Current Rheumatology Reports

, Volume 6, Issue 5, pp 391–398 | Cite as

Current advances in the human lupus genetics

  • Nan Shen
  • Betty P. Tsao


Genetic predisposition has been firmly established as a key element in susceptibility to systemic lupus erythematosus (SLE). During the past three decades, association studies have assessed many genes for potential roles in predisposing to SLE. These studies have identified a few risk factors including hereditary deficiency of complement components, major histocompatibility complex class II alleles, and allelic variants for the Fc portion of IgG (FCGR) genes. In recent years, a few groups have completed linkage analyses in data sets from families containing multiple members affected with SLE. Results from these initial genome scans are encouraging; approximately eight chromosomal regions have been identified exhibiting evidence for significant linkage to SLE and have been confirmed using independent cohorts (1q23, 1q25-31, 1q41-42, 2q35-37, 4p16-15.2, 6p11-21, 12q24, and 16q12), suggesting the high likelihood of the presence of one or multiple SLE susceptibility genes at each locus. Another approach of linkage analyses conditioned on pedigrees where one affected member manifesting a particular clinical condition has also identified many chromosomal regions linked to SLE. Within several established susceptibility loci, evidence for association of positional candidate genes is emerging. Within 2q35-37, an intronic single nucleotide polymorphism (SNP) of the positional candidate gene program cell death 1 gene has been associated with SLE susceptibility. The SLE-associated SNP affects a transcription factor, RUNX1, binding site. Recently, SNPs of novel positional candidate genes that influence RUNX1 binding motifs have also been associated with other autoimmune diseases, suggesting the possibility of a common theme shared among susceptibility genes for autoimmune diseases. In the coming years, susceptibility genes responsible for the observed linkage will be identified, and will lead to further delineating genetic pathways involved in susceptibility to SLE.


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References and Recommended Reading

  1. 1.
    Tsao BP: The genetics of human systemic lupus erythematosus. Trends Immunol 2003, 24:595- 602.PubMedCrossRefGoogle Scholar
  2. 2.
    Wakeland EK, Liu K, Graham RR, Behrens TW: Delineating the genetic basis of systemic lupus erythematosus. Immunity 2001, 15:397- 408.PubMedCrossRefGoogle Scholar
  3. 3.
    Wanstrat A, Wakeland E: The genetics of complex autoimmune diseases: non-MHC susceptibility genes. Nat Immunol 2001, 2:802- 809.CrossRefGoogle Scholar
  4. 4.
    Arbuckle MR, McClain MT, Rubertone MV, et al.: Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med 2003, 349:1526- 1533. An interesting article that describes the sequential accrual of autoantibodies during the development of SLE.PubMedCrossRefGoogle Scholar
  5. 5.
    Tsao BP: The genetics of human lupus. In Dubois’ Lupus Erythematosus, edn 6. Edited by Wallace DJ, Hahn BH. Philadelphia: Lippincott Williams & Wilkins; 2002:97- 120.Google Scholar
  6. 6.
    Graham RR, Ortmann WA, Langefeld CD, et al.: Visualizing human leukocyte antigen class II risk haplotypes in human systemic lupus erythematosus. Am J Hum Genet 2002, 71:543- 553. A systematic scan of the MHC region for susceptibility loci of SLE.PubMedCrossRefGoogle Scholar
  7. 7.
    Barilla-LaBarca ML, Atkinson JP: Rheumatic syndromes associated with complement deficiency. Curr Opin Rheumatol 2003, 15:55- 60.PubMedCrossRefGoogle Scholar
  8. 8.
    Botto M, Dell’Agnola C, Bygrave AE, et al.: Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies. Nat Genet 1998, 19:56- 59.PubMedCrossRefGoogle Scholar
  9. 9.
    Taylor PR, Carugati A, Fadok VA, et al.: A hierarchical role for classical pathway complement proteins in the clearance of apoptotic cells in vivo. J Exp Med 2000, 192:359- 366.PubMedCrossRefGoogle Scholar
  10. 10.
    Yang Y, Chung EK, Zhou B, et al.: The intricate role of complement component C4 in human systemic lupus erythematosus. Curr Dir Autoimmun 2004, 7:98- 132.PubMedGoogle Scholar
  11. 11.
    Einav S, Pozdnyakova OO, Ma M, Carroll MC: Complement C4 is protective for lupus disease independent of C3. J Immunol 2002, 168:1036- 1041.PubMedGoogle Scholar
  12. 12.
    Chen Z, Koralov SB, Kelsoe G: Complement C4 inhibits systemic autoimmunity through a mechanism independent of complement receptors CR1 and CR2. J Exp Med 2000, 192:1339- 1352.PubMedCrossRefGoogle Scholar
  13. 13.
    Kelly JA, Moser KL, Harley JB: The genetics of systemic lupus erythematosus: putting the pieces together. Genes Immun 2002, 3(Suppl 1):S71- S85.PubMedCrossRefGoogle Scholar
  14. 14.
    Tsao BP: An update on genetic studies of systemic lupus erythematosus. Curr Rheumatol Rep 2002, 4:359–367.PubMedCrossRefGoogle Scholar
  15. 15.
    Huang YF, Wang W, Han JY, et al.: Increased frequency of the mannose-binding lectin LX haplotype in Chinese systemic lupus erythematosus patients. Eur J Immunogenet 2003, 30:121- 124.PubMedCrossRefGoogle Scholar
  16. 16.
    Sullivan KE, Jawad AF, Piliero LM, et al.: Analysis of polymorphisms affecting immune complex handling in systemic lupus erythematosus. Rheumatology (Oxford) 2003, 42:446- 452.CrossRefGoogle Scholar
  17. 17.
    Karassa FB, Trikalinos TA, Ioannidis JP: Role of the Fcgamma receptor IIa polymorphism in susceptibility to systemic lupus erythematosus and lupus nephritis: a meta-analysis. Arthritis Rheum 2002, 46:1563- 1571.PubMedCrossRefGoogle Scholar
  18. 18.
    Wu J, Edberg JC, Redecha PB, et al.: A novel polymorphism of FcgRIIIa (CD16) alters receptor function and predisposes to autoimmune disease. J Clin Invest 1997, 100:1059- 1070.PubMedGoogle Scholar
  19. 19.
    Karassa FB, Trikalinos TA, Ioannidis JP: The Fc gamma RIIIAF158 allele is a risk factor for the development of lupus nephritis: a meta-analysis. Kidney Int 2003, 63:1475- 1482.PubMedCrossRefGoogle Scholar
  20. 20.
    Li X, Wu J, Carter RH, et al.: A novel polymorphism in the Fcgamma receptor IIB (CD32B) transmembrane region alters receptor signaling. Arthritis Rheum 2003, 48:3242- 3252.PubMedCrossRefGoogle Scholar
  21. 21.
    Chu ZT, Tsuchiya N, Kyogoku C, et al.: Association of Fcgamma receptor IIb polymorphism with susceptibility to systemic lupus erythematosus in Chinese: a common susceptibility gene in the Asian populations. Tissue Antigens 2004, 63:21- 27.PubMedCrossRefGoogle Scholar
  22. 22.
    Kyogoku C, Dijstelbloem HM, Tsuchiya N, et al.: Fcgamma receptor gene polymorphisms in Japanese patients with systemic lupus erythematosus: contribution of FCGR2B to genetic susceptibility. Arthritis Rheum 2002, 46:1242–1254.PubMedCrossRefGoogle Scholar
  23. 23.
    Siriboonrit U, Tsuchiya N, Sirikong M, et al.: Association of Fcgamma receptor IIb and IIIb polymorphisms with susceptibility to systemic lupus erythematosus in Thais. Tissue Antigens 2003, 61:374- 383.PubMedCrossRefGoogle Scholar
  24. 24.
    Magnusson V, Zunec R, Odeberg J, et al.: Polymorphisms of the Fc gamma receptor type IIB gene are not associated with systemic lupus erythematosus in the Swedish population. Arthritis Rheum 2004, 50:1348- 1350.PubMedCrossRefGoogle Scholar
  25. 25.
    Su K, Li X, Edberg JC, et al.: A promoter haplotype of the immunoreceptor tyrosine-based inhibitory motif-bearing FcgammaRIIb alters receptor expression and associates with autoimmunity. II. Differential binding of GATA4 and Yin- Yang1 transcription factors and correlated receptor expression and function. J Immunol 2004, 172:7192- 7199.PubMedGoogle Scholar
  26. 26.
    Su K, Wu J, Edberg JC, et al.: A promoter haplotype of the immunoreceptor tyrosine-based inhibitory motif-bearing FcgammaRIIb alters receptor expression and associates with autoimmunity. I. Regulatory FCGR2B polymorphisms and their association with systemic lupus erythematosus. J Immunol 2004, 172:7186- 7191. A well-conducted study describes a SLE-associated functional haplotype of a strong candidate gene.PubMedGoogle Scholar
  27. 27.
    Magnusson V, Johanneson B, Lima G, et al.: Both risk alleles for FcgammaRIIA and FcgammaRIIIA are susceptibility factors for SLE: a unifying hypothesis. Genes Immun 2004, 5:130- 137.PubMedCrossRefGoogle Scholar
  28. 28.
    Edberg JC, Langefeld CD, Wu J, et al.: Genetic linkage and association of Fcgamma receptor IIIA (CD16A) on chromosome 1q23 with human systemic lupus erythematosus. Arthritis Rheum 2002, 46:2132- 2140.PubMedCrossRefGoogle Scholar
  29. 29.
    Nishimura H, Honjo T: PD-1: an inhibitory immunoreceptor involved in peripheral tolerance. Trends Immunol 2001, 22:265- 268.PubMedCrossRefGoogle Scholar
  30. 30.
    Nishimura H, Nose M, Hiai H, et al.: Development of lupuslike autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 1999, 11:141- 151.PubMedCrossRefGoogle Scholar
  31. 31.
    Nishimura H, Okazaki T, Tanaka Y, et al.: Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science 2001, 291:319- 322.PubMedCrossRefGoogle Scholar
  32. 32.
    Prokunina L, Castillejo-Lopez C, Oberg F, et al.: A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans. Nat Genet 2002, 32:666- 669.PubMedCrossRefGoogle Scholar
  33. 33.
    Nielsen C, Hansen D, Husby S, et al.: Association of a putative regulatory polymorphism in the PD-1 gene with susceptibility to type 1 diabetes. Tissue Antigens 2003, 62:492- 497.PubMedCrossRefGoogle Scholar
  34. 34.
    Prokunina L, Gunnarsson I, Sturfelt G, et al.: The systemic lupus erythematosus-associated PDCD1 polymorphism PD1.3A in lupus nephritis. Arthritis Rheum 2004, 50:327- 328.PubMedCrossRefGoogle Scholar
  35. 35.
    Lin SC, Yen JH, Tsai JJ, et al.: Association of a programmed death 1 gene polymorphism with the development of rheumatoid arthritis, but not systemic lupus erythematosus. Arthritis Rheum 2004, 50:770- 775.PubMedCrossRefGoogle Scholar
  36. 36.
    Tokuhiro S, Yamada R, Chang X, et al.: An intronic SNP in a RUNX1 binding site of SLC22A4, encoding an organic cation transporter, is associated with rheumatoid arthritis. Nat Genet 2003, 35:341- 348.PubMedCrossRefGoogle Scholar
  37. 37.
    Helms C, Cao L, Krueger JG, et al.: A putative RUNX1 binding site variant between SLC9A3R1 and NAT9 is associated with susceptibility to psoriasis. Nat Genet 2003, 35:349- 356.PubMedCrossRefGoogle Scholar
  38. 38.
    Alarcon-Riquelme ME: A RUNX trio with a taste for autoimmunity. Nat Genet 2003, 35:299- 300. An interesting commentary that gene variants affecting binding of a transcription factor may increase risk for autoimmune diseases.PubMedCrossRefGoogle Scholar
  39. 39.
    Russell AI, Cunninghame Graham DS, Shepherd C, et al.: Polymorphism at the C-reactive protein locus influences gene expression and predisposes to systemic lupus erythematosus. Hum Mol Genet 2004, 13:137- 147. This study is interesting because it provides functional evidence implicating a strong candidate gene.PubMedCrossRefGoogle Scholar
  40. 40.
    Szalai AJ, McCrory MA, Cooper GS, Wu J, Kimberly RP: Association between baseline levels of C-reactive protein (CRP) and a dinucleotide repeat polymorphism in the intron of the CRP gene. Genes Immun 2002, 3:14- 19.PubMedCrossRefGoogle Scholar
  41. 41.
    Pascual M, Lopez-Nevot MA, Caliz R, et al.: A poly(ADPribose) polymerase haplotype spanning the promoter region confers susceptibility to rheumatoid arthritis. Arthritis Rheum 2003, 48:638- 641.PubMedCrossRefGoogle Scholar
  42. 42.
    Tsao BP, Cantor RM, Grossman JM, et al.: PARP alleles within the linked chromosomal region are associated with systemic lupus erythematosus. J Clin Invest 1999, 103:1135- 1140.PubMedCrossRefGoogle Scholar
  43. 43.
    Parks CG, Cooper GS, Dooley MA, et al.: Systemic lupus erythematosus and genetic variation in the interleukin 1 gene cluster: a population based study in the southeastern United States. Ann Rheum Dis 2004, 63:91- 94.PubMedCrossRefGoogle Scholar
  44. 44.
    Sanchez E, Orozco G, Lopez-Nevot MA, et al.: Polymorphisms of toll-like receptor 2 and 4 genes in rheumatoid arthritis and systemic lupus erythematosus. Tissue Antigens 2004, 63:54- 57.PubMedCrossRefGoogle Scholar
  45. 45.
    Sawabe T, Horiuchi T, Koga R, et al.: Aberrant HS1 molecule in a patient with systemic lupus erythematosus. Genes Immun 2003, 4:122- 131.PubMedCrossRefGoogle Scholar
  46. 46.
    Otsuka J, Horiuchi T, Yoshizawa S, et al.: Association of a fouramino acid residue insertion polymorphism of the HS1 gene with systemic lupus erythematosus: molecular and functional analysis. Arthritis Rheum 2004, 50:871- 881. This study provides novel insights of a candidate gene.PubMedCrossRefGoogle Scholar
  47. 47.
    Li N, Nakamura K, Jiang Y, et al.: Gain-of-function polymorphism in mouse and human Ltk: implications for the pathogenesis of systemic lupus erythematosus. Hum Mol Genet 2004, 13:171- 179. A successful implementation of the mouse to the human approach in the genetic basis of SLE.PubMedCrossRefGoogle Scholar
  48. 48.
    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- 14879.PubMedCrossRefGoogle Scholar
  49. 49.
    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- 14874.PubMedCrossRefGoogle Scholar
  50. 50.
    Gaffney PM, Ortmann WA, Selby SA, et al.: Genome screening in human systemic lupus erythematosus: results from a second Minnesota cohort and combined analyses of 187 sibpair families. Am J Hum Genet 2000, 66:547- 556.PubMedCrossRefGoogle Scholar
  51. 51.
    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 4p16-15.2. Am J Hum Genet 2000, 67:1460- 1469.PubMedCrossRefGoogle Scholar
  52. 52.
    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- 178.PubMedCrossRefGoogle Scholar
  53. 53.
    Shai R, Quismorio FP, Jr., Li L, et al.: Genome-wide screen for systemic lupus erythematosus susceptibility genes in multiplex families. Hum Mol Genet 1999, 8:639- 644.PubMedCrossRefGoogle Scholar
  54. 54.
    Nath SK, Quintero-Del-Rio AI, Kilpatrick J, et al.: Linkage at 12q24 with systemic lupus erythematosus (SLE) is established and confirmed in Hispanic and European American families. Am J Hum Genet 2004, 74:73- 82. This study provides strong evidence for linkage of a novel locus to SLE.PubMedCrossRefGoogle Scholar
  55. 55.
    Cantor RM, Yuan J, Napier S, et al.: Systemic lupus erythematosus genome scan: support at 1q23, 2q33, 16q12 and 17q21 and novel evidence at 3p24, 10q23, 13q32 and 18q23. Arthritis Rheum 2004, In press. A new whole genome scan that uses a cohort collected in the United States.Google Scholar
  56. 56.
    Koskenmies S, Lahermo P, Julkunen H, et al.: Linkage mapping of systemic lupus erythematosus (SLE) in Finnish families multiply affected by SLE. J Med Genet 2004, 41:e2- e5.PubMedCrossRefGoogle Scholar
  57. 57.
    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- 731.PubMedGoogle Scholar
  58. 58.
    Moser KL, Gray-McGuire C, Kelly J, et al.: Confirmation of genetic linkage between human systemic lupus erythematosus and chromosome 1q41. Arthritis Rheum 1999, 42:1902- 1907.PubMedCrossRefGoogle Scholar
  59. 59.
    Graham RR, Langefeld CD, Gaffney PM, et al.: Genetic linkage and transmission disequilibrium of marker haplotypes at chromosome 1q41 in human systemic lupus erythematosus. Arthritis Res 2001, 3:299- 305.PubMedCrossRefGoogle Scholar
  60. 60.
    Magnusson V, Lindqvist AK, Castillejo-Lopez C, et al.: Fine mapping of the SLEB2 locus involved in susceptibility to systemic lupus erythematosus. Genomics 2000, 70:307- 314.PubMedCrossRefGoogle Scholar
  61. 61.
    Johanneson B, Lima G, Von Salome J, et al.: A major susceptibility locus for systemic lupus erythemathosus maps to chromosome 1q31. Am J Hum Genet 2002, 71:1060- 1071.PubMedCrossRefGoogle Scholar
  62. 62.
    Lander ES, Kruglyak L: Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 1995, 11:241- 247.PubMedCrossRefGoogle Scholar
  63. 63.
    Kelly JA, Thompson K, Kilpatrick J, et al.: Evidence for a susceptibility gene (SLEH1) on chromosome 11q14 for systemic lupus erythematosus (SLE) families with hemolytic anemia. Proc Natl Acad Sci U S A 2002, 99:11766- 11771.PubMedCrossRefGoogle Scholar
  64. 64.
    Namjou B, Nath SK, Kilpatrick J, et al.: Genome scan stratified by the presence of anti-double-stranded DNA (dsDNA) autoantibody in pedigrees multiplex for systemic lupus erythematosus (SLE) establishes linkages at 19p13.2 (SLED1) and 18q21.1 (SLED2). Genes Immun 2002, 3(Suppl 1):S35- S41.PubMedCrossRefGoogle Scholar
  65. 65.
    Namjou B, Nath SK, Kilpatrick J, et al.: Stratification of pedigrees multiplex for systemic lupus erythematosus and for self-reported rheumatoid arthritis detects a systemic lupus erythematosus susceptibility gene (SLER1) at 5p15.3. Arthritis Rheum 2002, 46:2937- 2945.PubMedCrossRefGoogle Scholar
  66. 66.
    Nath SK, Kelly JA, Namjou B, et al.: Evidence for a susceptibility gene, SLEV1, on chromosome 17p13 in families with vitiligo- related systemic lupus erythematosus. Am J Hum Genet 2001, 69:1401- 1406.PubMedCrossRefGoogle Scholar
  67. 67.
    Nath SK, Kelly JA, Reid J, et al.: SLEB3 in systemic lupus erythematosus (SLE) is strongly related to SLE families ascertained through neuropsychiatric manifestations. Hum Genet 2002, 111:54- 58.PubMedCrossRefGoogle Scholar
  68. 68.
    Quintero-Del-Rio AI, Kelly JA, Kilpatrick J, et al.: The genetics of systemic lupus erythematosus stratified by renal disease: linkage at 10q22.3 (SLEN1), 2q34- 35 (SLEN2), and 11p15.6 (SLEN3). Genes Immun 2002, 3(Suppl 1):S57- S62.PubMedCrossRefGoogle Scholar
  69. 69.
    Scofield RH, Bruner GR, Kelly JA, et al.: Thrombocytopenia identifies a severe familial phenotype of systemic lupus erythematosus and reveals genetic linkages at 1q22 and 11p13. Blood 2003, 101:992- 997.PubMedCrossRefGoogle Scholar
  70. 70.
    Sawalha AH, Namjou B, Nath SK, et al.: Genetic linkage of systemic lupus erythematosus with chromosome 11q14 (SLEH1) in African-American families stratified by a nucleolar antinuclear antibody pattern. Genes Immun 2002, 3(Suppl_1):S31- S34.PubMedCrossRefGoogle Scholar
  71. 71.
    Nath SK, Namjou B, Garriott CP, et al.: Linkage analysis of SLE susceptibility: confirmation of SLER1 at 5p15.3. Genes Immun 2004, 5:209- 214.PubMedCrossRefGoogle Scholar
  72. 72.
    Nath SK, Namjou B, Kilpatrick J, et al.: A candidate region on 11p13 for systemic lupus erythematosus: a linkage identified in African-American families. J Investig Dermatol Symp Proc 2004, 9:64- 67.PubMedCrossRefGoogle Scholar
  73. 73.
    Rao S, Olson JM, Moser KL, et al.: Linkage analysis of human systemic lupus erythematosus-related traits: a principal component approach. Arthritis Rheum 2001, 44:2807- 2818.PubMedCrossRefGoogle Scholar
  74. 74.
    Tsao BP, Grossman JM, Riemekasten G, et al.: Familiality and co-occurrence of clinical features of systemic lupus erythematosus. Arthritis Rheum 2002, 46:2678- 2685.PubMedCrossRefGoogle Scholar
  75. 75.
    Shen N, Chen SL, Wu H, et al.: Fine mapping of the putative SLE susceptibility locus at 1q23 in a Chinese cohort. Arthritis Rheum 2002, 46:S391.Google Scholar
  76. 76.
    Shen N, Feng X-B, Chen SL, et al.: Identification of a novel candidate gene within the putative SLE susceptibility locus at 16q12 in a Chinese cohort [abstract]. Arthritis Rheum 2003, 48:S257.Google Scholar

Copyright information

© Current Science Inc 2004

Authors and Affiliations

  • Nan Shen
  • Betty P. Tsao
    • 1
  1. 1.Division of Rheumatology, Department of Medicine, Rehabilitation CenterUCLA School of MedicineLos AngelesUSA

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