Systemic lupus erythematosus (SLE), a chronic, remitting, relapsing, inflammatory, and often febrile multisystemic disorder of connective tissue, acute or insidious at onset, is characterized principally by involvement of the skin, joints, kidneys, and serosal membranes. Lupus erythematosus is ... Systemic lupus erythematosus (SLE), a chronic, remitting, relapsing, inflammatory, and often febrile multisystemic disorder of connective tissue, acute or insidious at onset, is characterized principally by involvement of the skin, joints, kidneys, and serosal membranes. Lupus erythematosus is thought to represent a failure of the regulatory mechanisms of the autoimmune system. - Genetic Heterogeneity of Systemic Lupus Erythematosus See MAPPING and MOLECULAR GENETICS sections for a discussion of genetic heterogeneity of susceptibility to SLE. An autosomal recessive form of systemic lupus erythematosus (SLEB16; 614420) is caused by mutation in the DNASE1L3 gene (602244) on chromosome 3p14.3.
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 ... 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.
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 ... 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.
- 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 ... - 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; dbSNP 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 dbSNP 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 (dbSNP rs1800947) and CRP4 (dbSNP 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 Wegener granulomatosis (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, 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, dbSNP rs1234315 (combined P value = 2.34 x 10(-26), odds ratio = 1.37, 95% confidence interval 1.29-1.45) and dbSNP 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 dbSNP 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 dbSNP 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 dbSNP 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 (dbSNP 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 (dbSNP 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/G promoter polymorphism in the TNFA gene (191160.0004). The findings were significant in European-derived population (odds ratio of 4.0 for A/A and 2.1 for the A allele), but not in Asian-derived populations. - Association with the C4A and C4B Genes on Chromosome 6p21.3 Yang et al. (2007) investigated interindividual gene copy number variation (CNV) of complement component C4 in relation to susceptibility to SLE. They found that long C4 genes were strongly correlated with C4A (120810); short C4 genes were correlated with C4B (120820). In comparison with healthy subjects, patients with SLE clearly had the gene copy number (GCN) of total C4 and C4A shifted to the lower side. The risk of SLE disease susceptibility increased significantly among subjects with only 2 copies of total C4 (patients 9.3%; unrelated controls 1.5%) but decreased in those with 5 or more copies of C4 (patients 5.79%; controls 12%). Zero copies and 1 copy of C4A were risk factors for SLE, whereas 3 or more copies of C4A appeared to be protective. Family-based association tests suggested that a specific haplotype with a single short C4B in tight linkage disequilibrium with the -308A allele of TNFA (191160.0004) was more likely to be transmitted to patients with SLE. Boteva et al. (2012) genotyped 1,028 SLE cases, including 501 patients from the UK and 537 from Spain, and 1,179 controls for gene copy number of total C4, C4A, C4B, and the 2-bp insertion SNP (C4AQ0; 120810.0001) resulting in a null allele. The loss-of-function SNP in C4A was not associated with SLE in either population. Boteva et al. (2012) used multiple logistic regression to determine the independence of C4 CNV from known SNP and HLA-DRB1 associations. Overall, the findings indicated that partial C4 deficiency states are not independent risk factors for SLE in UK and Spanish populations. Although complete homozygous deficiency of complement C4 is one of the strongest genetic risk factors for SLE, partial C4 deficiency states do not independently predispose to the disease. - Association with the TNXB Gene on Chromosome 6p21.3 In a genomewide case-control association study of 178 Japanese SLE patients and 899 controls, Kamatani et al. (2008) found significant association between SLE and a SNP (dbSNP rs3130342) in the 5-prime flanking region of the TNXB gene (600985) on chromosome 6p21.3 (p = 9.3 x 10(-7)); odds ratio, 3.11). The association was replicated independently with 203 cases and 294 controls (p = 0.04; odds ratio, 1.52). Analysis in their Japanese SLE patients showed that the association with dbSNP rs3130342 was independent of C4 copy number, suggesting that the association previously reported between SLE and CNV of the C4A gene (see Yang et al., 2007) likely reflected linkage disequilibrium between C4A CNV and dbSNP rs3130342. Stratified analysis also demonstrated that the association between dbSNP rs3130342 and SLE was independent of the HLA-DRB1*1501 allele association with SLE. Kamatani et al. (2008) concluded that TNXB is a candidate gene for SLE susceptibility in the Japanese population. - Association with the TNFAIP3 Gene on Chromosome 6q23 In separate genomewide association studies, Graham et al. (2008) and Musone et al. (2008) found association between single-nucleotide polymorphisms (SNPs) in the TNFAIP3 region (191163) and risk of SLE. Graham et al. (2008) found association with SLE of a SNP that is also associated with rheumatoid arthritis (RA; 180300). - Association with the IRF5 Gene on Chromosome 7q32 Sigurdsson et al. (2005) and Graham et al. (2006) showed that a common IRF5 (607218) haplotype, which drives elevated expression of multiple unique forms of IRF5, is an important risk factor for SLE (SLEB10; 612251). - Association with the DNASE1 Gene on Chromosome 16p13.3 In 2 unrelated females with SLE and no family history of the disorder, Yasutomo et al. (2001) identified heterozygosity for a mutation in the DNASE1 gene (125505.0001). The patients, aged 13 and 17 years, were diagnosed as having SLE based on clinical features, high serum titers of antibodies against double-stranded DNA, and Sjogren syndrome. Both patients had substantially lower levels of DNASE1 activity in the sera than in other SLE patients without a DNASE1 mutation. However, the DNASE1 activity of SLE patients without DNASE1 mutations is lower than that of healthy controls. The patient's B cells had 30 to 50% of the DNASE1 activity of cells from controls, showing that heterozygous mutation of DNASE1 reduces the total activity of this enzyme. In 350 Korean patients with SLE and 330 Korean controls, Shin et al. (2004) identified a nonsynonymous SNP in exon 8 of the DNASE1 gene, 2373A-G (Q244R; 125505.0002), that was significantly associated with an increased risk of the production of anti-RNP and anti-dsDNA antibodies among SLE patients. The frequency of the arg/arg minor allele was much higher in patients who had the anti-RNP antibody (31%) than in patients who did not have this antibody (14%) (P = 0.0006). - Association with the ITGAM Gene on Chromosome 16p11.2 See SLEB6, 609939. Nath et al. (2008) identified and replicated an association between ITGAM (120980) at 16p11.2 and risk of SLE in 3,818 individuals of European descent. The strongest association was at a nonsynonymous SNP, dbSNP rs1143679 (120980.0001). Nath et al. (2008) further replicated this association in 2 independent samples of individuals of African descent. The International Consortium for Systemic Lupus Erythematosus Genetics et al. (2008) likewise identified an association between SNPs in ITGAM in 720 women of European ancestry with SLE and in 2 additional independent sample sets. Several previously identified associations such as the strong association between SLE and the HLA region on 6p21 and the previously confirmed non-HLA locus IRF5 (607218) on 7q32 were found. The International Consortium for Systemic Lupus Erythematosus Genetics et al. (2008) also found association with replication for KIAA1542 (611780) at 11p15.5, PXK (611450) in 3p14.3, and a SNP at 1q25.1. Hom et al. (2008) identified SNPs near the ITGAM and ITGAX (151510) genes that were associated with SLE; they believed variants of ITGAM to be driving the association. - Association with the IL6 Gene on chromosome 7p21 Linker-Israeli et al. (1999) used PCR and RFLP analysis to genotype the AT-rich minisatellite in the 3-prime flanking region and the 5-prime promoter-enhancer of IL6 (147620) in SLE patients and controls. In both African-Americans and Caucasians, short allele sizes (less than 792 bp) at the 3-prime minisatellite were found exclusively in SLE patients, whereas the 828-bp allele was overrepresented in controls. No association was found between SLE and alleles in the 5-prime region of IL6. Patients homo- or heterozygous for the SLE-associated 3-prime minisatellite alleles secreted higher levels of IL6, had higher percentages of IL6-positive monocytes, and showed significantly enhanced IL6 mRNA stability. Linker-Israeli et al. (1999) concluded that the AT-rich minisatellite in the 3-prime region flanking of IL6 is associated with SLE, possibly by increasing accessibility for transcription factors. - Association with the IL18 Gene on Chromosome 11q22 Sanchez et al. (2009) selected 9 SNPs spanning the IL18 gene (600953) and genotyped an independent set of 752 Spanish systemic lupus erythematosis patients and 595 Spanish controls. A -1297T-C SNP (dbSNP rs360719) survived correction for multiple tests and was genotyped in 2 case-control replication cohorts from Italy and Argentina. Combined analysis for the risk C allele remained significant (pooled odds ratio = 1.37, 95% CI 1.21-1.54, corrected p = 1.16 x 10(-6)). There was a significant increase in the relative expression of IL18 mRNA in individuals carrying the risk -1297C allele; in addition, -1297C allele created a binding site for the transcriptional factor OCT1 (POU2F1; 164175). Sanchez et al. (2009) suggested that the dbSNP rs360719 variant may play a role in susceptibility to SLE and in IL18 expression. - Association with the CSK Gene on Chromosome 15q23-q25 The c-Src tyrosine kinase CSK (124095) physically interacts with the intracellular phosphatase LYP (PTPN22; 600716) and can modify the activation state of downstream Src kinases, such as LYN (165120), in lymphocytes. Manjarrez-Orduno et al. (2012) identified an association of CSK with SLE and refined its location to the intronic polymorphism dbSNP rs34933034 (odds ratio = 1.32; p = 1.04 x 10(-9)). The risk allele at this SNP is associated with increased CSK expression and augments inhibitory phosphorylation of LYN. In carriers of the risk allele, there is increased B-cell receptor-mediated activation of mature B cells, as well as higher concentrations of plasma IgM, relative to individuals in the nonrisk haplotype. Moreover, the fraction of transitional B cells is doubled in the cord blood of carriers of the risk allele, due to an expansion of late transitional cells in a stage targeted by selection mechanisms. Manjarrez-Orduno et al. (2012) concluded that their results suggested that the LYP-CSK complex increases susceptibility to lupus at multiple maturation and activation points in B cells. - Association with the EGR2 Gene on Chromosome 10q21 Based on phenotypic changes in knockout mice, Myouzen et al. (2010) evaluated if polymorphisms in the EGR2 gene (129010) on chromosome 10q21 influence SLE susceptibility in humans. A significant positive correlation with expression was identified in a SNP located at the 5-prime flanking region of EGR2. In a case-control association study using 3 sets of SLE cohorts by genotyping 14 tag SNPs in the EGR2 gene region, a peak of association with SLE susceptibility was observed for dbSNP rs10761670. This SNP was also associated with susceptibility to rheumatoid arthritis (RA; 180300), suggesting that EGR2 is a common risk factor for SLE and RA. Among the SNPs in complete linkage disequilibrium with dbSNP rs10761670, 2 SNPs (dbSNP rs1412554 and dbSNP rs1509957) affected the binding of transcription factors and transcriptional activity in vitro, suggesting that they may be candidates of causal regulatory variants in this region. The authors proposed that EGR2 may be a genetic risk factor for SLE, in which increased gene expression may contribute to SLE pathogenesis.