Linkage and interaction of loci on 1q23 and 16q12 may contribute to susceptibility to systemic lupus erythematosus

OBJECTIVE: Six recent genome scans of different systemic lupus erythematosus (SLE) multiplex family cohorts showed multiple putative susceptibility loci. In the present study, we examined 4 previously identified loci to replicate findings of significant linkage to 1q23 and 16q12, and to support findings of suggestive linkage to 14q21-23 and 20p12 in a cohort of 115 multiethnic nuclear families containing 145 SLE-affected sibpairs. METHODS: Model-free, multipoint linkage analyses (SIBPAL2, SAGE version 4.0) and exclusion mapping (GeneHunter) were performed. RESULTS: Linkages to 1q23 (peak at D1S2675, mean allele sharing [MAS] 0.56; P = 0.003) and to 16q12 (peaks between D16S753 and D16S757, MAS 0.57; P = 0.003) were confirmed, but linkage evidence at 20p12 was weak and inconsistent (MAS 0.52-0.56; from P = 0.005 to P not significant). Evidence for linkage to 1q23 and 16q12 was stronger in 68 non-Caucasian affected sibpairs than in 77 Caucasian affected sibpairs. Exclusion mapping ruled out linkage at 14q21-23 (lambda(s) [sib recurrence risk or genotypic risk ratio] = 1.8). Because the pericentromeric region of chromosome 16 has been identified by genome scans in several autoimmune diseases, we postulated that it might harbor an autoimmune modifier gene. To explore this possibility, we tested for an interaction between 16q12 and 1q23, and between 16q12 and 20p12. Haplotype sharing at 1q23 increased concomitantly with increased haplotype sharing at 16q12 (P = 0.008 by nonparametric Jonckheere-Terpstra exact statistical test). No evidence supporting an interaction between 16q12 and 20p12 was observed. Analysis of sibpairs sharing 2 alleles at 16q12 also showed increased allele sharing at 1q23 (MAS from 0.56 to 0.65). CONCLUSION: These data support the presence of SLE susceptibility genes at 1q23 and 16q12, particularly in non-Caucasians. The skewed distribution of haplotypes suggests that genetic interaction of these two loci may affect SLE susceptibility.     

人系统性红斑狼疮遗传易感性研究进展

系统性红斑狼疮(SLE)是一种多因素疾病,其发病机制至今尚未明确.但越来越多的研究证据表明,遗传易感性在疾病发生中起重要作用.人类基因组研究显示约50多个基因座(loci)与SLE有关,独立队列研究证实至少有9个区域有明显相关性,包括lq23、lq31-32、lq41-42、2q35-37、4p16-15.2、6p21-11、11p13、12q24及16q12-13.对具体患者,多个不同位点的基因组合可引起疾病表型的多样性.近期研究进一步证实,遗传因素在决定疾病易感性及临床表型时起作用,不同种族、地域人群中所涉及的相关基因有所差异.     

An update on genetic studies of systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a complex, multifactorial autoimmune disease. Genetic factors are thought to contribute to its pathogenesis. There have been numerous recent advances in the study of murine and human lupus genetics. In well-defined experimental transgenic or gene-knockout mouse models, the development of lupus-like disease has implicated specific genes and pathways in the disease pathogenesis. Linkage analyses have mapped multiple susceptibility loci and disease suppressive loci using inbred strains of mice that spontaneously develop lupus-like disease. Elegant genetic dissection and function studies have led to the recent identification of two murine candidate susceptibility genes, Ifi202 (encoding an interferon-inducible protein) and Cr2 (encoding complement receptors 1 and 2). In human lupus, casecontrol studies have established associations of SLE with certain major histocompatibility class II alleles, complement deficiencies, and polymorphisms of Fcψ receptor genes, a complement-related gene, and cytokine genes. During the past several years, linkage analyses using SLE multiplex families have provided many chromosomal regions for further exploration of susceptibility genes. Six regions exhibiting significant linkage to SLE are promising. Studies are underway to fine map these linked regions and to identify the genes in the susceptibility regions. An understanding of the genes involved in the development of lupus should provide targets for more focused therapy in lupus.     

Haplotypes of the HRES-1 endogenous retrovirus are associated with development and disease manifestations of systemic lupus erythematosus

OBJECTIVE: Endogenous retroviral sequences represent a link between viral and genetic factors that may influence the development of systemic lupus erythematosus (SLE). The HRES-1 human endogenous retroviral sequence is centrally located at the 1q42 chromosomal region relative to microsatellites previously associated with SLE. We therefore undertook the present study to determine the haplotypes of the HRES-1 locus and their linkage to SLE. METHODS: One hundred six patients with SLE, 82 unrelated healthy Caucasian individuals, and 70 healthy members of 34 lupus families were examined. HRES-1 was amplified by polymerase chain reaction (PCR) and analyzed by sequencing and restriction enzyme mapping. Microsatellites were analyzed by PCR. Haplotype construction and transmission disequilibrium testing (TDT) were performed in lupus families. RESULTS: Based on 4 single-nucleotide polymorphisms (SNPs) within a 935-base interval, we detected 6 HRES-1 haplotypes that were differentially segregated in unrelated Caucasian patients and control subjects (chi(2) = 16.86, P = 0.0048) and were in linkage disequilibrium (LD) with the D1S225 microsatellite (P = 0.0002). The microsatellites D1S225, D1S235, and D1S2785 (but not D1S229) were linked to SLE by TDT. Interestingly, LD between HRES-1 SNPs at bases 653 and 1259 was reduced in patients with SLE (P = 0.048). The HRES-1 653C/1259C-harboring alleles were associated with the presence of renal disease (P = 0.0021) and with the absence of lung disease (P = 0.0323), while the 956A allele was associated with the antiphospholipid syndrome in patients with SLE (P = 0.0036). CONCLUSION: The HRES-1 locus represents a recombination hot spot at the 1q42 chromosomal region that influences the development and disease manifestations of SLE.     

Confirmation of genetic linkage between human systemic lupus erythematosus and chromosome 1q41.

OBJECTIVE: Genetic susceptibility to systemic lupus erythematosus (SLE) is undoubtedly complex and, presumably, involves multiple loci. Linkage of SLE to D1S229 at chromosome 1q41 has been previously reported in a cohort of 52 affected sibpairs. The present study sought to confirm this reported linkage in an independent cohort of 127 extended multiplex SLE pedigrees containing 107 affected sibpairs. METHODS: Genotype data were collected for D1S229 and 18 flanking microsatellite markers spanning chromosome 1q32-1q42. Analyses of genotype data included a model-based logarithm of odds (LOD) score approach, affected sibpair analyses, and transmission disequilibrium tests. RESULTS: A maximum LOD score of 1.46 was found with D1S229 in a subgroup of 78 European American pedigrees, with additional support from multiple markers clustered around D1S229. Increased allele sharing in affected siblings was most significant at D1S2616, particularly in European Americans (P = 0.0005), followed by D1S229 (P = 0.002), D1S490 (P = 0.028), and D1S1605 (P = 0.037). Although linkage in a subgroup of 40 African American pedigrees was not suggested by the analyses of any marker tested in the chromosomal region surrounding D1S229, a maximum LOD score of 3.03 was found with D1S3462, mapped 15 centimorgans distal to D1S229. CONCLUSION: Our linkage analysis results in European Americans at D1S229 are remarkably similar to those previously reported. That at least 1 genetic effect near this locus is important for susceptibility to lupus should now be generally accepted, and efforts to identify the gene are thereby justified.     

Deletion of C4A genes in patients with systemic lupus erythematosus

To define the relationship between inheritance of major histocompatibility complex (MHC) alleles and susceptibility to the development of systemic lupus erythematosus (SLE), we examined the MHC class I, II, and III phenotypes of white SLE patients and characterized the structures of their class III MHC genes, using Southern blotting. Nine of 88 SLE patients (10.2%) were C4A null. As detected by Southern blot analysis, the C4A gene was deleted from both chromosomes in 8 of the 9 C4A-null patients. Deletions affecting only 1 chromosome (heterozygous) were detected in the remaining C4A-null patient and in 34.5% of SLE patients who were not C4A deficient (compared with 12.5% of controls; P less than 0.05). These results indicate that deletion of the C4A gene is a common genetic marker for SLE. Deletions of C4A were observed most commonly as part of the HLA-B8;DR3 extended haplotype, although deletions were also detected in different HLA haplotypes. Because of the critical role of C4A in the processing of immune complexes, deficiency of C4A may, itself, confer susceptibility to the development of SLE.     

Genetics and systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a complex, multifactorial autoimmune disease. Genetic factors are believed to contribute to its pathogenesis. There have been numerous recent advances in the study of murine and human lupus genetics. In well-defined, experimental, transgenic or gene-knockout mouse models, the development of lupus-like disease has implicated specific genes and pathways in the disease pathogenesis. Linkage analyses have mapped multiple susceptibility loci and disease suppressive loci using inbred strains of mice that spontaneously develop lupus-like disease. Elegant genetic dissection has demonstrated that a component phenotype of SLE is displayed by each congenic strain carrying a single susceptibility locus on a resistant genetic background, whereas polycongenic strains exhibit fatal lupus nephritis. These studies suggest that genes in separate pathways can interact to augment or suppress the initiation and progression of systemic autoimmunity. In association studies of human lupus, the contributions of the MHC loci, Fcg receptors, various cytokines, components of the complement cascade, and proteins involved in apoptosis have been explored. Most recently, linkage analyses have been performed and provide many chromosomal regions for further exploration for susceptibility genes. Studies to identify the genes in the susceptibility regions are underway. An understanding of the genes involved in the development of lupus should provide targets for more focused therapy in lupus.     

Major histocompatibility complex genes and susceptibility to systemic lupus erythematosus in southern Chinese.

OBJECTIVE. To investigate the predisposing role of major histocompatibility complex (MHC) genes to systemic lupus erythematosus (SLE) in a Chinese population. METHODS. Polymorphism in the HLA-DRB, DQB, complement component C4, and 21-hydroxylase genes was analyzed by restriction fragment length polymorphism analysis and oligonucleotide probing of in vitro-amplified DNA from 88 Chinese patients with SLE and 69 matched control subjects. RESULTS. HLA-DRw15 and DQw1 were significantly more frequent in patients (corrected P less than 0.006, relative risk 5.2), but none of the 9 sequence variants of DQw1 were increased. The C4A gene deletion usually associated with SLE in Caucasoid and black patients was absent from all Chinese subjects, but possession of other C4 deletions and of DRw15 conferred the greatest risk (relative risk = 8.3). CONCLUSION. Different MHC haplotypes predispose to lupus in Chinese than in other ethnic groups. Our data suggest that the susceptibility lies at, or telomeric to, the DR locus, and that DRw15 and C4 deletions may act synergistically in conferring disease susceptibility.     

Genome scan of human systemic lupus erythematosus: Evidence for linkage on chromosome 1q in African-American pedigrees

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by production of autoantibodies against intracellular antigens including DNA, ribosomal P, Ro (SS-A), La (SS-B), and the spliceosome. Etiology is suspected to involve genetic and environmental factors. Evidence of genetic involvement includes: associations with HLA-DR3, HLA-DR2, Fcγ receptors (FcγR) IIA and IIIA, and hereditary complement component deficiencies, as well as familial aggregation, monozygotic twin concordance >20%, λ_s > 10, purported linkage at 1q41–42, and inbred mouse strains that consistently develop lupus. We have completed a genome scan in 94 extended multiplex pedigrees by using model-based linkage analysis. Potential [log₁₀ of the odds for linkage (lod) > 2.0] SLE loci have been identified at chromosomes 1q41, 1q23, and 11q14–23 in African-Americans; 14q11, 4p15, 11q25, 2q32, 19q13, 6q26–27, and 12p12–11 in European-Americans; and 1q23, 13q32, 20q13, and 1q31 in all pedigrees combined. An effect for the FcγRIIA candidate polymorphism) at 1q23 (lod = 3.37 in African-Americans) is syntenic with linkage in a murine model of lupus. Sib-pair and multipoint nonparametric analyses also support linkage (P < 0.05) at nine loci detected by using two-point lod score analysis (lod > 2.0). Our results are consistent with the presumed complexity of genetic susceptibility to SLE and illustrate racial origin is likely to influence the specific nature of these genetic effects.     

Systemic lupus erythematosus genome scan: support for linkage at 1q23, 2q33, 16q12-13, and 17q21-23 and novel evidence at 3p24, 10q23-24, 13q32, and 18q22-23

OBJECTIVE: To identify chromosome regions likely to harbor genes that predispose to the development of systemic lupus erythematosus (SLE) by analyzing a full genome scan in nuclear families ascertained for siblings with SLE. METHODS: Approximately 400 multiallelic markers spaced an average of 10 cM apart were genotyped in a multiethnic panel of 238 individuals from 62 multiplex SLE families having 88 affected sibling pairs and 456 total sibling pairs. Findings were analyzed by 2 model-free statistical linkage procedures. RESULTS: Evidence supporting linkage to 4 previously reported (1q23, 2q33, 16q12-13, and 17q21-23) and 4 novel (3p24, 10q23-24, 13q32, and 18q22-23) chromosome regions was revealed. Stratification by family ethnicity indicated that linkage to 3 regions, 2q33, 10q23-24, and 18q22-23, was derived primarily from the Caucasian families, while linkage to 17q21-23 was seen primarily in the non-Caucasian families. CONCLUSION: Linkage to the same chromosome regions in independent cohorts is a critical step in finding the genes that predispose to a complex disorder such as SLE. Four linked regions also seen in independent SLE cohorts lend credibility to the 4 novel regions identified by these analyses. Substantial linkage information was gleaned by genotyping and analyzing the unaffected siblings. These results provide additional evidence that the SLE clinical phenotype is genetically complex, multigenic, and heterogeneous.     

Genetic variation in C-reactive protein (CRP) gene may be associated with risk of systemic lupus erythematosus and CRP concentrations

OBJECTIVE: The gene coding for C-reactive protein (CRP) is located on chromosome 1q23.2, which falls within a linkage region thought to harbor a systemic lupus erythematosus (SLE) susceptibility gene. Recently, 2 single-nucleotide polymorphisms (SNP) in the CRP gene (+838, +2043) have been shown to be associated with CRP concentrations and/or SLE risk in a British family-based cohort. Our study was done to confirm the reported association in an independent population-based case-control cohort, and also to investigate the influence of 3 additional CRP tagSNP (-861, -390, +90) on SLE risk and serum CRP concentrations. METHODS: DNA from 337 Caucasian women who met the American College of Rheumatology criteria for definite (n = 324) or probable (n = 13) SLE and 448 Caucasian healthy female controls was genotyped for 5 CRP tagSNP (-861, -390, +90, +838, +2043). Genotyping was performed using restriction fragment length polymorphism-polymerase chain reaction, pyrosequencing, or TaqMan assays. Serum CRP levels were measured using ELISA. Association studies were performed using the chi-squared distribution, Z-test, Fisher's exact test, and analysis of variance. Haplotype analysis was performed using EH software and the haplo.stats package in R 2.1.2. RESULTS: While none of the SNP were found to be associated with SLE risk individually, there was an association with the 5 SNP haplotypes (p < 0.001). Three SNP (-861, -390, +90) were found to significantly influence serum CRP level in SLE cases, both independently and as haplotypes. CONCLUSION: Our data suggest that unique haplotype combinations in the CRP gene may modify the risk of developing SLE and influence circulating CRP levels.     

Cytotoxic T lymphocyte antigen 4 (CTLA-4) dimorphism in patients with systemic lupus erythematosus

OBJECTIVE: Genetic susceptibility to systemic lupus erythematosus (SLE) is conferred not only by various genes within the major histocompatibility complex (MHC) region, but also by several other non-MHC linked genes. The negatively signalling molecule CTLA-4 is involved in establishing and maintaining of peripheral T cell tolerance, which controls T cell activation and reactivity. Its attenuating action helps to prevent an inappropriate initiation of T cell responses to self antigens and to terminate ongoing T cell responses. We tested if there was an association between CTLA-4 and SLE, a disease with B and T cell hyperreactivity and impaired peripheral T cell tolerance. METHODS: Using the polymerase chain reaction--restriction fragment length polymorphism method with Bbv I digestion, we assessed an exon 1 transition dimorphism (49 A/G) of the CTLA-4 gene in 102 SLE patients and in 76 healthy controls. RESULTS: The distribution of CTLA-4 exon 1 genotypes in the SLE group was significantly different from that in the controls (chi 2 = 6.178, p < 0.05). 17.6% of the SLE patients were G/G homozygotes compared to 5.3% of the controls; 36.3% were A/G heterozygotes vs 40.8% of controls; and 46.1% were A/A homozygotes vs 53.9% of the controls. The frequency of the G allele was significantly higher in SLE patients (35.8%) than in controls (25.7%; chi 2 = 4.142, p = 0.042). CONCLUSION: Our results indicate that the non-MHC linked CTLA-4 gene could confer susceptibility in SLE, as it does in various other autoimmune diseases (Hashimoto thyroiditis, Graves' disease, IDDM).     

Major histocompatibility complex genes and susceptibility to systemic lupus erythematosus in southern chinese

Objective. To investigate the predisposing role of major histocompatibility complex (MHC) genes to systemic lupus erythematosus (SLE) in a Chinese population. Methods. Polymorphism in the HLA-DRB, DQB, complement component C4, and 21-hydroxylase genes was analyzed by restriction fragment length polymorphism analysis and oligonucleotide probing of in vitro-amplified DNA from 88 Chinese patients with SLE and 69 matched control subjects. Results. HLA-DRw15 and DQw1 were significantly more frequent in patients (corrected P < 0.006, relative risk 5.2), but none of the 9 sequence variants of DQw1 were increased. The C4A gene deletion usually associated with SLE in Caucasoid and black patients was absent from all Chinese subjects, but possession of other C4 deletions and of DRw15 conferred the greatest risk (relative risk = 8.3). Conclusion. Different MHC haplotypes predispose to lupus in Chinese than in other ethnic groups. Our data suggest that the susceptibility lies at, or telomeric to, the DR locus, and that DRw15 and C4 deletions may act synergistically in conferring disease susceptibility.     

Polymorphisms of the TAP2 transporter gene in systemic lupus erythematosus.

OBJECTIVES--To determine whether the TAP2 transporter gene, which lies between HLA-DP and HLA-DQ, is involved in determining susceptibility to systemic lupus erythematosus (SLE). METHODS--TAP2 types were determined by ARMS-PCR in 89 white patients with SLE and 156 control subjects. RESULTS--No particular TAP2 dimorphism or allele was associated with SLE or with any clinical/immunological subgroup of SLE. Furthermore, there was no evidence for significant linkage disequilibrium between TAP2 and HLA-DQ/DR in SLE. CONCLUSIONS--These data suggest that TAP2 is not a disease susceptibility gene for SLE and that the disease-predisposing haplotypes do not extend as far as TAP2. This indicates that any HLA-DP association with SLE must be independent of other class II (DQ/DR) associations.     

Evaluation of the BCL-2 gene locus as a susceptibility locus linked to the clinical expression of systemic lupus erythematosus (SLE)

Systemic lupus erythematosus (SLE) is an autoimmune disease characterised by the production of a large number of autoantibodies. It has been postulated that this may be the result of prolonged longevity of auto-reactive B cells due to defective regulation of programmed cell death (apoptosis). The proto-oncogenebcl-2 is involved in the control of apoptosis in immunocompetent cells, and its over-expression is noted in T and B cells from SLE patients. This study examined the genetic linkage between thebcl-2 gene locus and SLE susceptibility using the affected sib-pair method in SLE families. Seventeen caucasian multiplex families were evaluated. A polymorphic microsatellite marker closely linked to thebcl-2 gene on 18g21.3 was used to determine thebcl-2 genotype. We demonstrated that haplotype sharing among the affected sibling pairs was not statistically different from random (P>0.5). This suggests that thebcl-2 gene locus does not confer a genetic susceptibility to SLE expression.     

Haplotypes of the HRES‐1 endogenous retrovirus are associated with development and disease manifestations of systemic lupus erythematosus

Objective

Endogenous retroviral sequences represent a link between viral and genetic factors that may influence the development of systemic lupus erythematosus (SLE). The HRES‐1 human endogenous retroviral sequence is centrally located at the 1q42 chromosomal region relative to microsatellites previously associated with SLE. We therefore undertook the present study to determine the haplotypes of the HRES‐1 locus and their linkage to SLE.

Methods

One hundred six patients with SLE, 82 unrelated healthy Caucasian individuals, and 70 healthy members of 34 lupus families were examined. HRES‐1 was amplified by polymerase chain reaction (PCR) and analyzed by sequencing and restriction enzyme mapping. Microsatellites were analyzed by PCR. Haplotype construction and transmission disequilibrium testing (TDT) were performed in lupus families.

Results

Based on 4 single‐nucleotide polymorphisms (SNPs) within a 935‐base interval, we detected 6 HRES‐1 haplotypes that were differentially segregated in unrelated Caucasian patients and control subjects (χ² = 16.86, P = 0.0048) and were in linkage disequilibrium (LD) with the D1S225 microsatellite (P = 0.0002). The microsatellites D1S225, D1S235, and D1S2785 (but not D1S229) were linked to SLE by TDT. Interestingly, LD between HRES‐1 SNPs at bases 653 and 1259 was reduced in patients with SLE (P = 0.048). The HRES‐1 653C/1259C–harboring alleles were associated with the presence of renal disease (P = 0.0021) and with the absence of lung disease (P = 0.0323), while the 956A allele was associated with the antiphospholipid syndrome in patients with SLE (P = 0.0036).

Conclusion

The HRES‐1 locus represents a recombination hot spot at the 1q42 chromosomal region that influences the development and disease manifestations of SLE.

     

Inflammatory bowel disease gene hunting by linkage analysis: rationale, methodology, and present status of the field

Observed inflammatory bowel disease (IBD) familial clustering and increased monozygotic twin concordance has led to the hypothesis that genetic loci containing IBD susceptibility genes can be identified by whole genome linkage mapping approaches. Methodology including collecting carefully phenotyped multiplex pedigrees, genotyping using highly informative microsatellite markers and linkage analysis by non-parametric allele sharing methods has been established. Eleven published genome wide screens (GWS) have studied more than 1,200 multiplex IBD pedigrees. Two-thirds of affected relative pairs were Crohn's disease (CD), 20% ulcerative colitis (UC) and the remaining were mixed. Seven loci (IBDI-7) on chromosomes 16q, 12, 6p, 14q, 5q, 19, and 1p have been identified with genome wide significant and independently replicated linkage. Risk alleles/haplotypes have been defined for the IBD1 (CARD15/NOD2), IBD3 (HLA) and IBD5 (5q cytokine cluster) loci. There has been evidence for a second chromosome 16 locus (IBD8) independent of NOD2 that overlaps IBD1 on the pericentromeric p-arm. Several other regions show great promise for containing additional IBD loci, particularly chromosome 3p with genome wide evidence in one study at 3p26 and more centromeric evidence in several other studies, and chromosomes 2q, 3q, 4q, 7, 11p, and Xp each with suggestive evidence of linkage in one and additional evidence in two or more studies. Single GWSs and fine mapping studies containing very large sets of pedigrees and in particular, more UC pedigrees, and the use of creative analytic and disease stratification schemes are required to identify, establish and refine weaker IBD loci.     

Association of the A561C E-selectin polymorphism with systemic lupus erythematosus in 2 independent populations.

OBJECTIVE: E-selectin is expressed on cytokine stimulated endothelial cells and plays an important role in leukocyte-endothelium interactions and inflammatory cell recruitment. The gene for E-selectin is located at chromosome 1q 23-25 within the linkage area for systemic lupus erythematosus (SLE). The best characterized polymorphism in E-selectin molecule is A561C, which codes for Ser128Arg. We studied the prevalence of the A561C E-selectin gene polymorphism in patients with SLE and controls from 3 different ethnic populations. METHODS: Three cohorts of patients with SLE (1987 American College of Rheumatology criteria) and matching population controls were studied. These consisted of Caucasians of British Isles descent, Caucasians of Spanish origin, and Caucasians of Turkish origin. We used polymerase chain reaction and restriction fragment length polymorphism to genotype patients and controls. RESULTS: The numbers of patients and controls in each group were: UK (113 and 148), Spanish (145 and 179), and Turkish (93 and 96), respectively. The C allele occurred more frequently in UK and Spanish patients (OR 1.76, 95% CI 1.03-3.0, p = 0.037; and OR 1.84, 95% CI 1.1-3.09, p = 0.019), but not in Turkish patients (OR 1.03, 95% CI 0.55-1.97, p = 0.91). CONCLUSION: In 2 of 3 populations studied, the E-selectin C allele was significantly more common in SLE than in controls. E-selectin may be a susceptibility gene to SLE in these populations. Its role in disease expression and longterm outcomes such as accelerated atherosclerosis requires further study.