Systemic Lupus Erythematosus

A number sign (#) is used with this entry because of evidence that multiple genes are involved in the causation of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by production of autoantibodies against nuclear, cytoplasmic, and cell surface molecules that transcend organ-specific boundaries. Tissue deposition of antibodies or immune complexes induces inflammation and subsequent injury of multiple organs and finally results in clinical manifestations of SLE, including glomerulonephritis, dermatitis, thrombosis, vasculitis, seizures, and arthritis. Evidence strongly suggests the involvement of genetic components in SLE susceptibility (summary by Oishi et al., 2008).

Genetic Heterogeneity of Systemic Lupus Erythematosus

An autosomal recessive form of systemic lupus erythematosus (SLEB16; 614420) is caused by mutation in the DNASE1L3 gene (602244) on chromosome 3p14.3.

See MAPPING and MOLECULAR GENETICS sections for a discussion of genetic heterogeneity of susceptibility to SLE.

Lappat and Cawein (1968) suggested that drug-induced, specifically procainamide-induced, systemic lupus erythematosus is an expression of a pharmacogenetic polymorphism. Among close relatives of a procainamide SLE proband, they found antinuclear antibody in the serum in 3, and in all 5, 'significant' history or laboratory findings suggesting an immunologic disorder. Three had a coagulation abnormality. The finding of complement deficiency (see 120900) in cases of lupus as well as association with particular HLA types points to genetic factors responsible for familial aggregation of this disease. On the other hand, the evidence for viral etiology suggests nongenetic explanations. Lupus-like illness occurs (Schaller, 1972) in carriers of chronic granulomatous disease (306400).

Lessard et al. (1997) demonstrated that CYP2D6 (124030) is the major isozyme involved in the formation of N-hydroxyprocainamide, a metabolite potentially involved in the drug-induced lupus syndrome observed with procainamide. Lessard et al. (1999) stated that further studies were needed to demonstrate whether genetically-determined or pharmacologically-modulated low CYP2D6 activity could prevent drug-induced lupus during procainamide therapy.

Reed et al. (1972) described inflammatory vasculitis with persistent nodules in members of 2 generations. Three females in the preceding generation had rheumatoid arthritis. They noted aggravation on exposure to sunlight and suppression of lesions with chloroquine therapy. They considered this to be related to lupus erythematosus profunda (Tuffanelli, 1971), which has a familial occurrence and is probably related to SLE.

Brustein et al. (1977) described a woman with discoid lupus who had one child in whom lesions of discoid lupus began at age 2 months and a second child who developed a rash probably of lupus erythematosus at age 1 week. Sibley et al. (1993) described a family in which a brother and sister and a niece of theirs had SLE complicated by ischemic vasculopathy. Photographs of the hands and feet of 1 patient showing gangrene of several fingers and all toes were presented. Extensive osteonecrosis occurred in the niece.

Elcioglu and Hall (1998) reported 2 sibs with chondrodysplasia punctata born to a mother with systemic lupus erythematosus. One child was stillborn at 36 weeks' gestation and the other miscarried at 24 weeks' gestation following the exacerbation of the mother's SLE. Austin-Ward et al. (1998) also reported an infant with neonatal lupus and chondrodysplasia punctata born to a mother with SLE. The infant also had features similar to those seen in children exposed to oral anticoagulants, although there was no history of this. Elcioglu and Hall (1998) and Austin-Ward et al. (1998), along with Toriello (1998) in a commentary on these 2 papers, suggested that there is evidence for an association between maternal SLE and chondrodysplasia punctata in a fetus. The pathogenesis of this association, however, remained unclear. Kelly et al. (1999) reported a male infant with neonatal lupus erythematosus manifested as a rash typical of the disorder, who also had midface hypoplasia and multiple stippled epiphyses. It was the skin abnormality in the infant that led to the diagnosis of SLE in his mother. Over a 3-year follow-up, the child demonstrated strikingly short stature, midface hypoplasia, anomalous digital development, slow resolution of the stippled epiphyses, and near-normal cognitive development. Kozlowski et al. (2004) described 2 brothers with chondrodysplasia punctata, whose mother had longstanding lupus erythematosus and epilepsy, for which she had been treated with chloroquine and other therapeutic agents during both pregnancies. Kozlowski et al. (2004) pointed to 7 reported instances of the association between chondrodysplasia punctata and maternal SLE.

Kamat et al. (2003) described the first reported incidence of identical triplets who developed SLE. The diagnosis of SLE was made at ages 8, 9, and 11 years (in reverse birth order, the last born developing the disorder at age 8). Photosensitivity and skin lesions were all early manifestations. The 3 girls manifested different clinical signs and symptoms; however, all 3 had skin rash, fatigue, and biopsy-proven glomerulonephritis. The findings of laboratory studies were similar, including positivity for antinuclear antibodies, anti-native DNA, and anti-double-stranded DNA (dsDNA), as well as low levels of complement.

SLE and Nephritis

Stein et al. (2002) analyzed 372 affected individuals from 160 multiplex SLE families, of which 25 contained at least 1 affected male relative. The presence of renal disease was significantly increased in female family members with an affected male relative compared to those with no affected male relative (p = 0.002); the trend remained after stratifying by race and was most pronounced in European Americans. Stein et al. (2002) concluded that the increased prevalence of renal disease previously reported in men with SLE is, in large part, a familial rather than sex-based difference, at least in multiplex SLE families.

Xing et al. (2005) added 392 individuals from 181 new multiplex SLE families to the sample previously studied by Stein et al. (2002) and replicated the finding that the prevalence of renal disease was increased in families with affected male relatives compared to families with no affected male relatives. Xing et al. (2005) concluded that multiplex SLE families with at least 1 affected male relative constitute a distinct subpopulation of multiplex SLE families.

DeHoratius et al. (1975) found anti-RNA antibodies in 82% of SLE cases and 16% of their relatives, as compared with 5% of control cases. The relatives who showed antibody were exclusively close household contacts of SLE cases. Anti-RNA antibody was not found in unrelated household contacts of SLE cases. The findings supported the hypothesis that both an environmental agent, perhaps a virus, and genetic response are involved in the pathogenesis of SLE. See 601821 for information about Ro ribonucleoproteins.

Beaucher et al. (1977) found clinical and serologic abnormalities in the household dogs of 2 families with multiple cases of clinical and serologic SLE, as well as other autoimmune disorders. Since spontaneous SLE occurs in dogs, a transmissible agent may be involved.

Horn et al. (1978) described mixed connective tissue disease (MCTD) in a brother and sister from a sibship of 8. They were HLA-identical (A11B12; A2B12). MCTD has characteristics overlapping SLE, scleroderma and polymyositis. Sera give positive indirect immunofluorescence tests for antinuclear antibodies with a characteristic coarse, speckled pattern. The diagnosis is confirmed by finding antibodies against ribonucleoprotein.

Batchelor et al. (1980) found an association of hydralazine-induced SLE with HLA-DR4. Slow acetylators without SLE and cases of nondrug-induced SLE did not show the association. Thus, spontaneous SLE may be a fundamentally different entity. In an extensive kindred in which elliptocytosis and lipomatosis (151900) were segregating as independent dominants, Weinberg et al. (1980) found a high frequency of biologic false-positive serologic tests for syphilis (BFP STS). The latter trait appeared also to be a dominant, independent of the other two traits. Two female pedigree members with BFP STS developed SLE.

Reidenberg et al. (1980) found an excess of slow acetylator phenotype in SLE. On the other hand, Baer et al. (1986) could find no association between acetylator phenotype and SLE and from a review of the literature concluded that most workers have had similar results. See C3b receptor (120620) for information on a polymorphism related to SLE.

Sakane et al. (1989) studied T- and B-cell function, using an IL-2 activity assay and spontaneous plaque-forming cell assay, respectively, in 34 family members of 6 patients with SLE. Impaired IL2 activity was found in 15 of 29 relatives but in none of 5 unrelated persons sharing households with the probands. The B-cell assay was abnormal in 22 of 29 relatives but was also abnormal in 4 of 5 unrelated household members. The authors concluded that there is a strong genetic component to the impaired IL2 activity in relatives of patients with SLE; the evidence suggests a genetic basis for the B-cell abnormalities, but environmental influences may also play a role. Benke et al. (1989) observed increased oxidative metabolism in PHA-stimulated lymphocytes from a subgroup of patients with systemic lupus erythematosus. The authors suggested that the increased oxidative activity may generate a chemical change in the endogenous DNA in vivo and therefore may be a primary event in the pathogenesis of autoimmunity in some patients with SLE.

Using EMSA analysis, Solomou et al. (2001) showed that whereas stimulated T cells from normal individuals had increased binding of phosphorylated CREB (123810) to the -180 site of the IL2 promoter, nearly all stimulated T cells from SLE patients had increased binding primarily of phosphorylated CREM (123812) at this site and to the transcriptional coactivators CREBBP (600140) and EP300 (602700). Increased expression of phosphorylated CREM correlated with decreased production of IL2. Solomou et al. (2001) concluded that transcriptional repression is responsible for the decreased production of IL2 and anergy in SLE T cells.

Xu et al. (2004) demonstrated that activated T cells of lupus patients resisted anergy and apoptosis by markedly upregulating and sustaining cyclooxygenase-2 (COX2, or PTGS2; 600262) expression. Inhibition of COX2 caused apoptosis of the anergy-resistant lupus T cells by augmenting FAS (134637) signaling and markedly decreasing the survival molecule FLIP (603599), and this mechanism was found to involve anergy-resistant lupus T cells selectively. Xu et al. (2004) noted that the gene encoding COX2 is located in a lupus susceptibility region on chromosome 1. They also found that only some COX2 inhibitors were able to suppress the production of pathogenic autoantibodies to DNA by causing autoimmune T-cell apoptosis, an effect that was independent of PGE2. Xu et al. (2004) suggested that these findings could be useful in the design of lupus therapies.

Zhang et al. (2001) determined that SLE patients have increased serum levels of B-lymphocyte stimulator (BLYS, or TNFSF13B; 603969) compared with normal controls. Immunoprecipitation and Western blot analyses revealed expression of a 17-kD soluble form of BLYS in patients but not controls. Functional analysis demonstrated that most patient serum-derived BLYS exhibited increased costimulatory activity for B-cell proliferation in vitro. Patients with higher levels of BLYS also had significantly higher levels of anti-dsDNA in IgG, IgM, and IgA classes than did patients with low levels of BLYS. Although there was no correlation between increased BLYS levels and clinical SLE activity, there were slightly higher BLYS levels in patients with antinuclear antibodies (ANA) and significantly increased BLYS levels in patients with both ANA and a clinical impression of SLE, suggesting that elevated BLYS precedes the formal fulfillment of the criteria for SLE. Zhang et al. (2001) suggested that BLYS may play an antiapoptotic role in B-cell tolerance loss and that anti-BLYS may be a potential therapy for SLE and other autoimmune diseases.

Baechler et al. (2003) used global gene expression profiling of peripheral blood mononuclear cells to identify distinct patterns of gene expression that distinguished most SLE patients from healthy controls. Strikingly, approximately half of the patients studied showed dysregulated expression of genes in the interferon pathway. Furthermore, this interferon gene expression 'signature' served as a marker for more severe disease involving the kidneys, hematopoietic cells, and/or the central nervous system. These results provided insight into the genetic pathways underlying SLE, and identified a subgroup of patients who may benefit from therapies targeted at the interferon pathway.

Using ELISA, Balada et al. (2008) determined that the DNA deoxymethylcytosine content of purified CD4 (186940)-positive T cells was lower in patients with SLE than in controls. RT-PCR analysis detected no differences in DNMT1 (126375), DNMT3A (602769), or DNMT3B (602900) transcript levels between SLE patients and controls. However, simultaneous association of low complement counts with lymphopenia, high titers of anti-dsDNA, or a high SLE disease activity index resulted in an increase in at least 1 of the DNMTs. Balada et al. (2008) proposed that patients with active SLE and DNA hypomethylation have increased DNMT mRNA levels.

Kelly et al. (2002) stated that SLE primarily affects women of child-bearing age (F:M ratio, 9:1) and has a prevalence of approximately 1 case/2,500. Among African American populations, SLE is 3 times more prevalent than in European Americans, manifests at a younger age, and is more severe than in other American populations.

Glucocorticoids are widely used to treat patients with autoimmune diseases such as SLE. However, in the majority of SLE patients such treatment regimens cannot maintain disease control, and more aggressive approaches such as high-dose methylprednisolone pulse therapy are used to provide transient reduction in disease activity. Guiducci et al. (2010) demonstrated that, in vitro and in vivo, stimulation of plasmacytoid dendritic cells (PDCs) through TLR7 (300365) and TLR9 (605474) can account for the reduced activity of glucocorticoids to inhibit the interferon pathway in SLE patients and in 2 lupus-prone mouse strains. The triggering of PDCs through TLR7 and TLR9 by nucleic acid-containing immune complexes or by synthetic ligands activates the NF-kappa-B (see 164011) pathway essential for PDC survival. Glucocorticoids do not affect NF-kappa-B activation in PDCs, preventing glucocorticoid induction of PDC death and the consequent reduction of systemic IFN-alpha (147660) levels. Guiducci et al. (2010) concluded that their findings unveiled a new role for self nucleic acid recognition by TLRs and indicated that inhibitors of TLR7 and TLR9 signaling could prove to be effective corticosteroid-sparing drugs.

Block et al. (1975) comprehensively reviewed evidence from twin studies. Higher concordance for clinical and serologic abnormality for monozygotic twins supported a significant genetic factor.

Lahita et al. (1983) observed father-to-son transmission and noted prepubertal onset of familial SLE in males.

Fielder et al. (1983) found an unexpectedly high frequency of null (silent) alleles at the C4A (120810), C4B (120820) and C2 (613927) loci in patients with SLE. HLA-DR3 showed a high frequency in these patients, and a strong linkage disequilibrium between DR3 and the null alleles for C4A and C4B was found. On the basis of the data reported by Fielder et al. (1983), Green et al. (1986) concluded that association with null alleles at the C4 loci is primary and the DR3 association secondary to that. In addition to the association of SLE with MHC antigens DR2 and DR3 and with homozygous deficiency of early complement components, the fact that SLE occurs 3 to 4 times more frequently in blacks than in whites (Siegel et al., 1970; Fessel, 1974) points to genetic factors.

Sturfelt et al. (1990) found homozygous C4A deficiency in 13 of 80 patients (16%). Photosensitivity was a more impressive feature in these homozygotes than in other lupus patients. The T4/Leu-3 molecule (186940) is a T-cell differentiation antigen expressed on the surface of T helper/inducer cells. Monoclonal antibodies that can recognize this molecule include OKT4 and anti-Leu-3a, which bind to different determinants (epitopes) on the T4/Leu-3 molecule. This molecule has an important role in the recognition of class II MHC antigens by T cells. Polymorphism of the T4 epitope had, by the time of the report of Stohl et al. (1985), been identified only in blacks. Three phenotypes, corresponding to 3 genotypes, were identified: the most common, the T4 epitope-intact phenotype, is manifest when fluorescence intensity upon staining of T cells is as great with OKT4 as with anti-Leu-3a. The T4 epitope-deficient phenotype shows no staining with OKT4, and an intermediate phenotype, representing heterozygosity for deficiency, shows fluorescence intensity with OKT4 that is half that with anti-Leu-3a.

Genomewide Linkage Studies

Lee and Nath (2005) conducted a metaanalysis of 12 genome scans generated from 9 independent studies involving 605 SLE families with 1,355 affected individuals. They identified 2 loci, 6p22.3-6p21.1 and 16p12.3-16q12.2, that met genomewide significance (p less than 0.000417). Lee and Nath (2005) noted that 6p22.3-6p21.1 contains the HLA region.

Gaffney et al. (1998) reported the results of a genomewide microsatellite marker screen in 105 SLE sib-pair families. Eighty of the families were Caucasian; 5 were African American. By using multipoint nonparametric methods, the strongest evidence for linkage was found near the HLA locus; D6S257 gave a lod score of 3.90. D16S415 at 16q13 yielded a lod score of 3.64; D14S276 at 14q21-q23 yielded a lod score of 2.81; and D20S186 at 20p12 yielded a lod score of 2.62. Another 9 regions were identified with lod scores equal to or greater than 1.00. The data supported the hypothesis that multiple genes, including 1 in the HLA region, influence susceptibility to human SLE.

Gaffney et al. (2000) performed a second genomewide screen in a 'new' cohort of 82 SLE sib-pair families. Highest evidence of linkage was found in 4 intervals: 10p13, 7p22, 7q21, and 7q36; all 4 had a lod score greater than 2.0, and the locus on 7p22 had a lod score of 2.87. A combined analysis of cohorts 1 and 2 (187 sib-pair families total) showed that markers in 6p21-p11 (D6S426, lod score of 4.19) and 16q13 (D16S415, lod score of 3.85) met the criteria for significant linkage.

Using the ABI Prism linkage mapping set, which includes 350 polymorphic markers with an average spacing of 12 cM, Shai et al. (1999) screened the human genome in a sample of 188 lupus patients belonging to 80 lupus families, each with 2 or more affected relatives per family, to localize genetic intervals that may contain lupus susceptibility loci. Nonparametric multipoint linkage analysis suggested evidence for predisposing loci on chromosomes 1 and 18. However, no single locus with overwhelming evidence for linkage was found, suggesting that there are no 'major' susceptibility genes segregating in families with SLE, and that the genetic etiology is more likely to result from the action of several genes of moderate effect. Furthermore, support for a gene in the 1q44 region, as well as for a gene in the 1p36 region, was found clearly only in Mexican American families with SLE, but not in families of Caucasian ethnicity, suggesting that consideration of each ethnic group separately is crucial.

Lindqvist et al. (2000) performed genome scans in families with multiple SLE patients from Iceland and from Sweden. A number of regions gave lod scores greater than 2: among Icelandic families, 4p15-p13, Z = 3.20; 9p22, Z = 2.27; and 19q13, Z = 2.06, which are homologous to the murine regions containing the lmb2, sle2, and sle3 loci, respectively. The fourth region among Icelandic families is located on 19p13 (D19S247, Z = 2.58) and a fifth on 2q37 (D2S125, Z = 2.06). Only 2 regions showed lod scores above 2.0 in the Swedish families: 2q11 (D2S436, Z = 2.13) and 2q37 (D2S125, Z = 2.18). The combination of both family sets gave a highly significant lod score at D2S125, with a Z of 4.24 in favor of linkage for 2q37 (see 605218).

Gray-McGuire et al. (2000) presented the result of a genome scan of 126 pedigrees with 2 or more cases of SLE, including 469 sib pairs (affected and unaffected) and 175 affected relative pairs. Using the revised multipoint Haseman-Elston regression technique for concordant and discordant sib pairs and a conditional logistic regression technique for affected relative pairs, they identified linkage to chromosome 4p16-p15.2 (P = 0.0003, lod = 3.84) and presented evidence of an epistatic interaction between 4p16-p15.2 and chromosome 5p15 in European American families. Using data from an independent pedigree collection, they confirmed the linkage to 4p16-p15.2 in European American families. The most significant linkage that they found in the African American subset was to the previously identified region on 1q (601744).

Johanneson et al. (2002) genotyped a set of 87 multicase families with SLE from various European countries and recently admixed populations of Mexico, Colombia, and the United States for 62 microsatellite markers on chromosome 1. By parametric 2-point linkage analysis, 6 regions previously described as being related to SLE (1p36, 1p21, 1q23, 1q25, 1q31, and 1q43) were identified that had lod scores greater than or equal to 1.50. CD45 (151460) was considered a strong candidate gene because of its position in 1q31-q32 and because of its involvement in the regulation of the antigen-induced signaling of naive B and T cells. Johanneson et al. (2002) found no association between the 77C-G (151460.0001) mutation in the CD45 gene and SLE in the families they studied. The locus at 1q31 showed a significant 3-point lod score of 3.79 and was contributed by families from all populations, with several markers and under the same parametric model. They concluded that a locus at 1q31 contains a major susceptibility gene, important to SLE in 'general populations.'

Scofield et al. (2003) selected 38 pedigrees that had an SLE patient with thrombocytopenia from a collection of 184 pedigrees with multiple cases of SLE. They established linkage at chromosome 1q22-q23 (maximum lod = 3.71) in all 38 pedigrees and at 11p13 (maximum lod = 5.72) in the 13 African American pedigrees. Nephritis, serositis, neuropsychiatric involvement, autoimmune hemolytic anemia, anti-double-stranded DNA, and antiphospholipid antibody were associated with thrombocytopenia. The results showed that SLE was more severe in the families with a thrombocytopenic SLE patient, whether or not thrombocytopenia in an individual patient was considered.

Susceptibility Loci for SLE Mapped by Linkage Studies

See SLEB1 (601744) for discussion of an SLE susceptibility locus on chromosome 1q41. Variations in the TLR5 gene (603031) have been associated with SLE at this locus; see MOLECULAR GENETICS.

See SLEB2 (605218) for discussion of an SLE susceptibility locus on chromosome 2q37. Variations in the PDCD1 gene (605218) have been associated with SLE at this locus; see MOLECULAR GENETICS.

See SLEB3 (605480) for discussion of an SLE susceptibility locus on chromosome 4p.

See SLEB4 (608437) for discussion of an SLE susceptibility locus on chromosome 12q24.

See SLEB5 (609903) for discussion of an SLE susceptibility locus on chromosome 13q32.

See SLEB6 (609939) for discussion of an SLE susceptibility locus on chromosome 16q12-q13.

See SLEB7 (610065) for discussion of an SLE susceptibility locus on chromosome 20p12.

See SLEB8 (610066) for discussion of an SLE susceptibility locus on chromosome 20q13.1.

See SLEB9 (610927) for discussion of an SLE susceptibility locus on chromosome 1q32.

See SLEB10 (612251) for discussion of an SLE susceptibility locus on chromosome 7q32. Variations in the IRF5 gene (607218) have been associated with SLE at this locus; see MOLECULAR GENETICS.

See SLEB11 (612253) for discussion of an SLE susceptibility locus on chromosome 2q32.2-q32.3. Variations in the STAT4 gene (600558) have been associated with SLE at this locus; see MOLECULAR GENETICS.

See SLEB12 (612254) for discussion of an SLE susceptibility locus on chromosome 8p23.1.

See SLEB13 (612378) for discussion of an SLE susceptibility locus on chromosome 6p23. Variations in the TNFAIP3 gene (191163) have been associated with SLE at this locus; see MOLECULAR GENETICS.

See SLEB14 (613145) for discussion of an SLE susceptibility locus on chromosome 1q21-q23. Variations in the CRP gene (123260) have been associated with SLE at this locus; see MOLECULAR GENETICS.

See SLEB15 (300809) for a discussion of an SLE susceptibility locus on chromosome Xq28.

Susceptibility Loci for SLE with Nephritis

Renal disease occurs in 40 to 75% of SLE patients and contributes significantly to morbidity and mortality (Garcia et al., 1996). Quintero-Del-Rio et al. (2002) used 2 pedigree stratification strategies to explore the impact of the American College of Rheumatology's renal criterion for SLE classification upon genetic linkage with SLE. They identified susceptibility loci for SLE associated with nephritis on chromosomes 10q22.3 (SLEN1; 607965), 2q34-q35 (SLEN2; 607966), and 11p15.6 (SLEN3; 607967).

Susceptibility Locus for SLE with Hemolytic Anemia

A locus for susceptibility to SLE with hemolytic anemia as an early or prominent clinical manifestation shows linkage to 11q14 (SLEH1; 607279).

Susceptibility Locus for SLE with Vitiligo

A locus for susceptibility to SLE associated with vitiligo has been mapped to 17p13 (SLEV1; 606579).

Association with the HLA-DRB1 Locus

Using a dense map of polymorphic microsatellites across the HLA region in a large collection of families with SLE, Graham et al. (2002) identified 3 distinct haplotypes that encompassed the class II region and exhibited transmission distortion. By visualizing ancestral recombinants, they narrowed the disease-associated haplotypes containing DRB1*1501 and DRB1*0801 to a region of approximately 500 kb. They concluded that HLA class II haplotypes containing DRB1 and DQB1 alleles are strong risk factors for human SLE.

To identify risk loci for SLE susceptibility, Gateva et al. (2009) selected SNPs from 2,466 regions that showed nominal evidence of association to SLE (P less than 0.05) in a genomewide study and genotyped them in an independent sample of 1,963 cases and 4,329 controls. This new cohort replicated the association with HLA-DRB1 at rs3135394 (odds ratio = 1.98, 95% confidence interval = 1.84-2.14; combined P = 2.0 x 10(-60)).

Association with the TNIP1 Gene on Chromosome 5q32

In a study of 1,963 patients from the United States and Sweden with SLE compared with 4,329 controls, Gateva et al. (2009) identified association with the TNIP1 gene (607714) at chromosome 5q32 (rs7708392, combined P value = 3.8 x 10(-13); odds ratio = 1.27, 95% confidence interval = 1.10-1.35).

Han et al. (2009) performed a genomewide association study of SLE in a Chinese Han population by genotyping 1,047 cases and 1,205 controls using Illumina-Human610-Quad BeadChips and replicating 78 SNPs in 2 additional cohorts (3,152 cases and 7,050 controls). Han et al. (2009) found association with a SNP in the TNIP1 gene, rs10036748 (combined P = 1.67 x 10(-9); odds ratio = 0.81, 95% confidence interval = 0.75-0.87).

Association with the PTPN22 Gene on Chromosome 1p13

In a study of 525 unrelated North American white individuals with SLE, Kyogoku et al. (2004) found an association with the R620W polymorphism in the PTPN22 gene (600716.0001), with estimated minor (T) allele frequencies of 12.67% in SLE cases and 8.64% in controls. A single copy of the T allele (W620) increased risk of SLE (odds ratio = 1.37), and 2 copies of the allele more than doubled this risk (odds ratio = 4.37).

Orru et al. (2009) reported a 788G-A variant, resulting in an arg263-to-gln (R263Q; rs33996649) substitution within the catalytic domain of the PTPN22 gene, that leads to reduced phosphatase activity. They genotyped 881 SLE patients and 1,133 healthy controls from Spain and observed a significant protective effect (p = 0.006; OR, 0.58). Three replication cohorts of Italian, Argentinian, and Caucasian North American populations failed to reach significance; however, the combined analysis of 2,093 SLE patients and 2,348 controls confirmed the protective effect (p = 0.0017; OR, 0.63).

To confirm additional risk loci for SLE susceptibility, Gateva et al. (2009) selected SNPs from 2,466 regions that showed nominal evidence association to SLE (P less than 0.05) in a genomewide study and genotyped them in an independent sample of 1,963 cases and 4,329 controls. Gateva et al. (2009) showed an association with PTPN22 at rs2476601 (combined P value = 3.4 x 10(-12), odds ratio = 1.35, 95% confidence interval = 1.24-1.47).

Association with the CRP Gene on Chromosome 1q21-q23

Relative deficiency of pentraxin proteins is implicated in the pathogenesis of SLE. The C-reactive protein (CRP; 123260) response is defective in patients with acute flares of disease, and mice with targeted deletions of the APCS (104770) gene develop a lupus-like illness. In humans, the CRP and APCS genes are both within the 1q23-q24 interval that has been linked to SLE. Among 586 simplex SLE families, Russell et al. (2004) found that basal levels of CRP were influenced independently by 2 CRP polymorphisms, which they designated CRP2 (rs1800947) and CRP4 (rs1205), and the latter was associated with SLE and antinuclear autoantibody production. Russell et al. (2004) hypothesized that defective disposal of potentially immunogenic material may be a contributory factor in lupus pathogenesis.

Association with the FCGR2B Gene on Chromosome 1q22

In 193 Japanese patients with SLE and 303 healthy controls, Kyogoku et al. (2002) found that homozygosity for an ile232-to-thr polymorphism in the FCGR2B gene (I232T; 604590.0002) was significantly increased in SLE patients compared with controls.

In membrane separation studies using a human monocytic cell line, Floto et al. (2005) demonstrated that although wildtype FCGR2B readily partitioned into the raft-enriched gradient fractions, FCGR2B-232T was excluded from them. Floto et al. (2005) concluded that FCGR2B-232T is unable to inhibit activating receptors because it is excluded from sphingolipid rafts, resulting in the unopposed proinflammatory signaling thought to promote SLE.

Su et al. (2004) identified 10 SNPs in the first FCGR2B promoter in 66 SLE patients and 66 controls. They determined that the proximal promoter contains 2 functionally distinct haplotypes. Luciferase promoter analysis showed that the less frequent haplotype, which had a frequency of 9%, was associated with increased gene expression. A case-control study of 243 SLE patients and 366 matched controls demonstrated that the less frequent haplotype was significantly associated with the SLE phenotype and was not in linkage disequilibrium with FCGR2A and FCGR3A (146740) polymorphisms. Su et al. (2004) concluded that an expression variant of FCGR2B is a risk factor for SLE.

In 190 European American patients with SLE and 130 European American controls, Blank et al. (2005) found a significant association between homozygosity for a -343C polymorphism in the promoter region of the FCGR2B gene (604590.0001) and SLE. The surface expression of FCGR2B receptors was significantly reduced in activated B cells from -343C/C SLE patients. Blank et al. (2005) suggested that deregulated expression of the mutant FCGR2B gene may play a role in the pathogenesis of human SLE.

By comparing genotypes of patients with SLE from Hong Kong and the UK with those of ethnically matched controls, followed by metaanalysis using with other studies on southeast Asian and Caucasian SLE patients, Willcocks et al. (2010) found that homozygosity for T232 of the I232T FCGR2B polymorphism was strongly associated with SLE in both ethnic groups. When studies in Caucasians and southeast Asians were combined, T232 homozygosity was associated with SLE with an odds ratio of 1.73 (P = 8.0 x 10(-6)). Willcocks et al. (2010) noted that the T232 allele of the SNP is more common in southeast Asians and Africans, populations where malaria (see 611162) is endemic, than in Caucasians. Homozygosity for T232 was significantly associated with protection from severe malaria in Kenyan children (odds ratio = 0.56; P = 7.1 x 10(-5)), but no association was found with susceptibility to bacterial infection. Willcocks et al. (2010) proposed that malaria may have driven retention of a polymorphism predisposing to a polygenic autoimmune disease and thus may begin to explain the ethnic differences seen in the frequency of SLE.

Association with the FCGR3B Gene on Chromosome 1q23

Aitman et al. (2006) showed that copy number variation (CNV) of the orthologous rat and human Fcgr3 genes is a determinant of susceptibility to immunologically mediated glomerulonephritis. Positional cloning identified loss of the rat-specific Fcgr3 paralog 'Fcgr3-related sequence' (Fcgr3rs) as a determinant of macrophage overactivity and glomerulonephritis in Wistar Kyoto rats. In humans, low copy number of FCGR3B (610665), an ortholog of rat Fcgr3, was associated with glomerulonephritis in SLE.

Following up on the study of Aitman et al. (2006) in a larger sample, Fanciulli et al. (2007) confirmed and strengthened their previous finding of an association between low FCGR3B copy number and susceptibility to glomerulonephritis in SLE patients. Low copy number was also associated with risk of systemic SLE with no known renal involvement as well as with microscopic polyangiitis and granulomatosis with polyangiitis (608710), but not with organ-specific Graves disease (275000) or Addison disease (240200), in British and French cohorts. Fanciulli et al. (2007) concluded that low FCGR3B copy number or complete FCGR3B deficiency has a key role in the development of specific autoimmunity.

Willcocks et al. (2008) confirmed that low copy number of FCGR3B was associated with SLE in a Caucasian U.K. population, but they were unable to find an association in a Chinese population. Investigations of the functional effects of FCGR3B CNV revealed that FCGR3B CNV correlated with cell surface expression, soluble FCGR3B production, and neutrophil adherence to and uptake of immune complexes both in a patient family and in the general population. Willcocks et al. (2008) found that individuals from 3 U.K. cohorts with antineutrophil cytoplasmic antibody-associated systemic vasculitis (AASV) were more likely to have high FCGR3B CNV. They proposed that FCGR3B CNV is involved in immune complex clearance, possibly explaining the association of low CNV with SLE and high CNV with AASV.

Niederer et al. (2010) noted linkage disequilibrium (LD) between multiallelic FCGR3B CNV and SLE-associated SNPs in the FCGR locus. Despite LD between FCGR3B CNV and a variant in FCGR2B (I232T; 604590.0002) that abolishes inhibitory function, both reduced CN of FCGR3B and homozygosity of the FCGR2B-232T allele were individually strongly associated with SLE risk. Thus copy number of FCGR3B, which controls immune complex responses and uptake by neutrophils, and variations in FCGR2B, which controls factors such as antibody production and macrophage activation, are important in SLE pathogenesis.

Mueller et al. (2013) found that the increased risk of SLE associated with reduced copy number of FCGR3B can be explained by the presence of a chimeric gene, FCGR2B-prime, that occurs as a consequence of FCGR3B deletion on FCGR3B zero-copy haplotypes. The FCGR2B-prime gene consists of upstream elements and a 5-prime coding region that derive from FCGR2C, and a 3-prime coding region that derives from FCGR2B (604590). The coding sequence of FCGR2B-prime is identical to that of FCGR2B, but FCGR2B-prime would be expected to be under the control of 5-prime flanking sequences derived from FCGR2C. Mueller et al. (2013) found by flow cytometry, immunoblotting, and cDNA sequencing that presence of the chimeric FCGR2B-prime gene results in the ectopic presence of Fc-gamma-RIIb on natural killer cells, providing an explanation for SLE risk associated with reduced FCGR3B copy number. The 5 FCGR2/FCGR3 genes are arranged across 2 highly paralogous genomic segments on chromosome 1q23. To pursue the underlying mechanism of SLE disease association with FCGR3B copy number variation, Mueller et al. (2013) aligned the reference sequence (GRCh37) of the proximal block of the FCGR locus (chr1:161,480,906-161,564,008) to that of the distal block (chr1:161,562,570-161,645,839). Identification of informative paralogous sequence variants (PSVs) enabled Mueller et al. (2013) to narrow the potential breakpoint region to a 24.5-kb region of paralogy between then 2 ancestral duplicated blocks. The complete absence of nonpolymorphic PSVs in the 24.5-kb region prevented more precise localization of the breakpoints in FCGR3B-deleted or FCGR3B-duplicated haplotypes.

Association with the TNFSF6 Gene on Chromosome 1q23

The apoptosis genes FAS (TNFRSF6; 134637) and FASL (TNFSF6; 134638) are candidate contributory genes in human SLE, as mutations in these genes result in autoimmunity in several murine models of this disease. In humans, FAS mutations result in a familial autoimmune lymphoproliferative syndrome (e.g., 134637.0001). Wu et al. (1996) studied DNA from 75 patients with SLE using SSCP analysis for potential mutations of the extracellular domain of FASL. In 1 SLE patient who exhibited lymphadenopathy, they found an 84-bp deletion within exon 4 of the FASL gene, resulting in a predicted 28-amino acid in-frame deletion (see 134638.0001).

Association with the TNFSF4 Gene on Chromosome 1q25

By use of both a family-based study and a case-control study of SLE in U.K and Minnesota populations to screen the TNFRSF4 (600315) and TNFSF4 (603594) genes, Cunninghame Graham et al. (2008) found that an upstream region of TNFSF4 contains a single risk haplotype (GCTAATCATTTGA) for SLE that correlates with increased cell surface TNFSF4 expression and TNFSF4 transcript. The authors suggested that increased expression of TNFSF4 predisposes to SLE either by quantitatively augmenting T-cell/antigen-presenting cell (APC) interaction or by influencing the functional consequences of T-cell activation via TNFRSF4.

Han et al. (2009) performed a genomewide association study of SLE in a Chinese Han population by genotyping 1,047 cases and 1,205 controls using Illumina-Human610-Quad BeadChips and replicating 78 SNPs in 2 additional cohorts (3,152 cases and 7,050 controls). Han et al. (2009) found association with the TNFSF4 gene at 2 SNPs, rs1234315 (combined P value = 2.34 x 10(-26), odds ratio = 1.37, 95% confidence interval 1.29-1.45) and rs2205960 (combined P value = 2.53 x 10(-32), odds ratio = 1.46, 95% confidence interval 1.37-1.56).

Association with the CR2 Gene on Chromosome 1q32

Wu et al. (2007) analyzed the CR2 gene, which lies in the SLEB9 (610927) locus region, in 1,416 individuals from 258 Caucasian and 142 Chinese SLE simplex families and demonstrated that a common 3-SNP haplotype (120650.0001) was associated with SLE susceptibility (p = 0.00001) with a 1.54-fold increased risk for development of disease. Wu et al. (2007) concluded that the CR2 gene is likely a susceptibility gene for SLE.

Association with the TLR5 Gene on Chromosome 1q41-q42

A polymorphism in the TLR5 gene (R392X; 603031.0001), which maps to the SLEB1 (601744) locus, is associated with resistance to SLE development.

Association with the STAT4 Gene on Chromosome 2q32

In 1,039 patients with SLE and 1,248 controls, Remmers et al. (2007) identified an association between SLE (SLEB11; 612253) and the minor T allele of rs7574865 in intron 3 of the STAT4 gene (600558.0001). The risk allele was present in 31% of chromosomes of patients with SLE compared with 22% of those of controls (p = 1.87 x 10(-9)). Homozygosity of the risk allele (TT) compared to absence of the allele was associated with a more than doubled risk for lupus. The risk allele was also associated with susceptibility to rheumatoid arthritis (RA; 180300).

Association with the CTLA4 Gene on Chromosome 2q33

In a metaanalysis of 7 published studies and their own study, Barreto et al. (2004) examined the association between an 49A-G polymorphism in the CTLA4 gene (123890.0001) and SLE. The authors found that individuals with the GG genotype were at significantly higher risk of developing SLE; carriers of the A allele had a significantly lower risk of developing the disease, and the AA genotype acted as a protective genotype for SLE.

In a metaanalysis of 14 independent studies testing association between CTLA4 polymorphisms and SLE, Lee et al. (2005) confirmed that the 49A-G polymorphism is significantly associated with SLE susceptibility, particularly in Asians.

Association with the PDCD1 Gene on Chromosome 2q37

Prokunina et al. (2002) analyzed 2,510 individuals, including members of 5 independent sets of families as well as unrelated individuals affected with SLE, for SNPs that they had identified in the PDCD1 gene, which maps within the SLEB2 locus (605218). They showed that one intronic SNP (600244.0001) was associated with development of SLE in Europeans and Mexicans. The associated allele of this SNP alters a binding site for the RUNT-related transcription factor-1 (RUNX1; 151385) located in an intronic enhancer, suggesting a mechanism through which it can contribute to the development of SLE in humans.

Association with the TREX1 Gene on Chromosome 3p21

Lee-Kirsch et al. (2007) analyzed the 3-prime repair exonuclease gene TREX1 (606609) in 417 patients with SLE and 1,712 controls and identified heterozygosity for a 3-prime UTR variant and 11 nonsynonymous changes in 12 patients (see, e.g., 606609.0001). They identified only 2 nonsynonymous changes in 2 controls (p = 1.7 X 10(-7), relative risk = 25.3). In vitro studies of 2 frameshift mutations revealed that both caused altered subcellular distribution. The authors concluded that TREX1 is implicated in the pathogenesis of SLE.

Association with the BANK1 Gene on Chromosome 4q22-q24

Kozyrev et al. (2008) identified an association between SLE and a nonsynonymous G-to-A transition in the BANK1 gene that results in a substitution of his for arg at codon 61 (610292.0001), with the G allele conferring risk.

Association with the NKX2-5 Gene on Chromosome 5q34

Oishi et al. (2008) genotyped 3 SNPs in the NKX2-5 gene (600584) in 178 Japanese SLE patients and 1,425 controls and found association with rs3095870 in the 5-prime flanking region of NKX2-5 (p = 0.0037; odds ratio, 1.74). Individuals having the risk genotype for both NKX2-5 and 3748079 of the ITPR3 gene (147267) had a higher risk for SLE (odds ratio, 5.77).

Association with the ITPR3 Gene on Chromosome 6p21

Oishi et al. (2008) performed a case-control association study using more than 50,000 genomewide gene-based SNPs in a total of 543 Japanese SLE patients and 2,596 controls and identified significant association with a -1009C-T transition (rs3748079) located in a promoter region of the ITPR3 gene (p = 1.78 x 10(-8); odds ratio, 1.88). Studies in HEK293T cells showed that binding of NKX2-5 is specific to the nonsusceptibility -1009T allele, and individuals with the risk genotype of both ITPR3 and NKX2-5 (rs3095870) had a higher risk for SLE (odds ratio, 5.77). Oishi et al. (2008) concluded that genetic and functional interactions of ITPR3 and NKX2-5 play a crucial role in the pathogenesis of SLE.

Association with the TNFA Gene on Chromosome 6p21.3

In a metaanalysis of 19 studies, Lee et al. (2006) found an association between SLE and a -308A