A, et al. Aiolos regulates B cell activation and maturation to effector state. Immunity 1998; 9: 543–53

    Article  PubMed  CAS  Google Scholar 

  119. Nishimura H, Nose M, Hiai H, et al. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 1999; 11: 141–51

    Article  PubMed  CAS  Google Scholar 

  120. Bickerstaff MCM, Botto M, Hutchinson WL, et al. Serum amyloid P component controls chromatin degradation and prevent antinuclear autoimmunity. Nat Med 1999; 5: 694–7

    Article  PubMed  CAS  Google Scholar 

  121. Chen Z, Koralov SB and Kelso G. Complement C4 inhibits systemic autoimmunity through a mechanism independent of complement receptors CR1 and CR2. J Exp Med 2000; 192: 1339–51

    Article  PubMed  CAS  Google Scholar 

  122. Napirei M, Karsunky H, Zevnik B, et al. Features of systemic lupus erythematosus in Dnase 1-deficient mice. Nat Genet 2000; 25: 177–81

    Article  PubMed  CAS  Google Scholar 

  123. Bachmaier K, Krawczyk C, Kozieradzki I, et al. Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b. Nature 2000; 403: 211–6

    Article  PubMed  CAS  Google Scholar 

  124. Yan M, Wang H, Chan B, et al. Activation and accumulation of B cells in TACI-deficient mice. Nat Immunol 2001; 2: 638–43

    Article  PubMed  CAS  Google Scholar 

  125. Sachidanandam R, Weissman D, Schmidt SC, et al. A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms. Nature 2001; 409: 928–33

    Article  PubMed  CAS  Google Scholar 

  126. Spielman RS, Ewens WJ. The TDT and other family-based tests for linkage disequilibrium and association. Am J Hum Genet 1996; 59: 983–9

    PubMed  CAS  Google Scholar 

  127. Kruglyak L. Prospects for whole-genome linkage disequilibrium mapping of common disease genes. Nat Genet 1999; 22: 139–44

    Article  PubMed  CAS  Google Scholar 

  128. Collins A, Lonjou C, Morton NE. Genetic epidemiology of single nucleotide polymorphisms. Proc Natl Acad Sci U S A 1999; 96: 15173–7

    Article  PubMed  CAS  Google Scholar 

  129. Otto J. Predicting the range of linkage disequilibrium. Proc Natl Acad Sci U S A 2000; 97: 2–3

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported in part by a grant-in-aid for scientific research and the High Technology Research Center Grant from the Ministry of Education, Science, Technology, Sports, and Culture, Japan.

Author information

Authors and Affiliations

  1. Department of Pathology, Juntendo University School of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan

    Toshikazu Shirai, Yi Jiang & Sachiko Hirose

  2. Department of Biomedical Engineering, Toin Human Science and Technology Center, Toin University of Yokohama, Yokohama, Japan

    Hiroyuki Nishimura

Authors
  1. Toshikazu Shirai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hiroyuki Nishimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yi Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sachiko Hirose
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shirai, T., Nishimura, H., Jiang, Y. et al. Genome Screening for Susceptibility Loci in Systemic Lupus Erythematosus. Am J Pharmacogenomics 2, 1–12 (2002). https://doi.org/10.2165/00129785-200202010-00001

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00129785-200202010-00001

Keywords

Search

Navigation