Other entities represented in this entry:SYSTEMIC LUPUS ERYTHEMATOSUS, RESISTANCE TO, 1, INCLUDED▼ MappingThe genetic basis for systemic lupus erythematosus (SLE...
Other entities represented in this entry:
The genetic basis for systemic lupus erythematosus (SLE; 152700) is complex. Tsao et al. (1997) cited reports demonstrating that certain MHC class II alleles, as well as homozygosity for deficiency of complement genes C1Q (120550), C2 (613927), and C4 (120810), are associated with SLE in most ethnic groups studied. Polymorphism of the FCGR2A gene (146790) has been associated with the glomerulonephritis of SLE in some studies and possible linkage of the locus with lupus identified. Tsao et al. (1997) tested a candidate region on human 1q homologous to a murine SLE susceptibility region identified in NZB mice. They found that the tested markers located on 1q41-q42 showed linkage to SLE, as well as to the presence of IgG antichromatin antibodies. They studied a total of 43 families having at least 2 sibs with SLE. There were 52 affected sib pairs. Thirty families were from southern California, 8 from Taiwan, 2 from England, 2 from China, and 1 from Korea. Tsao et al. (1997) concluded that the 1q41-q42 region probably contains a susceptibility gene that confers risk for SLE in multiple ethnic groups. Kotzin (1997) reviewed their findings. He stated that the homologous locus on distal mouse chromosome 1 is termed Nba2 for 'New Zealand black autoimmunity-2.' Nba2 appears to be the most important non-MHC locus linked to nephritis and death in NZB mice. He commented that future analysis of a separate group of lupus families will be necessary to confirm whether there is a locus at 1q41-q42 with strong contributions to disease risk.
Moser et al. (1998) screened the human genome for linkage to SLE in 94 pedigrees containing 220 affecteds and 533 total subjects. The 31 African American and 55 European American pedigrees were analyzed separately as well as combined into a total collection of 94 pedigrees. They reported evidence for linkage to 16 potential SLE susceptibility loci, including a lod score of 3.37 in African Americans for the FCGR2A polymorphism (R131H; 146790.0001) on 1q23, previously shown to be associated with lupus nephritis in African Americans. Linkage to several other loci, including SLEB1, was found in African Americans, in European-Americans, and in all pedigrees combined.
▼ Molecular Genetics
Resistance to Systemic Lupus Erythematosus
TLR5, the innate immune receptor for bacterial flagellin, maps to chromosome 1q41 and contains a common 1147C-T polymorphism that encodes a premature stop codon (R392X; 603031.0001) associated with increased susceptibility to Legionnaire disease (608556). Using transmission disequilibrium testing in an SLE cohort containing 199 affected patients and their 75 unaffected sibs and 326 parents, Hawn et al. (2005) found that allele 1174C of TLR5, but not allele 1174T, which encodes the premature stop codon, was preferentially transmitted to SLE-affected offspring. Alleles of 3 other TLR5 SNPs were not preferentially transmitted. The allele frequency of 1174T in probands was 3.2% compared with 5.8% in unaffected individuals, consistent with a protective association. Individuals with the TLR5 stop codon produced significantly lower levels of proinflammatory cytokines than individuals with the wildtype genotype. Hawn et al. (2005) concluded that the TLR5 stop codon polymorphism is associated with resistance to SLE development, particularly in those seronegative for anti-dsDNA autoantibodies. They proposed that flagellated bacteria and the innate immune response may have a role in SLE development.
▼ Animal Model
Mohan et al. (1998) pursued genetic studies in the NZM2410 lupus strain of mice that had implicated genomic intervals on chromosomes 1 (Sle1), 4 (Sle2), and 7 (Sle3) as conferring strong lupus susceptibility. B6 mice that were congenic for Sle1 had elevated IgG antichromatin antibodies. Mohan et al. (1998) explored the antinuclear antibody fine specificities and underlying cellular defects in these mice. On the B6 background, Sle1 by itself was sufficient to generate a strong, spontaneous, humoral antinuclear antibody (ANA) response, staining Hep-2 nuclei homogeneously and reacting primarily with H2A/H2B/DNA subnucleosomes. Sle1 also led to an expanded pool of histone-reactive T cells. Mohan et al. (1998) hypothesized that Sle1 may lead to the presentation of chromatin in an immunogenic fashion or directly impact tolerance of chromatin-specific B cells. They commented on the work of Tsao et al. (1997) demonstrating in human lupus a chromosome 1 interval (syntenic to murine Sle1) that is linked to high-serum IgG antichromatin ANAs. They suggested that all of these studies advance Sle1 on murine chromosome 1 as a major player in orchestrating selective loss of B-cell and T-cell tolerance to chromatin. This is in sharp contrast to the more generalized (not nuclear antigen restricted) immunophenotypes that Sle2 and Sle3 lead to. The process of generating congenic recombinants and screening them for anti-H2A/H2B/DNA antibodies should allow investigators to narrow the Sle1 interval and permit positional cloning of the causative gene. They stated that 'until then, one thing seems certain: Enshrouded in the Sle1 interval is the quintessential lupus gene responsible for the 'L.E.' phenomenon Hargraves discovered 50 years ago.'
In a fine-mapping analysis of the location of Sle1 on the mouse chromosome, Morel et al. (2001) determined that 3 loci within this congenic interval, termed Sle1a, Sle1b, and Sle1c, can independently cause a loss of tolerance to chromatin, a necessary step for full disease induction. The epistatic interactions of Sle1 with other susceptibility loci to cause severe nephritis cannot be accounted for, however, by these 3 loci alone, suggesting the existence of an additional locus, termed Sle1d.
Kumar et al. (2006) noted that the z allele of Sle1 and its component sublocus Sle1b, derived from a lupus-prone mouse strain, are linked to a variety of lupus-related disease phenotypes, including antinuclear antibodies, splenomegaly, and glomerulonephritis. SLAM gene family members are located within the Sle1bz sublocus and have been linked to murine spontaneous lupus. Analysis of mice expressing Sle1z/Sle1bz showed impaired B-cell anergy, receptor revision, and deletion. Among SLAM family members, the Ly108.1 isoform of Ly108 (SLAMF6; 606446) was most highly expressed in immature B cells from lupus-prone Sle1z mice. The normal allele, Ly108.2, but not Ly108.1, sensitized immature B cells to deletion and Rag (see 179615) reexpression. Kumar et al. (2006) concluded that some of the genes causing murine lupus may function by crippling multiple B-cell tolerance mechanisms. They suggested that Ly108 isoforms may function as molecular rheostats, determining the stringency with which self-reactive B cells are censored during early development.