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This article is part of the series Genetic epidemiology .

Review

Genetic epidemiology: Systemic lupus erythematosus

Yasmeen A Ahmad and Ian N Bruce*

Author Affiliations

University of Manchester Rheumatism Research Centre, Central Manchester and Manchester Children's University NHS Trust, Manchester, UK

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Arthritis Res 2001, 3:331-336  doi:10.1186/ar324

The electronic version of this article is the complete one and can be found online at:


Received:30 April 2001
Revisions received:19 July 2001
Accepted:31 July 2001
Published:23 August 2001

© 2001 BioMed Central Ltd

Abstract

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.

Keywords:
candidate genes; disease susceptibility; linkage analysis; mouse models; SLE

Introduction

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 [1]. 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 [1]. 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.

The chromosomal locations of genes mediating susceptibility to lupus nephritis or systemic autoimmunity in the NZB/W, MRL, and BXSB mouse models have been determined through genome scans [2,3,4,5]. These studies show that lupus susceptibility is inherited in a complex fashion involving both genetic interactions and additive effects of individual genes. In all, 31 different gene designations have been defined thus far, distributed among 21 nonoverlapping 20-cM genome intervals (Table 1). Other investigators have mapped loci affecting a variety of component phenotypes associated with systemic autoimmunity [6]. The genomic segments on murine chromosomes 1, 4, and 7 are associated with disease susceptibility in multiple strain combinations, suggesting that these intervals contain genes or gene clusters that strongly influence autoimmunity. The Sle1, Sle2, and Sle3 loci have been individually identified as the major SLE susceptibility loci in NZM2410 mice [2] and their immunophenotypes have been characterised. Sle1 mediates loss of tolerance to nuclear antigens, Sle2 lowers the activation threshold of B cells, and Sle3 mediates dysregulation of CD4+ T cells [2]. The combination of Sle1 with any one of Sle2, Sle3, or Yaa (autoimmune accelerating gene) on the B6 genetic background results in the development of systemic autoimmunity with variably penetrant glomerulonephritis culminating in renal failure and death. In contrast, two-loci combinations of any of Sle2, Sle3, or Yaa did not mediate fatal disease. These results identify Sle1 as a strategic locus in SLE pathogenesis [7]. The NZW genome also has four epistatic modifiers, SLE suppressors (Sles1-Sles4), which suppress autoimmunity. The most potent, Sles1, switches off the Sle1 immunophenotype and can suppress the entire autoimmune pathological process [8]. Recent fine-mapping analysis of the Sle1 locus has identified a cluster of functionally related loci (Sle1a-d). These loci share a common pathway leading to loss of tolerance to chromatin but differ by various other serological and cellular phenotypes [9]. This potent susceptibility locus is syntenic with the 1q23-42 segment of the human chromosome.

Table 1. Positions of the named susceptibility loci from murine genome studies involving NZB, NZW, NZM2410, BXSB, and MRL/lpr mice (Wakeland et al, 1999) [2].

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

The traditional approach for locating a disease gene in humans is linkage analysis. Results from mouse models of SLE presented the first evidence for genetic linkage to an area of chromosome 1 in the mouse that is syntenic to human chromosome 1q23-42. In 1997, Tsao et al [14] published linkage evidence on the long arm of chromosome 1q41-42, using 43 families with 52 affected sibling pairs of mixed origin. Several additional linkage studies have been performed using sib-pairs and extended family pedigrees [15,16,17,18,19]. The parameters and test populations for each study as well as the genomic intervals detected in at least two mapping studies are summarised in Tables 2 and 3.

Table 2. Summary of human linkage studies in systemic lupus erythematosus

Table 3. Human systemic lupus erythematosus susceptibility loci identified in two or more mapping studies

As Table 2 shows, there are many sources of variation between these studies, including ethnic mix, sample size, specific markers used, and analytic models used. Another source of variation may relate to clinical phenotypes of the affected individuals. Localisation of genes with modest effects by linkage analysis is difficult and such variations may further limit the power of such studies. Despite these important limitations, there is some agreement as regards regions providing evidence of linkage. Several areas on chromosome 1 have been detected (1p36, 1q21-23 and 1q41-42) [15,16,17,18,19] that contain genes of immunological importance, some of which may have direct relevance to pathogenic processes in SLE (Table 4). The importance of using well-defined populations is emphasised by recent studies of Nordic multi-case families in which a susceptibility locus at chromosome 2q37 (SLEB2) has been reported [19]. A study of single-case Swedish families confirmed association with further markers in this region but, in contrast, there was no linkage to this area in 13 Mexican families [20].

Table 4. Candidate genes for systemic lupus erythematosus at regions identified by linkage analysis

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

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 [21] 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 [22] 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.

Mannose-binding protein

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 [25].

IL-6

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 [26] 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

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 [27] 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 [28]. These studies found no association with disease susceptibility. In contrast, Gibson et al [29] 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 [1]. 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 [31] 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.

Fc receptors

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 [32] 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 [33], 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 [34] 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.

Conclusion

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.

Abbreviations

Fc = crystallizable fragment [of antibody]; FcγR = Fc IgG receptor; IL = interleukin; SLE = systemic lupus erythematosus; TNF = tumour necrosis factor.

References

  1. Sullivan KE: Genetics of systemic lupus erythematosus: clinical implications.

    Rheum Dis Clin North Am 2000, 26:229-256. PubMed Abstract OpenURL

  2. Wakeland EK, Wandstrat AE, Liu K, Morel L: Genetic dissection of systemic lupus erythematosus.

    Curr Opin Immunol 1999, 11:701-707. PubMed Abstract | Publisher Full Text OpenURL

  3. 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. PubMed Abstract OpenURL

  4. 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. OpenURL

  5. 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. PubMed Abstract | Publisher Full Text OpenURL

  6. 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. PubMed Abstract | Publisher Full Text OpenURL

  7. 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. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  8. Morel L, Tian X-H, Croker BP, Wakeland EK: Epistatic modifiers of autoimmunity in murine models of lupus nephritis.

    Immunity 1999, 11:131-139. PubMed Abstract | Publisher Full Text OpenURL

  9. 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. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  10. 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. PubMed Abstract OpenURL

  11. 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. PubMed Abstract | Publisher Full Text OpenURL

  12. 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. PubMed Abstract | Publisher Full Text OpenURL

  13. 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. PubMed Abstract | Publisher Full Text OpenURL

  14. 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. PubMed Abstract | Publisher Full Text OpenURL

  15. Moser KL, Neas BR, Salmon JE, Yu H, Gray-McGuire C, Asundi N, Bruner GR, Fox J, Kelly J, Henshall S, Bacino D, Dietz M, Hogue R, Koelsch G, Nightingale L, Shaver T, Abdou NI, Albert DA, Carson C, Petri M, Treadwell EL, James JA, Harley JB: 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. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  16. 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. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  17. 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. PubMed Abstract | Publisher Full Text OpenURL

  18. Shai R, Quismorio FP Jr, 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. PubMed Abstract | Publisher Full Text OpenURL

  19. 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. PubMed Abstract | Publisher Full Text OpenURL

  20. 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. PubMed Abstract | Publisher Full Text OpenURL

  21. 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. PubMed Abstract | Publisher Full Text OpenURL

  22. 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. PubMed Abstract | Publisher Full Text OpenURL

  23. 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. PubMed Abstract OpenURL

  24. 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. PubMed Abstract OpenURL

  25. 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. PubMed Abstract | Publisher Full Text OpenURL

  26. 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. PubMed Abstract | Publisher Full Text OpenURL

  27. 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. PubMed Abstract OpenURL

  28. 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. PubMed Abstract | Publisher Full Text OpenURL

  29. 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. PubMed Abstract | Publisher Full Text OpenURL

  30. 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. PubMed Abstract | Publisher Full Text OpenURL

  31. 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. PubMed Abstract | Publisher Full Text OpenURL

  32. 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. PubMed Abstract | Publisher Full Text OpenURL

  33. 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. PubMed Abstract | Publisher Full Text OpenURL

  34. 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. PubMed Abstract | Publisher Full Text OpenURL