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Unraveling the genetics of systemic lupus erythematosus

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Abstract

The capacity to locate polymorphisms on a virtually complete map of the human genome coupled with the ability to accurately evaluate large numbers (by historical standards) of genetic markers has led to gene identification in complex diseases, such as systemic lupus erythematosus (SLE or lupus). While this is a phenotype with enormous clinical variation, the twin studies and the observed familial aggregation, along with the genetic effects now known, suggest a strong genetic component. Unlike type 1 diabetes, lupus genetics is not dominated by the powerful effect of a single locus. Instead, there are at least six known genetic association effects in lupus of smaller magnitude (odds ratio <2), and at least 17 robust linkages (established and arguably confirmed independently) defining potentially responsible genes that largely remain to be discovered. The more convincing genetic associations include the human leukocyte antigen region (with multiple genes), C1q, PTPN22, PDCD1, Fc receptor-like 3, FcγRIIA, FcγRIIIA, interferon regulatory factor 5, and others. How they contribute to disease risk remains yet to be clarified, beyond the obvious speculation derived from what has previously been learned about these genes. Certainly, they are expected to contribute to lupus risk independently and in combination with each other, with genes not yet identified, and with the environment. A substantial number of genes (>10) are expected to be identified to contribute to lupus or in its many subsets defined by clinical and laboratory features.

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References

  1. Harvey AM, Shulman LE, Tumulty PA, Conley CL, Schoenrich EH (1954) Systemic lupus erythematosus: review of the literature and clinical analysis of 138 cases. Medicine 33:291–437

    PubMed  CAS  Google Scholar 

  2. Ward MM (2005) Association between physician volume and in-hospital mortality in patients with systemic lupus erythematosus. Arthritis Rheum 52(6):1646–1654

    PubMed  Google Scholar 

  3. Sacks JJ, Helmick CG, Langmaid G, Sniezek JE (2002) Trends in deaths from systemic lupus erythematosus, United States, 1979–1998. MMWR Morb Mortal Wkly Rep 51(17):371–374

    Google Scholar 

  4. Grumet FC, Coukell A, Bodmer JG, Bodmer WF, McDevitt HO (1971) Histocompatibility (HL-A) antigens associated with systemic lupus erythematosus. A possible genetic predisposition to disease. N Engl J Med 285:193–196

    Article  PubMed  CAS  Google Scholar 

  5. Alarcon-Segovia D, Alarcon-Riquelme ME, Cardiel MH, Caeiro F, Massardo L, Villa AR, Pons-Estel BA; Grupo Latinoamericano de Estudio del Lupus Eritematoso (GLADEL) (2005) Familial aggregation of systemic lupus erythematosus, rheumatoid arthritis, and other autoimmune diseases in 1,177 lupus patients from the GLADEL cohort. Arthritis Rheum 52(4):1138–1147

    PubMed  Google Scholar 

  6. Risch N, Merikangas K (1996) The future of genetic studies of complex human diseases. Science 273(5281):1516–1517

    PubMed  CAS  Google Scholar 

  7. Fielder AH, Walport MJ, Batchelor JR, Rynes RI, Black CM, Dodi IA, Hughes GR (1983) Family study of the major histocompatibility complex in patients with systemic lupus erythematosus: importance of null alleles of C4A and C4B in determining disease susceptibility. Br Med J (Clin Res Ed) 286(6363):425–428

    CAS  Google Scholar 

  8. Reveille JD, Arnett FC, Wilson RW, Bias WB, McLean RH (1985) Null alleles of the fourth component of complement and HLA haplotypes in familial systemic lupus erythematosus. Immunogenetics 21:299–311

    PubMed  CAS  Google Scholar 

  9. Arnett FC, Goldstein R, Duvic M, Reveille JD (1988) Major histocompatibility complex genes in systemic lupus erythematosus, Sjogren’s syndrome, and polymyositis. Am J Med 85:38–41

    PubMed  CAS  Google Scholar 

  10. Green JR, Montasser M, Woodrow JC (1986) The association of HLA-linked genes with systemic lupus erythematosus. Ann Hum Genet 50(Pt 1):93–96

    PubMed  CAS  Google Scholar 

  11. Hawkins BR, Wong KL, Wong RW, Chan KH, Dunckley H, Serjeantson SW (1987) Strong association between the major histocompatibility complex and systemic lupus erythematosus in southern Chinese. J Rheumatol 14(6):1128–1131

    PubMed  CAS  Google Scholar 

  12. Schur PH, Marcus-Bagley D, Awdeh Z, Yunis EJ, Alper CA (1990) The effect of ethnicity on major histocompatibility complex complement allotypes and extended haplotypes in patients with systemic lupus erythematosus. Arthritis Rheum 33:985–992

    PubMed  CAS  Google Scholar 

  13. Howard PF, Hochberg MC, Bias WB, Arnett FC Jr, McLean RH (1986) Relationship between C4 null genes, HLA-D region antigens, and genetic susceptibility to systemic lupus erythematosus in Caucasian and black Americans. Am J Med 81:187–193

    PubMed  CAS  Google Scholar 

  14. Cowland JB, Andersen V, Halberg P, Morling N (1994) DNA polymorphism of HLA class II genes in systemic lupus erythematosus. Tissue Antigens 43(1):34–37

    PubMed  CAS  Google Scholar 

  15. Yao Z, Kimura A, Hartung K, Haas PJ, Volgger A, Brunnler G, Bonisch J, Albert ED (1993) Polymorphism of the DQA1 promoter region (QAP) and DRB1, QAP, DQA1, DQB1 haplotypes in systemic lupus erythematosus. SLE Study Group members. Immunogenetics 38(6):421–429

    PubMed  CAS  Google Scholar 

  16. Reinersten JL, Klippel JH, Johnson AH, Steinberg AD, Decker JL, Mann DL (1982) Family studies of B lymphocyte alloantigens in systemic lupus erythematosus. J Rheumatol 9:253–262

    PubMed  CAS  Google Scholar 

  17. Black CM, Welsh KI, Fielder A, Hughes GR, Batchelor JR (1982) HLA antigens and Bf allotypes in SLE: evidence for the association being with specific haplotypes. Tissue Antigens 19:115–120

    PubMed  CAS  Google Scholar 

  18. Petry F, Berkel AI, Loos M (1997) Multiple identification of a particular type of hereditary C1q deficiency in the Turkish population: review of the cases and additional genetic and functional analysis. Hum Genet 100(1):51–56

    PubMed  CAS  Google Scholar 

  19. Miura-Shimura Y, Nakamura K, Ohtsuji M, Tomita H, Jiang Y, Abe M, Zhang D, Hamano Y, Tsuda H, Hashimoto H, Nishimura H, Taki S, Shirai T, Hirose S (2002) C1q regulatory region polymorphism down-regulating murine c1q protein levels with linkage to lupus nephritis. J Immunol 169(3):1334–1339

    PubMed  CAS  Google Scholar 

  20. Racila DM, Sontheimer CJ, Sheffield A, Wisnieski JJ, Racila E, Sontheimer RD (2003) Homozygous single nucleotide polymorphism of the complement C1QA gene is associated with decreased levels of C1q in patients with subacute cutaneous lupus erythematosus. Lupus 12(2):124–132

    PubMed  CAS  Google Scholar 

  21. Edberg JC, Langefeld CD, Wu J, Moser KL, Kaufman K, Kelly J, Bansal V, Brown WM, Salmon JE, Rich SS, Harley JB, Kimberly RP (2002) Genetic linkage and association of Fcγ receptor IIIA (CD16A) on chromosome 1q23 with human systemic lupus erythematosus. Arthritis Rheum 46:2132–2140

    PubMed  CAS  Google Scholar 

  22. Zuniga R, Ng S, Peterson MG, Reveille JD, Baethge BA, Alarcon GS, Salmon JE (2001) Low-binding alleles of Fcgamma receptor types IIA and IIIA are inherited independently and are associated with systemic lupus erythematosus in Hispanic patients. Arthritis Rheum 44:361–367

    PubMed  CAS  Google Scholar 

  23. Kyogoku C, Dijstelbloem HM, Tsuchiya N, Hatta Y, Kato H, Yamaguchi A, Fukazawa T, Jansen MD, Hashimoto H, van de Winkel JG, Kallenberg CG, Tokunaga K (2002) Fcgamma receptor gene polymorphisms in Japanese patients with systemic lupus erythematosus: contribution of FCGR2B to genetic susceptibility. Arthritis Rheum 46:1242–1254

    PubMed  CAS  Google Scholar 

  24. Manger K, Repp R, Jansen M, Geisselbrecht M, Wassmuth R, Westerdaal NA, Pfahlberg A, Manger B, Kalden JR, van de Winkel JG (2002) Fcgamma receptor IIa, IIIa, and IIIb polymorphisms in German patients with systemic lupus erythematosus: association with clinical symptoms. Ann Rheum Dis 61:786–792

    PubMed  CAS  Google Scholar 

  25. Duits AJ, Bootsma H, Derksen RH, Spronk PE, Kater L, Kallenberg CG, Capel PJ, Westerdaal NA, Spierenburg GT, Gmelig-Meyling FH (1995) Skewed distribution of IgG Fc receptor IIa (CD32) polymorphism is associated with renal disease in systemic lupus erythematosus patients. Arthritis Rheum 38:1832–1836

    PubMed  CAS  Google Scholar 

  26. Salmon JE, Millard S, Schachter LA, Arnett FC, Ginzler EM, Gourley MF, Ramsey-Goldman R, Peterson MG, Kimberly RP (1996) Fc gamma RIIA alleles are heritable risk factors for lupus nephritis in African Americans. J Clin Invest 97:1348–1354

    PubMed  CAS  Google Scholar 

  27. Sato H, Iwano M, Akai Y, Nishino T, Fujimoto T, Shiiki H, Dohi K (2001) FcgammaRIIa polymorphism in Japanese patients with systemic lupus erythematosus. Lupus 10:97–101

    PubMed  CAS  Google Scholar 

  28. Karassa FB, Trikalinos TA, Ioannidis JP (2002) Role of the Fcgamma receptor IIa polymorphism in susceptibility to systemic lupus erythematosus and lupus nephritis: a meta-analysis. Arthritis Rheum 46:1563–1571

    PubMed  CAS  Google Scholar 

  29. Kaufman KM, Kelly JA, Herring BJ, Adler AJ, Glenn SB, Namjou B, Frank SG, Dawson SL, Bruner GR, James JA, Harley JB (2006) Evaluation of the genetic association of the PTPN22 R620W polymorphism in familial and sporadic SLE. Arthritis Rheum 54(8):2533–2540

    PubMed  CAS  Google Scholar 

  30. Criswell LA, Pfeiffer KA, Lum RF, Gonzales B, Novitzke J, Kern M, Moser KL, Begovich AB, Carlton VEH, 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 

  31. Kyogoku C, Langefeld CD, Ortmann WA, Lee A, Selby S, Carlton VEH, 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 

  32. Prasad Linga 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 association of PDCD1. Genes Immun 6:658–662

    Google Scholar 

  33. Gomez LM, Anaya JM, Gonzalez CI, Pineda-Tamayo R, Otero W, Arango A, Martin J (2005) PTPN22 C1858T polymorphism in Colombian patients with autoimmune disease. Genes Immun 6:628–631

    PubMed  CAS  Google Scholar 

  34. Kochi Y, Yamada R, Suzuki A, Harley JB, Shirasawa S, Sawada T, Bae SC, Tokuhiro S, Chang X, Sekine A, Takahashi A, Tsunoda T, Ohnishi Y, Kaufman KM, Kang CP, Kang C, Otsubo S, Yumura W, Mimori A, Koike T, Nakamura Y, Sasazuki T, Yamamoto K (2005) A functional variant in FCRL3, encoding Fc receptor-like 3, is associated with rheumatoid arthritis and several autoimmunities. Nat Genet 37(5):478–485

    PubMed  CAS  Google Scholar 

  35. 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(3):528–537

    PubMed  CAS  Google Scholar 

  36. Graham RR, Kozyrev SV, Baechler EC, Reddy MV, Plenge RM, Bauer JW, Ortmann WA, Koeuth T, Gonzalez Escribano MF, Pons-Estel B, Petri M, Daly M, Gregersen PK, Martin J, Altshuler D, Behrens TW, Alarcon-Riquelme ME; Argentine and Spanish 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(5):550–555

    PubMed  CAS  Google Scholar 

  37. Smerdel-Ramoya A, Finholt C, Lilleby V, Gilboe IM, Harbo HF, Maslinski S, Forre O, Thorsby E, Lie BA (2005) Systemic lupus erythematosus and the extended major histocompatibility complex-evidence for several predisposing loci. Rheumatology (Oxford) 44(11):1368–1373

    CAS  Google Scholar 

  38. McHugh NJ, Owen P, Cox B, Dunphy J, Welsh K (2006) MHC class II, tumour necrosis factor alpha, and lymphotoxin alpha gene haplotype associations with serological subsets of systemic lupus erythematosus. Ann Rheum Dis 65(4):488–494

    PubMed  CAS  Google Scholar 

  39. Celada A, Barras C, Benzonana G, Jeannet M (1980) Increased frequency of HLA-DRw3 in systemic lupus erythematosus. Tissue Antigens 15(3):283–288

    Article  PubMed  CAS  Google Scholar 

  40. Dunckley H, Gatenby PA, Serjeantson SW (1986) DNA typing of HLA-DR antigens in systemic lupus erythematosus. Immunogenetics 24(3):158–162

    PubMed  CAS  Google Scholar 

  41. Gomez-Reino JJ, Martinez-Laso J, Vicario JL, Paz-Artal E, Aragon A, Martin-Villa JM, De Juan MD, Perez-Aciego P, Arnaiz-Villena A (1991) Immunogenetics of systemic lupus erythematosus in Spanish patients: differential HLA markers. Immunobiology 182(5):465–471

    PubMed  CAS  Google Scholar 

  42. Reinharz D, Tiercy JM, Mach B, Jeannet M (1991) Absence of DRw15/3 and of DRw15/7 heterozygotes in Caucasian patients with systemic lupus erythematosus. Tissue Antigens 37(1):10–15

    PubMed  CAS  Google Scholar 

  43. Reveille JD, Moulds JM, Ahn C, Friedman AW, Baethge B, Roseman J, Straaton KV, Alarcon GS (1998) Systemic lupus erythematosus in three ethnic groups. I. The effects of HLA class II, C4, and CR1 alleles, socioeconomic factors, and ethnicity at disease onset. LUMINA Study Group. Lupus in minority populations, nature versus nurture. Arthritis Rheum 41(7):1161–1172

    PubMed  CAS  Google Scholar 

  44. Ruuska P, Hameenkorpi R, Forsberg S, Julkunen H, Makitalo R, Ilonen J, Tiilikainen A (1992) Differences in HLA antigens between patients with mixed connective tissue disease and systemic lupus erythematosus. Ann Rheum Dis 51(1):52–55

    PubMed  CAS  Google Scholar 

  45. Olsen ML, Goldstein R, Arnett FC, Duvic M, Pollack M, Reveille JD (1989) C4A gene deletion and HLA associations in black Americans with systemic lupus erythematosus. Immunogenetics 30(1):27–33

    PubMed  CAS  Google Scholar 

  46. Dunckley H, Gatenby PA, Hawkins B, Naito S, Serjeantson SW (1987) Deficiency of C4A is a genetic determinant of systemic lupus erythematosus in three ethnic groups. J Immunogenet 14(4–5):209–218

    PubMed  CAS  Google Scholar 

  47. Hawkins BR, Wong KL, Wong RW, Chan KH, Dunckley H, Serjeantson SW (1987) Strong association between the major histocompatibility complex and systemic lupus erythematosus in southern Chinese. J Rheumatol 14(6):1128–1131

    PubMed  CAS  Google Scholar 

  48. Man XY, Luo HR, Li XP, Yao YG, Mao CZ, Zhang YP (2003) Polymerase chain reaction based C4AQ0 and C4BQ0 genotyping: association with systemic lupus erythematosus in southwest Han Chinese. Ann Rheum Dis 62(1):71–73

    PubMed  CAS  Google Scholar 

  49. Ayed K, Gorgi Y, Ayed-Jendoubi S, Bardi R (2004) The involvement of HLA-DRB1*, DQA1*, DQB1* and complement C4A loci in diagnosing systemic lupus erythematosus among Tunisians. Ann Saudi Med 24(1):31–35

    PubMed  Google Scholar 

  50. van der Linden MW, van der Slik AR, Zanelli E, Giphart MJ, Pieterman E, Schreuder GM, Westendorp RG, Huizinga TW (2001) Six microsatellite markers on the short arm of chromosome 6 in relation to HLA-DR3 and TNF-308A in systemic lupus erythematosus. Genes Immun 2(7):373–380

    PubMed  Google Scholar 

  51. Suarez A, Lopez P, Mozo L, Gutierrez C (2005) Differential effect of IL10 and TNF{alpha} genotypes on determining susceptibility to discoid and systemic lupus erythematosus. Ann Rheum Dis 64(11):1605–1610

    PubMed  CAS  Google Scholar 

  52. Lee YH, Harley JB, Nath SK (2006) Meta-analysis of TNF-alpha promoter −308 A/G polymorphism and SLE susceptibility. Eur J Hum Genet 14(3):364–371

    PubMed  CAS  Google Scholar 

  53. Rood MJ, van Krugten MV, Zanelli E, van der Linden MW, Keijsers V, Schreuder GM, Verduyn W, Westendorp RG, de Vries RR, Breedveld FC, Verweij CL, Huizinga TW (2000) TNF-308A and HLA-DR3 alleles contribute independently to susceptibility to systemic lupus erythematosus. Arthritis Rheum 43(1):129–134

    PubMed  CAS  Google Scholar 

  54. Sullivan KE, Wooten C, Schmeckpeper BJ, Goldman D, Petri MA (1997) A promoter polymorphism of tumor necrosis factor alpha associated with systemic lupus erythematosus in African-Americans. Arthritis Rheum 40(12):2207–2211

    PubMed  CAS  Google Scholar 

  55. Azizah MR, Kuak SH, Ainol SS, Rahim MN, Normaznah Y, Norella K (2004) Association of the tumor necrosis factor alpha gene polymorphism with susceptibility and clinical–immunological findings of systemic lupus erythematosus. Asian Pac J Allergy Immunol 22(2–3):159–163

    PubMed  CAS  Google Scholar 

  56. Gambelunghe G, Gerli R, Bocci EB, Del Sindaco P, Ghaderi M, Sanjeevi CB, Bistoni O, Bini V, Falorni A (2005) Contribution of MHC class I chain-related A (MICA) gene polymorphism to genetic susceptibility for systemic lupus erythematosus. Rheumatology (Oxford) 44(3):287–292

    CAS  Google Scholar 

  57. Sirikong M, Tsuchiya N, Chandanayingyong D, Bejrachandra S, Suthipinittharm P, Luangtrakool K, Srinak D, Thongpradit R, Siriboonrit U, Tokunaga K (2002) Association of HLA-DRB1*1502–DQB1*0501 haplotype with susceptibility to systemic lupus erythematosus in Thais. Tissue Antigens 59(2):113–117

    PubMed  CAS  Google Scholar 

  58. Martin-Villa JM, Martinez-Laso J, Moreno-Pelayo MA, Castro-Panete MJ, Martinez-Quiles N, Alvarez M, de Juan MD, Gomez-Reino JJ, Arnaiz-Villena A (1998) Differential contribution of HLA-DR, DQ, and TAP2 alleles to systemic lupus erythematosus susceptibility in Spanish patients: role of TAP2*01 alleles in Ro autoantibody production. Ann Rheum Dis 57(4):214–219

    Article  PubMed  CAS  Google Scholar 

  59. Correa PA, Molina JF, Pinto LF, Arcos-Burgos M, Herrera M, Anaya JM (2003) TAP1 and TAP2 polymorphisms analysis in northwestern Colombian patients with systemic lupus erythematosus. Ann Rheum Dis 62(4):363–365

    PubMed  CAS  Google Scholar 

  60. Agnello V (1978) Association of systemic lupus erythematosus and SLE-like syndromes with hereditary and acquired complement deficiency states. Arthritis Rheum 21(5 Suppl):S146–S152

    PubMed  CAS  Google Scholar 

  61. Jonsson G, Truedsson L, Sturfelt G, Oxelius VA, Braconier JH, Sjoholm AG (2005) Hereditary C2 deficiency in Sweden: frequent occurrence of invasive infection, atherosclerosis, and rheumatic disease. Medicine (Baltimore) 84(1):23–34

    Google Scholar 

  62. Glass D, Raum D, Gibson D, Stillman JS, Schur PH (1976) Inherited deficiency of the second component of complement. Rheumatic disease associations. J Clin Invest 58(4):853–861

    PubMed  CAS  Google Scholar 

  63. Sullivan KE, Petri MA, Schmeckpeper BJ, McLean RH, Winkelstein JA (1994) Prevalence of a mutation causing C2 deficiency in systemic lupus erythematosus. J Rheumatol 21(6):1128–1133

    PubMed  CAS  Google Scholar 

  64. Nguyen C, Limaye N, Wakeland EK (2002) Susceptibility genes in the pathogenesis of murine lupus. Arthritis Res 4(Suppl 3):S255–S263

    PubMed  Google Scholar 

  65. Morel L, Blenman KR, Croker BP, Wakeland EK (2001) The major murine systemic lupus erythematosus susceptibility locus, Sle1, is a cluster of functionally related genes. Proc Natl Acad Sci USA 98(4):1787–1792

    PubMed  CAS  Google Scholar 

  66. Boackle SA, Holers VM, Chen X, Szakonyi G, Karp DR, Wakeland EK, Morel L (2001) Cr2, a candidate gene in the murine Sle1c lupus susceptibility locus, encodes a dysfunctional protein. Immunity 15(5):775–785

    PubMed  CAS  Google Scholar 

  67. Kumar KR, Li L, Yan M, Bhaskarabhatla M, Mobley AB, Nguyen C, Mooney JM, Schatzle JD, Wakeland EK, Mohan C (2006) Regulation of B cell tolerance by the lupus susceptibility gene Ly108. Science 312(5780):1665–1669

    PubMed  CAS  Google Scholar 

  68. Wandstrat AE, Nguyen C, Limaye N, Chan AY, Subramanian S, Tian XH, Yim YS, Pertsemlidis A, Garner HR Jr, Morel L, Wakeland EK (2004) Association of extensive polymorphisms in the SLAM/CD2 gene cluster with murine lupus. Immunity 21(6):769–780

    PubMed  CAS  Google Scholar 

  69. Graham RR, Ortmann WA, Langefeld CD, Jawaheer D, Selby SA, Rodine PR, Baechler EC, Rohlf KE, Shark KB, Espe KJ, Green LE, Nair RP, Stuart PE, Elder JT, King RA, Moser KL, Gaffney PM, Bugawan TL, Erlich HA, Rich SS, Gregersen PK, Behrens TW (2002) Visualizing human leukocyte antigen class II risk haplotypes in human systemic lupus erythematosus. Am J Hum Genet 71(3):543–553

    PubMed  CAS  Google Scholar 

  70. So AK, Fielder AH, Warner CA, Isenberg DA, Batchelor JR, Walport MJ (1990) DNA polymorphism of major histocompatibility complex class II and class III genes in systemic lupus erythematosus. Tissue Antigens 35(3):144–147

    PubMed  CAS  Google Scholar 

  71. Reveille JD, Arnett FC, Olsen ML, Moulds JM, Papasteriades CA, Moutsopoulos HM (1995) HLA-class II alleles and C4 null genes in Greeks with systemic lupus erythematosus. Tissue Antigens 46(5):417–421

    PubMed  CAS  Google Scholar 

  72. Dong RP, Kimura A, Hashimoto H, Akizuki M, Nishimura Y, Sasazuki T (1993) Difference in HLA-linked genetic background between mixed connective tissue disease and systemic lupus erythematosus. Tissue Antigens 41(1):20–25

    PubMed  CAS  Google Scholar 

  73. Doherty DG, Ireland R, Demaine AG, Wang F, Veerapan K, Welsh KI, Vergani D (1992) Major histocompatibility complex genes and susceptibility to systemic lupus erythematosus in southern Chinese. Arthritis Rheum 35(6):641–646

    PubMed  CAS  Google Scholar 

  74. Awdeh ZL, Raum D, Yunis EJ, Alper CA (1983) Extended HLA/complement allele haplotypes: evidence for T/t-like complex in man. Proc Natl Acad Sci USA 80(1):259–263

    PubMed  CAS  Google Scholar 

  75. Arnett FC (1997) The genetics of human lupus. In: Wallace DJ, Hahn BH (eds) Dubois’ lupus erythematosus. Williams and Wilkins, Baltimore, MD, pp 77–117

    Google Scholar 

  76. Truedsson L, Sturfelt G, Nived O (1993) Prevalence of the type I complement C2 deficiency gene in Swedish systemic lupus erythematosus patients. Lupus 2:325–327

    PubMed  CAS  Google Scholar 

  77. Walport MJ (1993) Complement deficiency and disease. Br J Rheumatol 32(4):269–273

    PubMed  CAS  Google Scholar 

  78. Johnson CA, Densen P, Hurford RK Jr, Colten HR, Wetsel RA (1992) Type I human complement C2 deficiency. A 28-base pair gene deletion causes skipping of exon 6 during RNA splicing. J Biol Chem 267(13):9347–9353

    PubMed  CAS  Google Scholar 

  79. Ittiprasert W, Kantachuvesiri S, Pavasuthipaisit K, Verasertniyom O, Chaomthum L, Totemchokchyakarn K, Kitiyanant Y (2005) Complete deficiencies of complement C4A and C4B including 2-bp insertion in codon 1213 are genetic risk factors of systemic lupus erythematosus in Thai populations. J Autoimmun 25(1):77–84

    PubMed  CAS  Google Scholar 

  80. Morgan BP, Walport MJ (1991) Complement deficiency and disease. Immunol Today 12(9):301–306

    PubMed  CAS  Google Scholar 

  81. Petry F, Loos M (2005) Common silent mutations in all types of hereditary complement C1q deficiencies. Immunogenetics 57(8):566–571

    PubMed  CAS  Google Scholar 

  82. Pickering MC, Botto M, Taylor PR, Lachmann PJ, Walport MJ (2000) Systemic lupus erythematosus, complement deficiency, and apoptosis. Adv Immunol 76:227–324

    PubMed  CAS  Google Scholar 

  83. Botto M, Walport MJ (2002) C1q, autoimmunity and apoptosis. Immunobiology 205(4–5):395–406

    PubMed  CAS  Google Scholar 

  84. Sontheimer RD, Racila E, Racila DM (2005) C1q: its functions within the innate and adaptive immune responses and its role in lupus autoimmunity. J Invest Dermatol 125(1):14–23

    PubMed  CAS  Google Scholar 

  85. Bowness P, Davies KA, Norsworthy PJ, Athanassiou P, Taylor-Wiedeman J, Borysiewicz LK, Meyer PAR, Walport MJ (1994) Hereditary C1q deficiency and systemic lupus erythematosus. Q J Med 87:455–494

    CAS  Google Scholar 

  86. Walport MJ, Davies KA, Botto M (1998) C1q and systemic lupus erythematosus. Immunobiology 199:265–285

    PubMed  CAS  Google Scholar 

  87. Korb LC, Ahearn JM (1997) C1q binds directly and specifically to surface blebs of apoptotic human keratinocytes: complement deficiency and systemic lupus erythematosus revisited. J Immunol 158(10):4525–4528

    PubMed  CAS  Google Scholar 

  88. Botto M, Dell’Agnola C, Bygrave AE, Thompson EM, Cook HT, Petry F, Loos M, Pandolfi PP, Walport MJ (1998) Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies. Nat Genet 19(1):56–59

    PubMed  CAS  Google Scholar 

  89. Turner MW, Hamvas RM (2000) Mannose-binding lectin: structure, function, genetics and disease associations. Rev Immunogenet 2:305–322

    PubMed  CAS  Google Scholar 

  90. Sumiya M, Super M, Tabona P, Arai T, Turner MW, Summerfield JA (1991) Molecular basis of opsonic defect in immunodeficient children. Lancet 337(8757):1569–1570

    PubMed  CAS  Google Scholar 

  91. Lipscombe RJ, Sumiya M, Hill AV, Lau YL, Levinsky RJ, Summerfield JA, Turner MW (1992) High frequencies in African and non-African populations of independent mutations in the mannose binding protein gene. Hum Mol Genet 1(9):709–715

    PubMed  CAS  Google Scholar 

  92. Madsen HO, Garred P, Kurtzhals JA, Lamm LU, Ryder LP, Thiel S, Svejgaard A (1994) A new frequent allele is the missing link in the structural polymorphism of the human mannan-binding protein. Immunogenetics 40(1):37–40

    PubMed  CAS  Google Scholar 

  93. Madsen HO, Garred P, Thiel S, Kurtzhals JA, Lamm LU, Ryder LP, Svejgaard A (1995) Interplay between promoter and structural gene variants control basal serum level of mannan-binding protein. J Immunol 155(6):3013–3020

    PubMed  CAS  Google Scholar 

  94. Lee YH, Witte T, Momot T, Schmidt RE, Kaufman KM, Harley JB, Sestak AL (2005) The mannose-binding lectin gene polymorphisms and systemic lupus erythematosus: two case–control studies and a meta-analysis. Arthritis Rheum 52(12):3966–3974

    PubMed  CAS  Google Scholar 

  95. Huang YF, Wang W, Han JY, Wu XW, Zhang ST, Liu CJ, Hu QG, Xiong P, Hamvas RM, Wood N, Gong FL, Bittles AH (2003) Increased frequency of the mannose-binding lectin LX haplotype in Chinese systemic lupus erythematosus patients. Eur J Immunogenet 30:121–124

    PubMed  CAS  Google Scholar 

  96. Villarreal J, Crosdale D, Ollier W, Hajeer A, Thomson W, Ordi J, Balada E, Villardell M, Teh LS, Poulton K (2001) Mannose binding lectin and FcRIIa (CD32) polymorphism in Spanish systemic lupus erythematosus patients. Rheumatology (Oxford) 40:1009–1012

    CAS  Google Scholar 

  97. Tsutsumi A, Sasaki K, Wakamiya N, Ichikawa K, Atsumi T, Ohtani K, Suzuki Y, Koike T, Sumida T (2001) Mannose-binding lectin gene: polymorphisms in Japanese patients with systemic lupus erythematosus, rheumatoid arthritis and Sjögren’s syndrome. Genes Immun 2:99–104

    PubMed  CAS  Google Scholar 

  98. Garred P, Madsen HO, Halberg P, Petersen J, Kronborg G, Svejgaard A, Andersen V, Jacobsen S (1999) Mannose-binding lectin polymorphisms and susceptibility to infection in systemic lupus erythematosus. Arthritis Rheum 42:2145–2152

    PubMed  CAS  Google Scholar 

  99. Ip WK, Chan SY, Lau CS, Lau YL (1998) Association of systemic lupus erythematosus with promoter polymorphisms of the mannose-binding lectin gene. Arthritis Rheum 41:1663–1668

    PubMed  CAS  Google Scholar 

  100. 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(2):141–151

    PubMed  CAS  Google Scholar 

  101. 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 Autoimmunity 14(2):169–178

    CAS  Google Scholar 

  102. 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 

  103. Nishimura H, Honjo T (2001) PD-1: an inhibitory immunoreceptor involved in peripheral tolerance. Trends Immunol 22(5):265–268

    PubMed  CAS  Google Scholar 

  104. 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(5502):319–322

    PubMed  CAS  Google Scholar 

  105. Prokunina L, Castilejo-Lopez C, Oberg F, Gunnarsson I, Berg L, Magnusson V, Brookes A, Tentler D, Kristjansdottr H, Grondal G, Bolstad AI, Svenungsson E, Lundberg I, Sturfelt G, Jonssen A, Truedsson Lima G, Alcocer-Varela J, Jonsson R, Gyllensten UB, Harley JB, Alarcon-Segovia D, Steinsson K, Alarcon-Riquelme ME (2002) A regulatory polymorphism within the PD-1 gene is associated with susceptibility to systemic lupus erythematosus. Nat Genet 32:666–669

    PubMed  CAS  Google Scholar 

  106. Prokunina L, Gunnarsson I, Sturfelt G, Truedsson L, Seligman VA, Olson JL, Seldin MF, Criswell LA, Alarcon-Riquelme ME (2004) The systemic lupus erythematosus-associated PDCD1 polymorphism PD1.3A in lupus nephritis. Arthritis Rheum 50(1):327–328

    PubMed  CAS  Google Scholar 

  107. 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(8):2590–2597

    PubMed  CAS  Google Scholar 

  108. Bottini N, Musumeci L, Alonso A, Rahmouni S, Konstantina N, 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 1 diabetes. Nat Genet 36:337–338

    PubMed  CAS  Google Scholar 

  109. Orozco G, Sanchez E, Gonzalez-Gay MA, Lopez-Nevot MA, Torres B, Caliz R, Ortego-Centeno N, Jimenez-Alonzo J, Pascual-Salcedo D, balsa A, de Pablo R, Nunez-Roldan A, Gonzales-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 

  110. Begovich AB, Carlton VEH, Honigberg LA, Schrodi SJ, Chokkalingam AP, Alexander HC, Ardlie KG, Huang Q, Smith AM, Spoerke JM, Conn MT, Chang M, Chang SP, 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 

  111. Smyth D, Cooper JD, Collins JE, Heward JM, Franklyn JA, Howson JMM, 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 RCJ, Gough SCL, 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 

  112. 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 1 diabetes in multiplex families. Genes Immun 5:678–680

    PubMed  CAS  Google Scholar 

  113. 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 

  114. Velaga MR, Wilson V, Jennings CE, Owen CJ, Herington S, Donaldson PT, Ball SG, James RA, Quinton R, Perros P, Pearce SHS (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(11):5562–5865

    Google Scholar 

  115. Wu H, Cantor RM, Cunninghame Graham DS, Lingren CM, Farwell L, De 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. Arthritis Rheum 52:2396–2402

    PubMed  CAS  Google Scholar 

  116. Bottini N, Vang T, Cucca F, Mustelin T (2006) Role of PTPN22 in type 1 diabetes and other autoimmune diseases. Semin Immunol 18(4):207–213

    PubMed  CAS  Google Scholar 

  117. 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(12):1317–1319

    PubMed  CAS  Google Scholar 

  118. Kimberly RP, Salmon JE, Edberg JC (1995) Receptors for immunoglobulin G. Molecular diversity and implications for disease. Arthritis Rheum 38(3):306–314

    PubMed  CAS  Google Scholar 

  119. Stein MP, Edberg JC, Kimberly RP, Mangan EK, Bharadwaj D, Mold C, Du Clos TW (2000) C-reactive protein binding to FcgammaRIIa on human monocytes and neutrophils is allele-specific. J Clin Invest 105(3):369–376

    PubMed  CAS  Google Scholar 

  120. Callejas JL, Sabio JM, Haro MD, Camps M, Ramon ED, Garcia-Hernandez FJ, Koeleman B, Martin J, Gonzalez-Escribano MF (2006) Polymorphisms of the FCRL3 gene in a Spanish population of systemic lupus erythematosus patients. Rheumatology (Oxford) 45(8):1044–1048

    Google Scholar 

  121. de Veer MJ, Holko M, Frevel M, Walker E, Der S, Paranjape JM, Silverman RH, Williams BR (2001) Functional classification of interferon-stimulated genes identified using microarrays. J Leukoc Biol 69:912–920

    PubMed  Google Scholar 

  122. 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 

  123. Crow MK, Wohlgemuth J (2003) Microarray analysis of gene expression in lupus. Arthritis Res Ther 5:279–287

    PubMed  CAS  Google Scholar 

  124. Richter MF, Dumenil G, Uze G, Fellous M, Pellegrini S (1998) Specific contribution of TYK2 JH regions to the binding and expression of the interferon alpha/beta receptor component IFNAR1. J Biol Chem 273:24723–24729

    PubMed  CAS  Google Scholar 

  125. Ragimbeau J, Dondi E, Alcover A, Eid P, Uze G, Pellegrini S (2003) The tyrosine kinase Thk2 controls IFNAR1 cell surface expression. EMBO J 22:537–547

    PubMed  CAS  Google Scholar 

  126. Barnes B, Lubyova B, Pitha PM (2002) On the role of IRF in host defense. J Interferon Cytokine Res 22:59–71

    PubMed  CAS  Google Scholar 

  127. 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(7063):1365–1369

    PubMed  CAS  Google Scholar 

  128. Kelly JA, Moser KL, Harley JB (2002) The genetics of systemic lupus erythematosus: putting the pieces together. Genes Immun 3(Suppl 1):S71–S85

    PubMed  CAS  Google Scholar 

  129. Johanneson B, Lima G, Alarcon-Riquelme M, Collaboration on the genetics of SLE, BIOMED II Collaboration on the Genetics of SLE and Sjogrens Syndrome (2001) Analysis of chromosome 1 for SLE susceptibility loci in a new set of 69 multicase families. Am J Hum Genet 69(Suppl 4):S1970

    Google Scholar 

  130. 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 

  131. Johansson CM, Zunec R, Garcia MA, Scherbarth HR, Tate GA, Paira S, Navarro SM, Perandones CE, Gamron S, Alvarellos A, Graf CE, Manni J, Berbotto GA, Palatnik SA, Catoggio LJ, Battagliotti CG, Sebastiani GD, Migliaresi S, Galeazzi M, Pons-Estel BA, Alarcon-Riquelme ME; Collaborative Group on the Genetics of SLE; Argentine Collaborative Group (2004) Chromosome 17p12-q11 harbors susceptibility loci for systemic lupus erythematosus. Hum Genet 115(3):230–238

    PubMed  CAS  Google Scholar 

  132. Tsao BP, Cantor RM, Grossman JM, Shen N, Teophilov NT, Wallace DJ, Arnett FC, Hartung K, Goldstein R, Kalunian KC, Hahn BH, Rotter JI (1999) PARP alleles within the linked chromosomal region are associated with systemic lupus erythematosus. J Clin Invest 103(8):1135–1140

    PubMed  CAS  Google Scholar 

  133. Graham RR, Langefeld CD, Gaffney PM, Ortmann WA, Selby SA, Baechler EC, Shark KB, Ockenden TC, Rohlf KE, Moser KL, Brown WM, Gabriel SE, Messner RP, King RA, Horak P, Elder JT, Stuart PE, Rich SS, Behrens TW (2001) Genetic linkage and transmission disequilibrium of marker haplotypes at chromosome 1q41 in human systemic lupus erythematosus. Arthritis Res 3:299–305

    PubMed  CAS  Google Scholar 

  134. Gray-McGuire C, Moser KL, Gaffney PM, Kelly J, Yu H, Olson JM, Jedrey CM, Jacobs KB, Kimberly RP, Neas BR, Rich SS, Behrens TW, Harley JB (2000) Genome scan of human systemic lupus erythematosus by regression modeling: evidence of linkage and epistasis at 4p16-15.2. Am J Hum Genet 67:1460–1469

    PubMed  CAS  Google Scholar 

  135. 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 

  136. Kelly JA, Reid J, Kilpatrick J, Harris B, Berry-Brattan CK, Frank S, Hutchings D, Cooney C, Johnson S, Bacino D, Rossacci K, Aberle T, Namjou B, Nath SK, Bruner GR, Scofield RH, James JA, Harley JB (2002) Combined genome scan results for 266 pedigrees multiplex for systemic lupus erythematosus (SLE): significant evidence of genetic linkage at 1q22–23 and 11p13. Am J Hum Genet 71(Suppl 4):S1573

    Google Scholar 

  137. Nath SK, Quintero-Del-Rio AI, Kilpatrick J, Feo L, Ballesteros M, Harley JB (2004) Linkage at 12q24 with systemic lupus erythematosus (SLE) is established and confirmed in Hispanic and European American families. Am J Hum Genet 74(1):73–82

    PubMed  CAS  Google Scholar 

  138. Gaffney PM, Ortmann WA, Selby SA, Shark KB, Ockenden TC, Rohlf KE, Walgrave NL, Boyum WP, Malmgren ML, Miller ME, Kearns GM, Messner RP, King RA, Rich SS, Behrens TW (2000) Genome screening in human systemic lupus erythematosus: results from a second Minnesota cohort and combined analyses of 187 sib-pair families. Am J Hum Genet 66(2):547–556

    PubMed  CAS  Google Scholar 

  139. Nath SK, Namjou B, Hutchings D, Garriott CP, Pongratz C, Guthridge J, James JA (2004) Systemic lupus erythematosus (SLE) and chromosome 16: confirmation of linkage to 16q12–13 and evidence for genetic heterogeneity. Eur J Hum Genet 12(8):668–672

    PubMed  CAS  Google Scholar 

  140. Quintero-Del-Rio AI, Kelly JA, Kilpatrick J, James JA, Harley JB (2002) The genetics of systemic lupus erythematosus stratified by renal disease: Linkage at 10q22.3 (SLEN1), 2q34–35 (SLEN2) and 11p15.6 (SLEN3). Genes Immun 3:S57–S62

    PubMed  CAS  Google Scholar 

  141. Quintero-Del-Rio AI, Kelly JA, Garriott CP, Hutchings DC, Frank SG, Aston CE, Harley JB (2004) SLEN2 (2q34–35) and SLEN1 (10q22.3) replication in systemic lupus erythematosus stratified by nephritis. Am J Hum Genet 75:346–348

    PubMed  CAS  Google Scholar 

  142. Namjou B, Kelly JA, Kilpatrick J, Harley JB (2004) Genetic linkages with lupus at 3p14–21 in families with cigarette smoking affected or anti-La precipitins. Arthritis Rheum 50(Suppl 9):S1618

    Google Scholar 

  143. Namjou B, Nath SK, Kilpatrick J, Kelly JA, Reid J, James JA, Harley JB (2002) 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 46(11):2937–2945

    PubMed  CAS  Google Scholar 

  144. Nath SK, Namjou B, Garriott CP, Frank S, Joslin PA, Kilpatrick J, Kelly JA, Harley JB (2004) Linkage analysis of SLE susceptibility: confirmation of SLER1 at 5p15.3. Genes Immun 5(3):209–214

    PubMed  CAS  Google Scholar 

  145. Namjou B, Kelly JA, Kilpatrick J, Kaufman KM, Nath SK, Scofield RH, Harley JB (2005) Linkage at 5q14.3–15 in multiplex systemic lupus erythematosus pedigrees stratified by autoimmune thyroid disease. Arthritis Rheum 52(11):3646–3650

    PubMed  CAS  Google Scholar 

  146. Kelly JA, Thompson K, Kilpatrick J, Lam T, Nath SK, Gray-McGuire C, Reid J, Namjou B, Aston CE, Bruner GR, Scofield RH, Harley JB (2002) Evidence for a susceptibility gene (SLEH1) on chromosome 11q14 for systemic lupus erythematosus (SLE) families with hemolytic anemia. Proc Natl Acad Sci USA 99(18):11766–11771

    PubMed  CAS  Google Scholar 

  147. Nath SK, Kelly JA, Namjou B, Lam T, Bruner GR, Scofield RH, Aston CE, Harley JB (2001) Evidence for a susceptibility gene, SLEV1, on chromosome 17p13 in families with vitiligo-related systemic lupus erythematosus. Am J Hum Genet 69(6):1401–1406

    PubMed  CAS  Google Scholar 

  148. Spritz RA, Gowan K, Bennett DC, Fain PR (2004) Novel vitiligo susceptibility loci on chromosomes 7 (AIS2) and 8 (AIS3), confirmation of SLEV1 on chromosome 17, and their roles in an autoimmune diathesis. Am J Hum Genet 74(1):188–191

    PubMed  CAS  Google Scholar 

  149. Namjou B, Nath SK, Kilpatrick J, Kelly JA, Reid J, Reichlin M, James JA, Harley JB (2002) 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 1:S35–S41

    Google Scholar 

  150. McCarty DJ, Manzi S, Medsger TA Jr, Ramsey-Goldman R, LaPorte RE, Kwoh CK (1995) Incidence of systemic lupus erythematosus. Race and gender differences. Arthritis Rheum 38(9):1260–1270

    PubMed  CAS  Google Scholar 

  151. Kaslow RA, Masi AT (1978) Age, sex and race effects on mortality from systemic lupus erythematosus in the United States. Arthritis Rheum 21(4):473–479

    PubMed  CAS  Google Scholar 

  152. Fessel WJ (1974) Systemic lupus erythematosus in the community. Incidence, prevalence, outcome, and first symptoms; the high prevalence in black women. Arch Intern Med 134:1027–1035

    PubMed  CAS  Google Scholar 

  153. Yang Y, Chung EK, Zhou B, Lhotta K, Hebert LA, Birmingham DJ, Rovin BH, Yu CY (2004) The intricate role of complement component C4 in human systemic lupus erythematosus. Curr Dir Autoimmun 7:98–132

    PubMed  CAS  Google Scholar 

  154. Wilson WA, Perez MC (1988) Complete C4B deficiency in black Americans with systemic lupus erythematosus. J Rheumatol 15(12):1855–1858

    PubMed  CAS  Google Scholar 

  155. Ahmed S, Ihara K, Kanemitsu S, Nakashima H, Otsuka T, Tsuzaka K, Takeuchi T, Hara T (2001) Association of CTLA-4 but not CD28 gene polymorphisms with systemic lupus erythematosus in the Japanese population. Rheumatology (Oxford) 40:662–667

    CAS  Google Scholar 

  156. Pullmann R Jr, Lukac J, Skerenova M, Rovensky J, Hybenova J, Melus V, Celec S, Pullmann R, Hyrdel R (1999) Cytotoxic T lymphocyte antigen 4 (CTLA-4) dimorphism in patients with systemic lupus erythematosus. Clin Exp Rheumatol 17:725–729

    PubMed  Google Scholar 

  157. Lee YH, Kim YR, Ji JD, Sohn J, Song GG (2001) Polymorphisms of the CTLA-4 exon 1 and promoter gene in systemic lupus erythematosus. Lupus 10:601–605

    PubMed  CAS  Google Scholar 

  158. Mehrian R, Quismorio FP Jr, Strassmann G, Stimmler MM, Horwitz DA, Kitridou RC, Gauderman WJ, Morrison J, Brautbar C, Jacob CO (1998) Synergistic effect between IL-10 and bcl-2 genotypes in determining susceptibility to systemic lupus erythematosus. Arthritis Rheum 41:596–602

    PubMed  CAS  Google Scholar 

  159. D’Alfonso S, Rampi M, Bocchio D, Colombo G, Scorza-Smeraldi R, Momigliano-Richardi P (2000) Systemic lupus erythematosus candidate genes in the Italian population: evidence for a significant association with interleukin-10. Arthritis Rheum 43:120–128

    PubMed  CAS  Google Scholar 

  160. Gibson AW, Edberg JC, Wu J, Westendorp RG, Huizinga TW, Kimberly RP (2001) Novel single nucleotide polymorphisms in the distal IL-10 promoter affect IL-10 production and enhance the risk of systemic lupus erythematosus. J Immunol 166:3915–3922

    PubMed  CAS  Google Scholar 

  161. Eskdale J, Wordsworth P, Bowman S, Field M, Gallagher G (1997) Association between polymorphisms at the human IL-10 locus and systemic lupus erythematosus. Tissue Antigens 49:635–639

    Article  PubMed  CAS  Google Scholar 

  162. Ou TT, Tsai WC, Chen CJ, Chang JG, Yen JH, Wang WS, Lin CH, Tsai JJ, Liu HW (1998) Genetic analysis of interleukin-10 promoter region in patients with systemic lupus erythematosus in Taiwan. Kaohsiung J Med Sci 14:599–606

    PubMed  CAS  Google Scholar 

  163. Nath SK, Harley JB, Lee YH (2005) Polymorphisms of complement receptor 1 and interleukin-10 genes and systemic lupus erythematosus: a meta-analysis. Hum Genet 118(2):225–234

    PubMed  CAS  Google Scholar 

  164. Garred P, Voss A, Madsen HO, Junker P (2001) Association of mannose-binding lectin gene variation with disease severity and infections in a population-based cohort of systemic lupus erythematosus patients. Genes Immun 2:442–450

    PubMed  CAS  Google Scholar 

  165. Takahashi R, Tsutsumi A, Ohtani K, Muraki Y, Goto D, Matsumoto I, Wakamiya N, Sumida T (2005) Association of mannose binding lectin (MBL) gene polymorphism and serum MBL concentration with characteristics and progression of systemic lupus erythematosus. Ann Rheum Dis 64(2):311–314

    PubMed  CAS  Google Scholar 

  166. Sullivan KE, Wooten C, Goldman D, Petri M (1996) Mannose-binding protein genetic polymorphisms in black patients with systemic lupus erythematosus. Arthritis Rheum 39:2046–2051

    PubMed  CAS  Google Scholar 

  167. D’Alfonso S, Barizzone N, Giordano M, Chiocchetti A, Magnani C, Castelli L, Indelicato M, Giacopelli F, Marchini M, Scorza R, Danieli MG, Cappelli M, Migliaresi S, Bigliardo B, Sabbadini MG, Baldissera E, Galeazzi M, Sebastiani GD, Minisola G, Ravazzolo R, Dianzani U, Momigliano-Richiardi P (2005) Two single-nucleotide polymorphisms in the 5′ and 3′ ends of the osteopontin gene contribute to susceptibility to systemic lupus erythematosus. Arthritis Rheum 52(2):539–547

    PubMed  CAS  Google Scholar 

  168. Forton AC, Petri MA, Goldman D, Sullivan KE (2002) An osteopontin (SPP1) polymorphism is associated with systemic lupus erythematosus. Hum Mutat 19(4):459

    PubMed  CAS  Google Scholar 

  169. 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(7):510–516

    Article  PubMed  CAS  Google Scholar 

  170. 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(6):1665–1669

    PubMed  CAS  Google Scholar 

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  1. Department of Medicine, University of Oklahoma, Oklahoma City, OK, USA

    John B. Harley & Kenneth M. Kaufman

  2. Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK, 73104, USA

    John B. Harley, Jennifer A. Kelly & Kenneth M. Kaufman

  3. US Department of Veterans Affairs Medical Center, Oklahoma City, OK, USA

    John B. Harley & Kenneth M. Kaufman

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Harley, J.B., Kelly, J.A. & Kaufman, K.M. Unraveling the genetics of systemic lupus erythematosus. Springer Semin Immun 28, 119–130 (2006). https://doi.org/10.1007/s00281-006-0040-5

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