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.
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