The search for genes in the 1q23 linkage interval 67 has led to intensive study of the immunoglobulin receptors encoded there. There are three distinct but closely related classes of Fcγ receptors (FCGRs) in humans: FCGR1 (CD64), FCGR2A (CD32), and FCGR3A (CD16). They have different affinities for IgG and its subclasses, and those encoded on 1q23 include FCGR2A, FCGR2B, FCGR3A, and FCGR3B. The arginine variant at amino acid position 131 of FCGR2A (or R131) is associated with SLE, particularly in African-Americans 8, whereas FCGR3A-F176 is associated with SLE in European derived peoples and other ethnic groups 7. A gene dose effect with FCGR2A-R131 for the risk for SLE was also identified in a meta-analysis 9, with the risk for SLE increasing with the number of R alleles (RR > RH > HH). The data that FCGR3A-F176 is a risk factor for lupus nephritis are also convincing 10. Because both of these mutations produce receptors with lowered affinity for IgG 11, it is thought that these variants may predispose to autoimmunity through delayed clearance of immune complexes, but this remains an unproven hypothesis. Although one of these two variants is probably responsible for the linkage in this region, there are conflicting data on which is the most important, and this remains an area of active interest 791012.

PDCD1 (programmed cell death 1) is generally accepted as the gene responsible for the linkage at 2q34 13, and it is also associated with lupus nephritis 14. To date, this is the only gene to have been identified through fine mapping of a linkage interval, although this association does not go unchallenged in other populations tested 15. The presumed mechanism of action is through an intronic single nucleotide polymorphism (SNP) that alters a binding site for the RUNX1 transcription factor, leading to decreased expression of the PDCD1-encoded protein and delayed apoptosis 13. Auto-reactive T cells that fail to undergo apoptosis properly may persist to support autoimmune responses.

The genes responsible for linkage at the other loci are not so straightforward. Although it is generally accepted that human leukocyte antigen (HLA)-DR is associated with SLE 16, there are a number of other genes in the HLA region that may also contribute to this linkage, as discussed below. PARP (poly-[ADP-ribose] polymerase) was initially identified as the gene responsible for linkage at 1q41 17, but two subsequent studies in European-American 18 and French Caucasian 19 cohorts failed to confirm this association. Two additional studies conducted in Asian populations also failed to find an association with disease, although both found correlation of PARP alleles with clinical manifestations (discoid rash and anticardiolipin IgM 20, and nephritis and arthritis 21).

Clinical manifestations of SLE are extremely diverse and variable, both in individual patients and over time. We hypothesize that genetic factors contribute to this clinical diversity and that there will be subsets of genes that are over-represented in families with particular clinical manifestations. We therefore used stratification of multiplex pedigrees by phenotype to improve the genetic homogeneity of our cohorts and discover new loci linked to SLE. For example, by analyzing only the families in which one or more members have vitiligo, we identified linkage at 17p12 22 and six additional linked loci were discovered through stratification by other clinical and laboratory criteria. All of these have been established and confirmed in an independent cohort (Table 2).

Although several susceptibility loci for SLE have been identified by individual genome-wide scans, many of these loci have yielded inconsistent results across studies. Additionally, many individual studies are at the lower limit of acceptable power recommended for declaring significant linkage. The genome search meta-analysis has been proposed as a valid and robust method for combining several genome scan results 23. Recently, the results of two genome search meta-analyses were reported 2425. These studies identified many linked regions that may harbor the SLE susceptibility genes. The most interesting results emerging from these studies are significant linkages in the intervals of 6p21-6p22 and 16p12-16q13.

There are a few instances in which mutation of a single gene causes lupus or a lupus-like syndrome. The most common of these is a deficiency of complement component C2 27, which occurs in 1/10,000 individuals 28, and nearly one-third of these patients will develop SLE 29. Although the gene encoding C2 is in the same region as the major histocompatibility complex (MHC), two studies 3031 have concluded that MHC genes are not responsible for the phenotype in C2-deficient patients. The mild phenotype and female predominance in C2-deficient SLE patients may be due to other genetic influences that remain to be determined.

Most individuals carry four copies of the C4 gene cassette, which lies within the MHC cluster, but copy numbers can vary between 0 and 6 32. Minor variations within the cassette provide the designations C4A and C4B, and the majority of individuals carry two copies of each, although there is considerable variation in the population. Complete deficiency of all copies of the C4 cassette has been shown to cause severe SLE as well as susceptibility to infection, but this condition is quite rare 33. A partial deficiency, usually with deletion of a single C4A allele (also known as C4A*Q0 or C4 null), has been associated with disease risk; however, C4A*Q0 is in linkage disequilibrium with DR3 34, an MHC haplotype that is strongly associated with autoantibody production and SLE in its own right 4. Rare deficiencies in C1q, C1r, and C1s also appear to cause SLE 27.

It would appear to be no coincidence that C2, C4, and C1 are all components of the classical pathway, through which immune complexes activate complement. Genetic defects in C3 or in any of the terminal complement components (C5 to C9) generally result in increased sensitivity to infection, particularly from Gram-negative bacteria such as Neisseria meningitidis 27. The early complement components are important for keeping immune complexes in soluble form, as well as for clearance of apoptotic bodies 35. Additionally, C4 is critical for maintenance of B-cell tolerance 36, which may prove to be even more important than delayed immune complex clearance in the pathogenesis of SLE in these patients.

After considering these single genes, perhaps the next clearest genetic effect in SLE is in the HLA region. Although multiple studies conducted during the past 40 years have shown clear HLA associations 42637, it is currently uncertain which gene or genes may be responsible for increasing genetic risk. This region contains not only the HLA class I, II and III genes, but also the genes that encode complement components C2 and C4, tumor necrosis factor (TNF)-α and TNF-β (also known as lymphotoxin-α LTA), transporter associated with antigen processing (TAP)1 and TAP2, butyrophilin-like protein 2, and numerous heat-shock protein genes and others with possible immune significance. Furthermore, these genes are often inherited as a block, a phenomenon known as linkage disequilibrium, so that – for example – the TNF-α -308A variant associated with over-expression is often found in a haplotype block that also contains HLA-B8, C4A null, and HLA-DR3 38. It is unfortunate that most of the studies in this region focus on a single marker, most often either HLA-DR or TNF-α, either of which could be responsible for this extended haplotype. To add additional confusion to the issue of pathogenicity, more than one HLA allele has been found to associate with disease, for example DR3 and DR2, and these associations are not necessarily confined to a single ethnic group 37.

It is reasonable to think that any of these variants could contribute to the lupus phenotype. As discussed above, complete deficit of C2 or C4 appears to cause SLE, and more subtle alterations in the classical pathway may also cause some tendency toward autoimmunity. The HLA proteins are directly involved in antigen presentation, and in some cases, such as in HLA-B27 arthritis, this has been shown to lead to alteration in the immune repertoire 39. TNF-α is central to regulation of many inflammatory pathways, and treatment with TNF-α inhibitors can cause lupus flares or lupus-like symptoms, possibly through upregulation of IFN-α 40, indicating a complex role for this cytokine in SLE. TNF-β is key to the formation of normal lymph nodes 41, and the gene encoding TNF-β is one of the most consistently associated across populations, with seven positive reports and no negative reports to date 26. TAP1 and TAP2 are involved in peptide processing for antigen presentation, and transgenic mice that lack TAP are resistant to experimentally induced SLE 42. It is possible that any one of these defects alone could predispose to SLE, but it is also possible that it takes some combination of 'hits' to produce an extended haplotype that correlates more directly with disease risk.

When there are several studies on the same allele in a gene, meta-analysis can be a useful tool for sorting out any conflicting reports, but usually there are not enough studies performed to make this practical. For some of the more extensively studied genes, however, it represents a powerful tool. For example, the majority of the reports on the gene encoding interleukin-10 support association, as does a recent meta-analysis 43, although there is a body of literature that supports only associations with specific phenotypes as well as half a dozen negative reports. Meta-analysis also favors association with the mannose-binding lectin (MBL) gene, although the individual reports are evenly divided in favor and in opposition 44. The situation is similar with cytotoxic T lymphocyte associated antigen (CTLA)4, in which association is also favored even though the literature is mixed, with the strongest effects seen in Asian populations 45. TNF-α also has mixed reports but a positive meta-analysis, particularly in European-Americans 46; interpretation of this finding is problematic, however, because TNF-α is in linkage disequilibrium with HLA-DR 38. The cumulative data support an association of the protein tyrosine phos-phatase nonreceptor (PTPN)22 gene with SLE as well 47. Meta-analyses are not always positive, however; meta-analysis of the data on the widely studied insertion/deletion polymorphism in the angiotensin-converting enzyme gene does not favor association with SLE or lupus nephritis 48.

A number of murine models of lupus have been characterized, and they include both transgenic constructs and strains with naturally occurring disease (for review, see 4950515253545556). Some of these animal models have led us to discover single gene deficiencies that are found rarely in human disease, as well as a number of candidate genes for association. MRL/lpr mice, a murine model of lupus, are deficient in Fas 57, and deficiencies of Fas in humans cause autoimmune lymphoproliferative syndrome 58. DNAse1-deficient mice also serve as a model of lupus 59, and there are reports of DNAse1 deficiency leading to SLE in human families 6061. Although these examples suggest a general effect, the literature contains roughly equal numbers of reports for and against the association of Fas, Fas ligand, and DNAse1 with SLE in larger case-control studies 26. It is therefore difficult to draw any firm conclusions about the role of these genes in SLE pathogenesis in the general population. Other interesting mouse knockout models that develop autoimmune phenotypes include those for C1Q 62, Fcγ 63, and Toll-like receptor-7 64. Mapping of the genes responsible for disease in spontaneous models of lupus in mice is another area of active interest, and the overlap between the search for autoimmune genes in human and mouse is due to expand and integrate rapidly as new technologies are brought to bear on this area 51.

Genes in the IFN family have also been implicated in SLE. The well known IFN signature 65 has provided the inspiration for a number of candidate gene studies. Initial associations with IFN-γ 66 and the IFN receptors 67 have not been confirmed in additional cohorts 686970. Most recently, however, a study conducted in a large Nordic cohort 71 demonstrated an association with the IFN-regulatory factor (IRF)5 gene; and this has sparked a flurry of strong confirmation and characterization reports 727374. These four studies all confirm the association of IRF5 with SLE, which appears to be quite robust, although the genetics in this region are complex and several variations appear to combine to form the risk haplotypes 74. Additional work characterizing the IRF5 alleles associated with SLE is in progress.