Genetic epidemiology: Systemic lupus erythematosus
© BioMed Central Ltd 2001
Received: 30 April 2001
Accepted: 31 July 2001
Published: 23 August 2001
Systemic lupus erythematosus is the prototype multisystem autoimmune disease. A strong genetic component of susceptibility to the disease is well established. Studies of murine models of systemic lupus erythematosus have shown complex genetic interactions that influence both susceptibility and phenotypic expression. These models strongly suggest that several defects in similar pathways, e.g. clearance of immune complexes and/or apoptotic cell debris, can all result in disease expression. Studies in humans have found linkage to several overlapping regions on chromosome 1q, although the precise susceptibility gene or genes in these regions have yet to be identified. Recent studies of candidate genes, including Fcγ receptors, IL-6, and tumour necrosis factor-α, suggest that in human disease, genetic factors do play a role in disease susceptibility and clinical phenotype. The precise gene or genes involved and the strength of their influence do, however, appear to differ considerably in different populations.
Keywordscandidate genes disease susceptibility linkage analysis mouse models SLE
Systemic lupus erythematosus (SLE) is an autoimmune disease characterised by a striking preponderance in females, multisystem involvement, and autoantibodies directed primarily against nuclear antigens. Pathogenic mechanisms have been partly elucidated and defects in immune complex clearance, B-cell tolerance, and T-cell function have all been described. Little, however, is known about predisposing factors and mechanisms leading to disease induction. Through a variety of study designs, a strong genetic predisposition has been shown. For example, studies of affected probands estimate the sibling recurrence risk (λs) to be approximately 20. Twin studies have demonstrated concordance rates among monozygotic twins of 24-65%, compared with 2-9% in dizygotic twins . SLE is a complex, polygenic trait with contributions from MHC and non-MHC genes, and up to 100 genes may be involved in disease susceptibility . The study of SLE genetics is at an exciting and rapidly advancing stage. This review aims to update our current understanding of this area.
Mouse models of systemic lupus erythematosus
Genetic analyses in the mouse have provided some important insights into the pathogenic processes mediating disease in experimental models of SLE. Linkage analysis and congenic dissection have provided insights into the genetic basis for susceptibility in the classic lupus-prone mouse strains. These studies have delineated specific genetic pathways that are critical to the development of severe lupus nephritis and have identified allele-specific, suppressive modifiers capable of dramatically influencing disease progression. The 'synthesis' of mouse models of systemic autoimmunity via the production of targeted gene disruptions has also helped identify specific genes and gene combinations capable of causing and modifying disease.
Positions of the named susceptibility loci from murine genome studies involving NZB, NZW, NZM2410, BXSB, and MRL/lpr mice (Wakeland et al, 1999) .
Bxs1, Bxs2, Sbw1, Gld, Sle1, Nba2, Lbw7, Bxs3
Sle2, Sbw2, Lbm1, nba1, Lbw2, Lmb1, Sles2 *
Sle6, Lmb2, Lbw3
Lrdm1, Sle5, Sle3, Lbw5, Lmb3, Nba3
H2d/z, Sle4, Sles1 *
Other models of intense interest are those supporting an apoptosis-related autoantigen clearance defect, for example C1q knockout, DNase1-deficient, and serum-amyloid-P-deficient mice. These models have shown several important pathogenic abnormalities, including reduced macrophage clearance of apoptotic cells and increased concentrations of apoptotic bodies, in tissue samples associated with development of glomerulonephritis [10,11,12,13].
Human linkage studies in systemic lupus erythematosus
Summary of human linkage studies in systemic lupus erythematosus
Moser et al
Gaffney et al
Gaffney et al
Shai et al
Lindqvist et al
Number of families
Type of study
Number of affected individuals
Number of unaffected individuals
Number of ethnic groups
Ethnicity of families studied
Number of loci analysed
Basis of linkage
LOD = 1.5
LOD = 1.0
LOD = 1.0
LOD = 1.0
Human systemic lupus erythematosus susceptibility loci identified in two or more mapping studies
Moser et al
Gaffney et al
Gaffney et al
Shai et al
Lindqvist et al
Candidate genes for systemic lupus erythematosus at regions identified by linkage analysis
H3 & 4 histone family 2
Serum amyloid protein
Small ribonuclear protein
ADPRT (ADP-ribosyltransferase factor-1)
Study of individual genes in systemic lupus erythematosus
Many individual genes have been studied in SLE and a comprehensive analysis of these is beyond the scope of this review. Recent studies do, however, illustrate important points that are likely to apply to other genes in SLE.
Poly(ADP-ribose) polymerase ('PARP') is involved in DNA repair and apoptosis, both of which may be of relevance in SLE pathogenesis. The gene for this protein is also within the area of linkage for SLE (1q41-42). Using a multiallelic approach using a transmission disequilibrium test, Tsao et al  found a significant association of an 85-bp allele of the gene for poly(ADP-ribose) polymerase in affected white patients with SLE. In contrast, Criswell et al  studied three separate cohorts of SLE patients and failed to confirm this association. Differences in statistical modelling may account for this difference and the original finding may be a false-positive result.
This protein has structural and functional similarities to C1q. Several polymorphisms of the protein have been described in association with SLE in different populations [23,24]. Recent evidence also suggests that polymorphisms of mannose-binding protein may increase susceptibility to infection in SLE .
IL-6 is a pro-inflammatory cytokine that has a role in B-cell maturation and IgG production. High IL-6 production is associated with a G→C polymorphism at -174 in the promoter region. In a study of 211 German patients with SLE, Schotte et al  found no higher prevalence of the G allele than in the background population. This allele was, however, associated with discoid cutaneous lesions and anti-histone antibodies.
IL-10 is a Th2 cytokine that downregulates antigen presentation and immune complex clearance. IL-10 is increased in SLE patients and their family members. Lazarus et al  found the IL-10-1082G, IL-10-819C, and IL-10-592C haplotype was associated with Ro autoantibodies and renal involvement in white patients with SLE. In Chinese patients, a different haplotype was associated with renal disease but not Ro autoantibodies . These studies found no association with disease susceptibility. In contrast, Gibson et al  found single nucleotide polymorphisms in the IL-10 promoter region significantly associated with SLE susceptibility in African Americans.
Tumour necrosis factor-a
The tumor necrosis factor (TNF)-a gene lies within the MHC region on chromosome 6p. The HLA B8, DR3 haplotype has been associated with SLE in whites and confers a two- to threefold increased risk of SLE . The TNF-α -308A polymorphism is located within the promoter region of the gene and is associated with increased production of TNF-α. This polymorphism is in strong linkage disequilibrium with the HLA B8, DR3 haplotype, but it also has an independent effect in SLE [1,30]. In addition, Werth et al  have demonstrated an enhanced susceptibility to photosensitive cutaneous lesions in SLE patients with this polymorphism. However the TNF-a -308A polymorphism is also in linkage disequilibrium with other polymorphisms across the TNF-α locus, and the functional association remains to be established.
These receptors play a role in handling of immune complexes as well as in clearance of apoptotic cells. The Fc IgG receptor FcγRII and FcγRIII genes are both located at 1q23-24, and several polymorphisms have been described that affect the ability of receptors to bind. In a prospective study of Hispanic patients with SLE, Zuniga et al  observed that the low-affinity FcγR alleles (RIIa-R131 and RIIIa-F176) were inherited independently and were present at higher frequency in patients with SLE, especially as a haplotype. In SLE patients with nephritis, there was also a predominance of low-affinity alleles. Hatta et al , studying a Japanese population, also found an association between FcγRIIIB-NA2/NA2 genotype and development of SLE with an increased prevalence of nephritis. Selgiman et al  also recently reported that the FcγRIIIA-158F allele is a risk factor for nephritis in white patients with SLE. The exact role of these 'low-affinity' polymorphisms in disease susceptibility and expression remains controversial and further work is needed to fully elucidate their role.
These studies suggest that certain genetic defects (e.g. in complement, mannose-binding protein, and FcγR) associated with similar pathogenic mechanisms all can lead to susceptibility to SLE in different populations. The clinical expression of SLE, while diverse, may not be nearly as diverse as the range of genetic defects that may predispose to it. In addition, some genes not associated with susceptibility may nevertheless be important in phenotypic expression (e.g. those for IL-6, IL-10). In view of these observations, enriching populations with a particular phenotype might influence studies of susceptibility. Prospective studies will be important, both to accurately assess the association of certain markers with expression of disease and also to study the predictive value of genetic markers in defined populations.
The past decade has witnessed major advances in our understanding of the immunopathogenesis of SLE. Intensive study of several mouse models has allowed significant progress towards understanding the genetic contribution to the development and expression of the disease. The observed genetic synteny between human and murine loci provides valuable clues to the origins of human SLE, and future studies will make possible a clearer understanding of the role of genetic factors in disease susceptibility. The next challenge will be to focus on genetic and molecular pathways that determine an individual's particular phenotype as an aid to prognostication and early intervention to prevent complications.
crystallizable fragment [of antibody]
Fc IgG receptor
systemic lupus erythematosus
tumour necrosis factor.
- Sullivan KE: Genetics of systemic lupus erythematosus: clinical implications. Rheum Dis Clin North Am. 2000, 26: 229-256.PubMedView ArticleGoogle Scholar
- Wakeland EK, Wandstrat AE, Liu K, Morel L: Genetic dissection of systemic lupus erythematosus. Curr Opin Immunol. 1999, 11: 701-707. 10.1016/S0952-7915(99)00039-4.PubMedView ArticleGoogle Scholar
- Merino R, Shibata T, De Kossodo S, Izui S: Differential effect of the autoimmune Yaa and lpr genes on the acceleration of lupus-like syndrome in MRL/Mpj mice. Eur J Immunol. 1989, 19: 2131-2137.PubMedView ArticleGoogle Scholar
- Hogarth MB, Slingsby JH, Allen PJ, Thompson EM, Chandler P, Davies KA, Simpson E, Morley BJ, Walport MJ: Multiple lupus susceptibility loci map to chromosome 1 in BXSB mice. J Immunol. 1998, 28: 2753-2761.Google Scholar
- Santiago ML, Mary C, Parzy D, Jacquet C, Montagutelli X, Parkhouse RM, Lemoine R, Izui S, Reininger L: Linkage of major quantitative trait locus to Yaa gene-induced lupus-like nephritis in (NZW × C57BL/6) F1 mice. Eur J Immunol. 1998, 28: 4257-4267. 10.1002/(SICI)1521-4141(199812)28:12<4257::AID-IMMU4257>3.0.CO;2-H.PubMedView ArticleGoogle Scholar
- Ida A, Hirose S, Hamano Y, Kodera S, Jiang Y, Abe M, Zhang D, Nishimura H, Shirai T: Multigenic control of lupus associated antiphospholipid syndrome in a model of (NZW × BXSB) F1 mice. Eur J Immunol. 1998, 28: 2694-2703. 10.1002/1521-4141(199809)28:09<2694::AID-IMMU2694>3.3.CO;2-R.PubMedView ArticleGoogle Scholar
- Morel L, Croker BP, Blenman KR, Mohan C, Huang G, Gilkeson G, Wakeland EK: Genetic reconstitution of systemic lupus erythematosus immunopathology with polycongenic murine strains. Proc Natl Acad Sci U S A. 2000, 97: 6670-6675. 10.1073/pnas.97.12.6670.PubMedPubMed CentralView ArticleGoogle Scholar
- Morel L, Tian X-H, Croker BP, Wakeland EK: Epistatic modifiers of autoimmunity in murine models of lupus nephritis. Immunity. 1999, 11: 131-139.PubMedView ArticleGoogle Scholar
- Morel L, Blenman KR, Croker BP, Wakeland EK: 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: 1787-1792. 10.1073/pnas.031336098.PubMedPubMed CentralView ArticleGoogle Scholar
- Botto M, Dell'Agnola C, Bygrave AE, Thompson EM, Cook HT, Petry F, Loos M, Pandolfi PP, Walport MJ: Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies. Nat Genet. 1998, 19: 56-69.PubMedView ArticleGoogle Scholar
- Taylor PR, Carugati A, Fadok VA, Cook HT, Andrews M, Carroll MC, Savill JS, Henson PM, Botto M, Walport MJ: A hierarchical role for classical pathway complement proteins in the clearance of apoptotic cells in vivo. J Exp Med. 2000, 192: 359-366. 10.1084/jem.192.3.359.PubMedPubMed CentralView ArticleGoogle Scholar
- Napirei M, Karsunky H, Zevnik B, Stephan H, Mannherz HG, Moroy T: Features of systemic lupus erythematus in Dnase1-deficient mice. Nat Genet. 2000, 25: 177-181. 10.1038/76032.PubMedView ArticleGoogle Scholar
- Bickerstaff MC, Botto M, Hutchinson WL, Herbert J, Tennent GA, Bybee A, Mitchell DA, Cook HT, Butler PJ, Walport MJ, Pepys MB: Serum amyloid P component controls chromatin degradation and prevents antinuclear autoimmunity. Nat Med. 1999, 5: 694-697. 10.1038/9544.PubMedView ArticleGoogle Scholar
- Tsao BP, Cantor RM, Kalunian KC, Chen CJ, Badsha H, Singh R, Wallace DJ, Kitridou RC, Chen SL, Shen N, Song YW, Isenberg DA, Yu CL, Hahn BH, Rotter JI: Evidence for linkage of a candidate chromosome 1 region to human systemic lupus erythematosus. J Clin Invest. 1997, 99: 725-731.PubMedPubMed CentralView ArticleGoogle Scholar
- 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: 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. 10.1073/pnas.95.25.14869.PubMedPubMed CentralView ArticleGoogle Scholar
- Gaffney PM, Kearns GM, Shark KB, Ortmann WA, Selby SA, Malmgren ML, Rohlf KE, Ockenden TC, Messner RP, Rich S, Behrens TW: 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. 10.1073/pnas.95.25.14875.PubMedPubMed CentralView ArticleGoogle Scholar
- 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: 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. 2000, 66: 547-556. 10.1086/302767.PubMedPubMed CentralView ArticleGoogle Scholar
- Shai R, Quismorio FP, Li L, Kwon O-J, Morrison J, Wallace D, Neuwelt C, Brautbar C, Gauderman W, Jacob CO: Genome-wide screen for systemic lupus erythematosus susceptibility genes in multiplex families. Hum Mol Genet. 1999, 8: 639-644. 10.1093/hmg/8.4.639.PubMedView ArticleGoogle Scholar
- Lindqvist AK, Steinsson K, Johanneson B, Kristjansdottir H, Arnasson A, Grondal G, Johannesson I, Magnusson V, Sturfelt G, Truedsson L, Svenguson E, Lundberg I, Terwilliger JD, Gyllensten UB, Alarcon-Riquelme ME: A susceptibility locus for human systemic lupus erythematosus (hSLE1) on chromosome 2q. J Autoimmun. 2000, 14: 169-178. 10.1006/jaut.1999.0357.PubMedView ArticleGoogle Scholar
- Magnusson V, Lindqvist AK, Castillejo-Lopez C, Kristjansdottir H, Steinsson K, Grondal G, Sturfelt G, Truedsson L, Svenguson E, Lundberg I, Gunnarsson I, Boltstad AI, Haga HJ, Jonsson R, Klareskog L, Alcocer-Varela J, Alarcon-Segovia D, Terwilliger JD, Gyllensten UB, Alarcon-Riquelme ME: Fine mapping of the SLEB2 locus involved in susceptibility to systemic lupus erythematosus. Genomics. 2000, 70: 307-314. 10.1006/geno.2000.6374.PubMedView ArticleGoogle Scholar
- Tsao BP, Cantor RM, Grossman JM, Shen N, Teophilov NT, Wallace DJ, Arnett FC, Hartung K, Goldstein R, Kalunian KC, Hahn BH, Rotter JI: PARP alleles within the linked chromosomal region are associated with systemic lupus erythematosus. J Clin Invest. 1999, 103: 1135-1140.PubMedPubMed CentralView ArticleGoogle Scholar
- Criswell LA, Moser KL, Gaffney PM, Inda S, Ortmann WA, Lin D, Chen JJ, Li H, Gray-McGuire C, Neas BR, Rich SS, Harley JB, Behrens TW, Seldin MF: PARP alleles and SLE: failure to confirm association with disease susceptibility. J Clin Invest. 2000, 105: 1501-1502.PubMedGoogle Scholar
- Sullivan KE, Wooten C, Goldman D, Petri M: Mannose binding protein genetic polymorphisms in black patients with systemic lupus erythematosus. Arthritis Rheum. 1996, 39: 2046-2051.PubMedView ArticleGoogle Scholar
- Davies EJ, Teh LS, Ordi-Ros J, Snowden N, Hillarby MC, Hajeer A, Donn R, Perez-Pemen P, Villardell-Tarreds M, Ollier WE: A dysfunctional allele of the mannose binding protein gene associates with systemic lupus erythematosus in a Spanish population. J Rheumatol. 1997, 24: 485-488.PubMedGoogle Scholar
- Garred P, Madsen HO, Halberg P, Petersen J, Kronborg G, Svejgaard A, Andersen V, Jacobsen S: Mannose-binding lectin polymorphisms and susceptibility to infection in systemic lupus erythematosus. Arthritis Rheum. 1999, 42: 2145-2152. 10.1002/1529-0131(199910)42:10<2145::AID-ANR15>3.0.CO;2-#.PubMedView ArticleGoogle Scholar
- Schotte H, Schluter B, Rust S, Assmann G, Domschke W, Gaubitz M: Inteleukin-6 promoter polymorphism (-174 G/C) in Caucasian German patients with systemic lupus erythematosus. Rheumatology. 2001, 40: 393-400. 10.1093/rheumatology/40.4.393.PubMedView ArticleGoogle Scholar
- Lazarus M, Hajeer AH, Turner D, Sinnott P, Worthington J, Ollier WE, Hutchinson IV: Genetic variation in the interleukin 10 gene promoter and systemic lupus erythematosus. J Rheumatol. 1997, 24: 2314-2317.PubMedGoogle Scholar
- Mok CC, Lanchbury JS, Chan DW, Lau CS: Interleukin-10 promoter polymorphisms in Southern Chinese patients with sysemic lupus erythematosus. Arthritis Rheum. 1998, 41: 1090-1095. 10.1002/1529-0131(199806)41:6<1090::AID-ART16>3.0.CO;2-6.PubMedView ArticleGoogle Scholar
- Gibson AW, Edberg JC, Wu J, Westendorp RG, Huizinga TW, Kimberly RP: Novel single nucleotide polymorphism in the distal IL-10 promoter affect IL-10 production and enhance the risk of systemic lupus erythematosus. J Immunol. 2001, 166: 3915-3922.PubMedView ArticleGoogle Scholar
- Rood MJ, van Krugten MV, Zanelli E, van der Linden MW, Keijers V, Schreuder GM, Verduyn W, Westendorp RG, de Vries RR, Breedveld FC, Verweij CL, Huizinga TW: TNF-308A and HLA-DR3 alleles contribute independently to susceptibility to systemic lupus erythematosus. Arthritis Rheum. 2000, 43: 129-134. 10.1002/1529-0131(200001)43:1<129::AID-ANR16>3.0.CO;2-S.PubMedView ArticleGoogle Scholar
- Werth VP, Zhang W, Dortzbach K, Sullivan K: Association of a promoter polymorphism of tumor necrosis factor-alpha with subacute cutaneous lupus erythematosus and distinct photoregulation of transcription. J Invest Dermatol. 2000, 115: 726-730. 10.1046/j.1523-1747.2000.00118.x.PubMedView ArticleGoogle Scholar
- Zuniga R, Ng S, Peterson MGE, Reveille JD, Baethge BA, Alarcon GS, Salmon JE: Low-binding alleles of Fcγ receptor types IIA and IIIA are inherited independently and are associated with systemic lupus erythematosus in Hispanic patients. Arthritis Rheum. 2001, 44: 361-367. 10.1002/1529-0131(200102)44:2<361::AID-ANR54>3.3.CO;2-7.PubMedView ArticleGoogle Scholar
- Hatta Y, Tsuchiya N, Ohashi J, Matsushita M, Fujiwara K, Hagiwara K, Juji T, Tokunaga K: Association of Fc gamma receptor IIIB, but not Fc gamma receptor IIA and IIIA polymorphisms with systemic lupus erythematosus in Japanese. Genes Immun. 1999, 1: 53-60. 10.1038/sj.gene.6363639.PubMedView ArticleGoogle Scholar
- Selgiman VA, Suarez C, Lum R, Inda SE, Lin D, Li H, Olson JL, Seldin MF, Criswell LA: The FcγR IIIA-158F allele is a major risk factor for the development of lupus nephritis among Caucasians but not non-Caucasians. Arthritis Rheum. 2001, 44: 618-625. 10.1002/1529-0131(200103)44:3<618::AID-ANR110>3.3.CO;2-I.View ArticleGoogle Scholar