Related Articles

Objectives

Few studies have examined thrombosis in systemic lupus erythematosus (SLE), none have included Asian-Americans, and most have had small sample sizes. We analysed risk factors for thrombosis in a large, multiethnic SLE cohort.

Methods

We studied 1930 SLE subjects, including Caucasians, African-Americans, Asian-Americans and Hispanics. Data were derived from questionnaires and medical records. Documented history of thrombosis was the primary outcome. Explanatory variables included age at SLE diagnosis, gender, ethnicity, disease duration, smoking, antiphospholipid antibody (aPL) status, nephritis and specific medications.

Results

Smoking (OR 1.26, p = 0.011), longer disease duration (OR 1.26 per 5 years p = 0.027×10-7), nephritis (OR 1.35, p = 0.036), aPL positivity (OR 3.22, p<10-9) and immunomodulating medication use (OR 1.40, p = 0.011) were statistically significant risk factors for thrombosis. Younger age at SLE onset was protective (OR 0.52 for age ≤20, p = 0.001). After adjusting for disease severity and incorporating propensity scores, hydroxychloroquine use remained significantly protective for thrombosis (OR 0.62, p = 4.91×10-4).

Conclusions

This study confirms that older age at onset, longer disease duration, smoking, aPL positivity, history of nephritis and immunomodulating medication use are risk factors for thrombosis in SLE. These data are the first to confirm in a large and ethnically diverse SLE cohort that hydroxychloroquine use is protective for thrombosis.

Objectives

Systemic lupus erythematosus (SLE) is a chronic multisystem genetically complex autoimmune disease characterised by the production of autoantibodies to nuclear and cellular antigens, tissue inflammation and organ damage. Genome-wide association studies have shown that variants within the major histocompatibility complex (MHC) region on chromosome 6 confer the greatest genetic risk for SLE in European and Chinese populations. However, the causal variants remain elusive due to tight linkage disequilibrium across disease-associated MHC haplotypes, the highly polymorphic nature of many MHC genes and the heterogeneity of the SLE phenotype.

Methods

A high-density case-control single nucleotide polymorphism (SNP) study of the MHC region was undertaken in SLE cohorts of Spanish and Filipino ancestry using a custom Illumina chip in order to fine-map association signals in these haplotypically diverse populations. In addition, comparative analyses were performed between these two datasets and a northern European UK SLE cohort. A total of 1433 cases and 1458 matched controls were examined.

Results

Using this transancestral SNP mapping approach, novel independent loci were identified within the MHC region in UK, Spanish and Filipino patients with SLE with some evidence of interaction. These loci include HLA-DPB1, HLA-G and MSH5 which are independent of each other and HLA-DRB1 alleles. Furthermore, the established SLE-associated HLA-DRB1*15 signal was refined to an interval encompassing HLA-DRB1 and HLA-DQA1. Increased frequencies of MHC region risk alleles and haplotypes were found in the Filipino population compared with Europeans, suggesting that the greater disease burden in non-European SLE may be due in part to this phenomenon.

Conclusion

These data highlight the usefulness of mapping disease susceptibility loci using a transancestral approach, particularly in a region as complex as the MHC, and offer a springboard for further fine-mapping, resequencing and transcriptomic analysis.

Background

African Americans (AA) disproportionately develop lupus nephritis (LN) relative to European Americans and familial clustering supports causative genes. Since MYH9 underlies approximately 40% of end-stage renal disease (ESRD) in AA, we tested for genetic association with LN.

Methods

Seven MYH9 single nucleotide polymorphisms (SNPs) and the E1 risk haplotype were tested for association with LN in three cohorts of AA.

Results

A preliminary analysis revealed that the MYH9 E1 risk haplotype was associated with ESRD in 25 cases with presumed systemic lupus erythematosus (SLE)-associated ESRD, compared to 735 non-SLE controls (odds ratio 3.1; p = 0.010 recessive). Replication analyses were performed in 583 AA with SLE in the PROFILE cohort (318 with LN; 265 with SLE but without nephropathy) and 60 AA from the NIH (39 with LN; 21 with SLE but without nephropathy). Analysis of the NIH and larger PROFILE cohorts, as well as a combined analysis, did not support this association.

Conclusions

These results suggest that AA with ESRD and coincident SLE who were recruited from dialysis clinics more likely have kidney diseases in the MYH9-associated spectrum of focal segmental glomerulosclerosis. PROFILE and NIH participants, recruited from rheumatology practices, demonstrate that MYH9 does not contribute substantially to the development of LN in AA.

Objectives

To analyze if genetically determined Amerindian ancestry predicts the increased presence of risk alleles of known susceptibility genes for systemic lupus erythematosus.

Methods

Single nucleotide polymorphisms within 16 confirmed genetic susceptibility loci for SLE were genotyped in a set of 804 Mestizo lupus patients and 667 Mestizo normal healthy controls. In addition, 347 admixture informative markers were genotyped. Individual ancestry proportions were determined using STRUCTURE. Association analysis was performed using PLINK, and correlation of the presence of risk alleles with ancestry was done using linear regression.

Results

A meta-analysis of the genetic association of the 16 SNPs across populations showed that TNFSF4, STAT4, PDCD1, ITGAM, and IRF5 were associated with lupus in a Hispanic-Mestizo cohort enriched for European and Amerindian ancestry. In addition, two SNPs within the MHC region, previously associated in a genome-wide association study in Europeans, were also associated in Mestizos. Using linear regression we predict an average increase of 2.34 risk alleles when comparing a lupus patient with 100% Amerindian ancestry to an SLE patient with 0% American Indian Ancestry (p<0.0001). SLE patients with 43% more Amerindian ancestry are predicted to carry one additional risk allele.

Conclusion

Amerindian ancestry increased the number of risk alleles for lupus.

The objective of this study is to examine the clinical features and outcomes of patients with systemic lupus erythematosus (SLE) whose disease began in adolescence [juvenile-onset SLE (jSLE)] compared with adult-onset patients [adult-onset SLE (aSLE)] from a large multiethnic cohort. Systemic lupus erythematosus patients of African-American, Caucasian, or Hispanic ethnicity and ≥1 year follow-up were studied in two groups: jSLE (diagnosed at ≤18 years); aSLE (diagnosed at 19–50 years; matched for gender and disease duration at enrolment). Sociodemographic data, SLE manifestations, disease activity, damage accrual, SLE-related hospitalizations or emergency room visits, drug utilization, mortality and psychosocial characteristics and quality of life were compared. Data were analysed by univariable and multivariable analyses. Seventy-nine patients were studied (31 jSLE, 48 aSLE); 90% were women. Mean (SD) total disease duration was 6.8 (2.7) years in jSLE and 5.6 (3.3) years in aSLE (p = 0.077). Mean age at cohort entry was 18.4 (1.8) and 33.9 (9.2) years in jSLE and aSLE respectively. By univariable analysis, jSLE patients were more commonly of African-American descent, were more likely to have renal and neurological involvements, and to accrue renal damage; jSLE patients had lower levels of helplessness and scored higher in the physical component measure of the SF-36 than aSLE patients. Renal involvement [OR = 1.549, 95% CI (1.397–15.856)] and neurological involvement [OR = 1.642, 95% CI (1.689–15.786)] were independently associated with jSLE by multivariable analysis. There was a larger proportion of African-Americans within the jSLE group. After adjusting for ethnicity and follow-up time, jSLE patients experienced more renal and neurological manifestations, with more renal damage. There was a two-fold higher mortality rate in the jSLE group.

Variants of the osteopontin (OPN) gene have been associated with systemic lupus erythematosus (SLE) susceptibility and cytokine profiles in SLE patients. It is not known whether these alleles are associated with specific clinical phenotypes in SLE. We studied 252 well-characterized SLE patients from a multiethnic cohort, genotyping the rs11730582, rs28357094, rs6532040, and rs9138 SNPs in the OPN gene. Ancestry informative markers were used to control for genetic ancestry. The SLE-risk allele rs9138C in the 3′ UTR region was associated with photosensitivity in lupus patients across all ancestral backgrounds (meta-analysis OR = 3.2, 95% CI = 1.6–6.5, P = 1.0 × 10−3). Additionally, the promoter variant rs11730582C demonstrated suggestive evidence for association with two hematologic traits: thrombocytopenia (OR = 2.1, P = 0.023) and hemolytic anemia (OR = 2.6, P = 0.036). These clinical associations with SNPs in the promoter and 3′ UTR regions align with previously reported SLE-susceptibility SNPs in OPN and suggest potential roles for these variants in antibody-mediated cytopenias and skin inflammation in SLE.

Objective

Sequence variation in gene promoters is often associated with disease risk. In this study, we tested the hypothesis that common promoter variation in the APOH gene (encoding for β2-glycoprotein I) is associated with systemic lupus erythematosus (SLE) risk and SLE-related clinical phenotypes in a Caucasian cohort.

Methods

We used a case-control design and genotyped 345 SLE women and 454 healthy control women for 8 APOH promoter single nucleotide polymorphisms (SNPs) (−1284C>G, −1219G>A, −1190G>C, −759 A>G, − 700C>A, −643T>C, −38G>A, and −32C>A). Association analyses were performed on single SNPs and haplotypes. Haplotype analyses were performed using EH (Estimate Haplotype-frequencies) and Haploview programs. In vitro reporter gene assay was performed in COS-1 cells. Electrophoretic mobility shift assay (EMSA) was performed using HepG2 nuclear cells.

Results

Overall haplotype distribution of the APOH promoter SNPs was significantly different between cases and controls (P = 0.009). The −643C allele was found to be protective against carotid plaque formation (adjusted OR = 0.37, P = 0.013) among SLE patients. The −643C allele was associated with a ~ 2-fold decrease in promoter activity as compared to wild-type −643T allele (mean ± standard deviation: 3.94 ± 0.05 vs. 6.99 ± 0.68, P = 0.016). EMSA showed that the −643T>C SNP harbors a binding site for a nuclear factor. The −1219G>A SNP showed a significant association with the risk of lupus nephritis (age-adjusted OR = 0.36, P = 0.016).

Conclusion

Our data indicate that APOH promoter variants may be involved in the etiology of SLE, especially the risk for autoimmune-mediated cardiovascular disease.

Systemic lupus erythematosus (SLE) is a genetically complex disease with heterogeneous clinical manifestations. A polymorphism in the STAT4 gene has recently been established as a risk factor for SLE, but the relationship with specific SLE subphenotypes has not been studied. We studied 137 SNPs in the STAT4 region genotyped in 4 independent SLE case series (total n = 1398) and 2560 healthy controls, along with clinical data for the cases. Using conditional testing, we confirmed the most significant STAT4 haplotype for SLE risk. We then studied a SNP marking this haplotype for association with specific SLE subphenotypes, including autoantibody production, nephritis, arthritis, mucocutaneous manifestations, and age at diagnosis. To prevent possible type-I errors from population stratification, we reanalyzed the data using a subset of subjects determined to be most homogeneous based on principal components analysis of genome-wide data. We confirmed that four SNPs in very high LD (r2 = 0.94 to 0.99) were most strongly associated with SLE, and there was no compelling evidence for additional SLE risk loci in the STAT4 region. SNP rs7574865 marking this haplotype had a minor allele frequency (MAF) = 31.1% in SLE cases compared with 22.5% in controls (OR = 1.56, p = 10−16). This SNP was more strongly associated with SLE characterized by double-stranded DNA autoantibodies (MAF = 35.1%, OR = 1.86, p<10−19), nephritis (MAF = 34.3%, OR = 1.80, p<10−11), and age at diagnosis<30 years (MAF = 33.8%, OR = 1.77, p<10−13). An association with severe nephritis was even more striking (MAF = 39.2%, OR = 2.35, p<10−4 in the homogeneous subset of subjects). In contrast, STAT4 was less strongly associated with oral ulcers, a manifestation associated with milder disease. We conclude that this common polymorphism of STAT4 contributes to the phenotypic heterogeneity of SLE, predisposing specifically to more severe disease.

Author Summary

Systemic lupus erythematosus is a chronic disabling autoimmune disease, most commonly striking women in their thirties or forties. It can cause a wide variety of clinical manifestations, including kidney disease, arthritis, and skin disorders. Prognosis varies greatly depending on these clinical features, with kidney disease and related characteristics leading to greater morbidity and mortality. It is also complex genetically; while lupus runs in families, genes increase one’s risk for lupus but do not fully determine the outcome. It is thought that the interactions of multiple genes and/or interactions between genes and environmental factors may cause lupus, but the causes and disease pathways of this very heterogeneous disease are not well understood. By examining relationships between subtypes of lupus and specific genes, we hope to better understand how lupus is triggered and by what biological pathways it progresses. We show in this work that the STAT4 gene, very recently identified as a lupus risk gene, predisposes specifically to severe manifestations of lupus, including kidney disease.

Objective

To determine the factors associated with increased levels of fatigue over the course of the disease in systemic lupus erythematosus (SLE) patients from LUMINA (Lupus in Minorities: Nature versus Nurture), a longitudinal multiethnic cohort.

Methods

Patients with SLE (American College of Rheumatology revised and updated criteria), age ≥16 years, disease duration ≤ 5 years at entry into the cohort (T0), of Hispanic (Texan or Puerto Rican), African America or Caucasian ethnicity, were studied. The association between socioeconomic-demographic, health behaviors, behavioral and psychological, functional and clinical characteristics and fatigue was examined using generalized estimating equations to account for the longitudinal nature of the data.

Results

Five-hundred and fifteen patients (~91% female) contributed 2,609 visits to these analyses; there were: 93 (18.1%) Texan Hispanics, 101 (19.6%) Puerto Rican Hispanics, 169 (32.8%) African Americans, and 152 (29.5%) Caucasians; the patients mean (SD) age and follow up time were 37.2 (12.0) and 4.7 (3.2) years, respectively. Variables associated with increased levels of fatigue in the multivariable analyses were Caucasian ethnicity, the presence of constitutional symptoms(fever, weight loss), higher levels of pain, of abnormal illness-related behaviors and of helplessness (p’s between 0.0018 and <0.0001).

Conclusions

The presence of pain, abnormal illness-related behaviors, helplessness and constitutional manifestations were associated with increased levels of fatigue; however, lupus specific measures, such as disease activity and damage were not. Interventions aimed at decreasing fatigue need to take into account these findings.

Objective

A haplotype of the interferon regulatory factor 5 (IRF5) gene has been associated with the risk of developing systemic lupus erythematosus (SLE), and our previous studies have demonstrated that high levels of serum interferon-α (IFNα) activity are a heritable risk factor for SLE. The aim of this study was to determine whether the IRF5 SLE risk haplotype mediates the risk of SLE by predisposing patients to the development of high levels of serum IFNα activity.

Methods

IFNα levels in 199 SLE patients of European and Hispanic ancestry were measured with a sensitive functional reporter cell assay. The rs2004640, rs3807306, rs10488631, and rs2280714 single-nucleotide polymorphisms (SNPs) in IRF5 were genotyped in these patients. Haplotypes were categorized as SLE risk, neutral, or protective based on published data.

Results

SLE patients with risk/risk and risk/neutral IRF5 genotypes had higher serum IFNα activity than did those with protective/protective and neutral/protective genotypes (P = 0.025). This differential effect of IRF5 genotype on serum IFNα levels was driven largely by SLE patients who were positive for either anti–RNA binding protein (anti-RBP) or anti–double-stranded DNA (anti-dsDNA) autoantibodies (P = 0.012 for risk/risk or risk/neutral versus protective/protective or neutral/protective). The rs3807306 genotype was independently associated with high serum IFNα in this autoantibody group. We found no difference in IFNα activity according to IRF5 genotype in patients lacking either type of autoantibody or in patients positive for both classes of autoantibody.

Conclusion

The IRF5 SLE risk haplotype is associated with higher serum IFNα activity in SLE patients, and this effect is most prominent in patients positive for either anti-RBP or anti-dsDNA autoantibodies. This study demonstrates the biologic relevance of the SLE risk haplotype of IRF5 at the protein level.

Background

Osteonecrosis is common in systemic lupus erythematosus (SLE) and often disabling. The role of glucocorticoids in its development is well known.

Objective

To explore other possible risk factors for osteonecrosis in SLE.

Methods

A nested matched case–control study undertaken in the context of a large, longitudinal, multiethnic lupus cohort (LUMINA), currently formed of 571 SLE patients meeting American College of Rheumatology criteria. All those developing symptomatic osteonecrosis after the diagnosis of SLE were considered cases. Two controls matched for age, disease duration, ethnicity, and centre were selected for each case. Cases and controls were compared by univariable analyses using selected variables. Variables with p<0.10 and those thought clinically relevant were entered into conditional logistic regression models including either the average dose or the highest dose of glucocorticoids, with osteonecrosis as the dependent variable.

Results

32 cases were identified and 59 matched controls selected (in five cases only one control could be found). By univariable analyses, both groups were largely comparable for socioeconomic‐demographic, clinical, and laboratory variables. Cases were less exposed to hydroxychloroquine (as assessed by the percentage of exposure time) (p = 0.026), used higher doses of glucocorticoids (average and highest doses) (p = 0.011 and 0.001, respectively), and received cytotoxic drugs more often (p = 0.015). In the multivariable analyses only cytotoxic drug use (both models) and the highest dose of glucocorticoids remained associated with the occurrence of osteonecrosis.

Conclusions

Cytotoxic drug use is a risk factor for the development of symptomatic osteonecrosis in SLE patients, along with glucocorticoids. No definite protective factors were identified.

Objective

To define the contribution of polymorphisms in genes encoding tumor necrosis factor (TNF), mannose-binding lectin (MBL), and Fcγ receptor IIa (FCGR2A) as well as clinical factors, to the development of pneumonia in patients with systemic lupus erythematosus (SLE).

Methods

We studied 282 SLE patients from a multiethnic cohort. Pneumonia events and clinical risk factors for pneumonia were identified through medical record review. Genotyping was performed for MBL (+223, +230, and +239), TNF (−308, −238, and +488), and FCGR2A (−131H/R) polymorphisms. Univariate analyses were performed to identify clinical and genetic risk factors for pneumonia. Covariates for multivariate analysis included sex, ethnicity, treatment with immunomodulators, and leukopenia.

Results

Forty-two patients (15%) had at least 1 episode of pneumonia. Polymorphism of the TNF gene, particularly the −238A allele and a related haplotype, revealed the most striking and consistent association with pneumonia in univariate analyses. Results of multivariate analyses indicated an odds ratio (OR) for the TNF −238A allele of 3.5 (P = 0.007) and an OR for the related haplotype of 5.4 (P = 0.001). Male sex, treatment with immunomodulators, and leukopenia also influenced the risk of pneumonia.

Conclusion

These findings suggest that specific TNF variants may identify SLE patients who are at particularly high risk of developing pneumonia. Given the prevalence and excessive morbidity associated with pneumonia in SLE, these findings have clinical relevance and provide insight into the pathogenesis.

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, two SNPs in the CRP gene (+838, +2043) have been shown to be associated with CRP levels and/or SLE risk in a British family-based cohort. The current study was done to confirm the reported association in an independent population-based case-control cohort, and also to investigate the impact of three additional CRP tagSNPs (-861, -390, +90) on SLE risk and serum CRP levels.

Methods

DNA from 337 white women who met the ACR criteria for definite (n = 324) or probable (n = 13) SLE and 448 white female healthy controls was genotyped for five CRP tagSNPs (-861, -390, +90, +838, +2043). Genotyping was performed using PCR-RFLP, pyrosequencing or TaqMan assays. Serum CRP levels were measured using ELISA. Association studies were performed using the χ2 distribution, Z-test, Fisher's exact test and ANOVA. Haplotype analysis was performed using EH software and haplo.stats package in R 2.1.2.

Results

While none of the SNPs were found to be associated with SLE risk individually, there was an association with the five-SNP haplotypes (p<0.000001). Three SNPs (-861, -390, +90) were found to significantly influence serum CRP level in SLE cases, both independently and as haplotypes.

Conclusion

Our data suggests that unique haplotype combinations in the CRP gene may modify the risk of developing SLE and influence circulating CRP levels.

Genetic factors influence susceptibility to systemic lupus erythematosus (SLE). A recent family-based analysis in Caucasian and Chinese populations provided evidence for association of single-nucleotide polymorphisms (SNPs) in the complement receptor 2 (CR2/CD21) gene with SLE. Here we confirmed this result in a case-control analysis of an independent European-derived population including 2084 patients with SLE and 2853 healthy controls. A haplotype formed by the minor alleles of three CR2 SNPs (rs1048971, rs17615, rs4308977) showed significant association with decreased risk of SLE (30.4% in cases vs. 32.6% in controls, P = 0.016, OR = 0.90 [0.82-0.98]). Two of these SNPs are in exon 10, directly 5′ of an alternatively spliced exon preferentially expressed in follicular dendritic cells (FDC), and the third is in the alternatively spliced exon. Effects of these SNPs as well as a fourth SNP in exon 11 (rs17616) on alternative splicing were evaluated. We found that the minor alleles of these SNPs decreased splicing efficiency of exon 11 both in vitro and ex vivo. These findings further implicate CR2 in the pathogenesis of SLE and suggest that CR2 variants alter the maintenance of tolerance and autoantibody production in the secondary lymphoid tissues where B cells and FDCs interact.

Introduction

Systemic lupus erythematosus (SLE) is a highly heterogeneous disorder, characterized by differences in autoantibody profile, serum cytokines, and clinical manifestations. SLE-associated autoantibodies and high serum interferon alpha (IFN-α) are important heritable phenotypes in SLE which are correlated with each other, and play a role in disease pathogenesis. These two heritable risk factors are shared between ancestral backgrounds. The aim of the study was to detect genetic factors associated with autoantibody profiles and serum IFN-α in SLE.

Methods

We undertook a case-case genome-wide association study of SLE patients stratified by ancestry and extremes of phenotype in serology and serum IFN-α. Single nucleotide polymorphisms (SNPs) in seven loci were selected for follow-up in a large independent cohort of 538 SLE patients and 522 controls using a multi-step screening approach based on novel metrics and expert database review. The seven loci were: leucine-rich repeat containing 20 (LRRC20); protein phosphatase 1 H (PPM1H); lysophosphatidic acid receptor 1 (LPAR1); ankyrin repeat and sterile alpha motif domain 1A (ANKS1A); protein tyrosine phosphatase, receptor type M (PTPRM); ephrin A5 (EFNA5); and V-set and immunoglobulin domain containing 2 (VSIG2).

Results

SNPs in the LRRC20, PPM1H, LPAR1, ANKS1A, and VSIG2 loci each demonstrated strong association with a particular serologic profile (all odds ratios > 2.2 and P < 3.5 × 10-4). Each of these serologic profiles was associated with increased serum IFN-α. SNPs in both PTPRM and LRRC20 were associated with increased serum IFN-α independent of serologic profile (P = 2.2 × 10-6 and P = 2.6 × 10-3 respectively). None of the SNPs were strongly associated with SLE in case-control analysis, suggesting that the major impact of these variants will be upon subphenotypes in SLE.

Conclusions

This study demonstrates the power of using serologic and cytokine subphenotypes to elucidate genetic factors involved in complex autoimmune disease. The distinct associations observed emphasize the heterogeneity of molecular pathogenesis in SLE, and the need for stratification by subphenotypes in genetic studies. We hypothesize that these genetic variants play a role in disease manifestations and severity in SLE.

Background

Several members of the GIMAP gene family have been suggested as being involved in different aspects of the immune system in different species. Recently, a mutation in the GIMAP5 gene was shown to cause lymphopenia in a rat model of autoimmune insulin‐dependent diabetes. Thus it was hypothesised that genetic variation in GIMAP5 may be involved in susceptibility to other autoimmune disorders where lymphopenia is a key feature, such as systemic lupus erythematosus (SLE).

Material and methods

To investigate this, seven single nucleotide polymorphisms in GIMAP5 were analysed in five independent sets of family‐based SLE collections, containing more than 2000 samples.

Result

A significant increase in SLE risk associated with the most common GIMAP5 haplotype was found (OR 1.26, 95% CI 1.02 to 1.54, p = 0.0033). In families with probands diagnosed with trombocytopenia, the risk was increased (OR 2.11, 95% CI 1.09 to 4.09, p = 0.0153). The risk haplotype bears a polymorphic polyadenylation signal which alters the 3′ part of GIMAP5 mRNA by producing an inefficient polyadenylation signal. This results in higher proportion of non‐terminated mRNA for homozygous individuals (p<0.005), a mechanism shown to be causal in thalassaemias. To further assess the functional effect of the polymorphic polyadenylation signal in the risk haplotype, monocytes were treated with several cytokines affecting apoptosis. All the apoptotic cytokines induced GIMAP5 expression in two monocyte cell lines (1.5–6 times, p<0.0001 for all tests).

Conclusion

Taken together, the data suggest the role of GIMAP5 in the pathogenesis of SLE.

Objective

To determine whether C-reactive protein (CRP) measured by a high sensitivity (hs) assay is a surrogate marker of disease activity and damage in systemic lupus erythematosus (SLE).

Methods

Five hundred eighty-eight patients with SLE participating in a multiethnic cohort (Hispanic, African American, and Caucasian) were studied. Disease activity was measured with the Systemic Lupus Activity Measure-Revised (SLAM-R) and damage with the Systemic Lupus International Collaborating Clinics (SLICC) Damage Index (SDI). hs-CRP was measured by immunometric assay. Disease activity and hs-CRP were measured at enrollment and damage accrual at last visit. The association of hs-CRP with the SLAM-R and SDI was examined by univariable (Pearson's correlation) and multivariable (linear regression) analyses. The association of hs-CRP and each individual domain of the SLAM-R and SDI was examined by Spearman's correlation.

Results

hs-CRP was associated with the SLAM-R in the univariable (r = 0.35, p < 0.001) and multivariable (t = 7.11, coefficient ß = 0.27, p < 0.001) analyses. It also correlated with the constitutional, eye, pulmonary, gastrointestinal, neuromotor, and laboratory domains of the SLAM-R. hs-CRP was associated with the SDI (r = 0.12, p = 0.004) in the univariable analysis but not in the multivariable analysis. When the individual domains of the SDI were analyzed, hs-CRP correlated with the renal, pulmonary, cardiovascular, musculoskeletal, and diabetes domains.

Conclusion

hs-CRP was associated with disease activity but not with overall damage accrual; however, it correlated with specific domains of the damage index. hs-CRP may be useful to monitor the course of the disease and predict its intermediate outcome, but longitudinal studies with serial hs-CRP measurements are necessary to define its clinical value.

BACKGROUND—Avascular necrosis of bone (AVN) is a well known complication in patients with systemic lupus erythematosus (SLE).
OBJECTIVE—To investigate the role of antiphospholipid antibody status (IgM and IgG anticardiolipin antibodies and lupus anticoagulant) with adjustment for corticosteroid use as risk factors for the development of AVN.
METHODS— A cohort of 265 patients receiving long term follow up in our SLE clinic from 1978 to 1998 was analysed. Patients with AVN complications were detected and then matched for age, sex, ethnicity, duration of disease, and organ disease with two other patients with SLE. A further 31 patients were chosen at random for the analysis.
RESULTS—Eleven patients had AVN, giving a point prevalence of 4%. There were no significant differences demonstrable in the presence of individual antiphospholipid antibodies (aPL) or their combination between the group with AVN or the two control groups.
CONCLUSION—Incorporating an adjustment for corticosteroid use we were unable to show a link between the presence of aPL and the development of AVN in patients with SLE.



Background

Recently, a new genetic factor within the interferon regulatory factor 5 (IRF5) gene was demonstrated for systemic lupus erythematosus (SLE) through linkage and association: the rs2004640‐T allele. IRF5 is involved in the production of rheumatoid arthritis (RA) cytokines, and SLE already shares with RA one genetic factor within the tyrosine phosphatase PTPN22 gene.

Aim

To test the hypothesis that the SLE IRF5 genetic factor could also be shared with RA.

Patients and methods

100 French Caucasian trio families with RA were genotyped and analysed with the transmission disequilibrium test, the frequency comparison of the transmitted and untransmitted alleles, and the genotype relative risk. 97% power was available to detect at least a trend in favour of a factor similar to that reported for SLE.

Results

The analysis showed the absence of linkage and association globally and in “autoimmune” RA subsets, with a weak non‐significant trend against the IRF5rs20046470‐T allele. Given the robustness of familial‐based analysis, this slight negative trend provided strong evidence against even a weaker factor than that reported for SLE.

Conclusion

Our results exclude the IRF5rs2004640‐T allele as a major genetic factor for RA in this French Caucasian population.

ITGAM was recently found to be associated with systemic lupus erythematosus (SLE) in populations of not only European ancestry, but also in Hispanic- and African-Americans, Mexicans and Colombians. The risk alleles in the gene, however, were found to be monomorphic in two Asian populations examined: Japanese and Korean. In this study, using a collection of 910 SLE patients and 2360 controls from Chinese living in Hong Kong, analyzed by both genome-wide association and direct sequencing, we confirmed the association of the same risk alleles in ITGAM with the disease. These findings were further replicated in the Thai population with 278 patients and 383 ethnicity- and geography-matched controls. Subphenotype stratification analyses showed significantly more involvement of the gene in patients with renal nephritis and neurological disorders. Although our results support a pivotal role by rs1143679 (R77H) in disease association, our data also suggests an additional contribution from rs1143683, another non-synonymous polymorphism in this gene (A858V). Therefore, despite the low-allele frequencies of the risk alleles of the gene in our two Asian populations, ITGAM was confirmed to be a risk factor related to disease susceptibility and probably severe manifestations of SLE.

Objectives

The Xq28 region containing IRAK1 and MECP2 has been identified as a risk locus for systemic lupus erythematosus (SLE) in previous genetic association studies. However, due to the strong linkage disequilibrium between IRAK1 and MECP2, it remains unclear which gene is affected by the underlying causal variant(s) conferring risk of SLE.

Methods

We fine-mapped ≥136 SNPs in a ~227kb region on Xq28, containing IRAK1, MECP2 and 7 adjacent genes (L1CAM, AVPR2, ARHGAP4, NAA10, RENBP, HCFC1 and TMEM187), for association with SLE in 15,783 case-control subjects derived from 4 different ancestral groups.

Results

Multiple SNPs showed strong association with SLE in European Americans, Asians and Hispanics at P<5×10−8 with consistent association in subjects with African ancestry. Of these, 6 SNPs located in the TMEM187-IRAK1-MECP2 region captured the underlying causal variant(s) residing in a common risk haplotype shared by all 4 ancestral groups. Among them, rs1059702 best explained the Xq28 association signals in conditional testings and exhibited the strongest P value in trans-ancestral meta-analysis (Pmeta=1.3×10−27, OR=1.43), and thus was considered to be the most-likely causal variant. The risk allele of rs1059702 results in the amino acid substitution S196F in IRAK1 and had previously been shown to increase NF-κB activity in vitro. We also found that the homozygous risk genotype of rs1059702 was associated with lower mRNA levels of MECP2, but not IRAK1, in SLE patients (P=0.0012) and healthy controls (P=0.0064).

Conclusion

These data suggest contributions of both IRAK1 and MECP2 to SLE susceptibility.

Objective

To determine the features predictive of time-to-integument damage in patients with systemic lupus erythematosus (SLE) from a multiethnic cohort (LUMINA).

Methods

SLE LUMINA patients (n=580), age ≥16 years, disease duration ≤5 years at baseline (T0), of African American, Hispanic and Caucasian ethnicity were studied. Integument damage was defined per the SLICC damage index (scarring alopecia, extensive skin scarring and skin ulcers lasting at least six months); factors associated with time-to-its occurrence were examined by Cox proportional univariable and multivariable (main model) hazards regression analyses. Two alternative models were also examined; in model 1 all patients, regardless of when integument damage occurred (n=94), were included; in model 2 a time-varying approach (GEE) was employed.

Results

Thirty-nine (6.7%) of 580 patients developed integument damage over a mean (SD) total disease duration of 5.9 (3.7) years and were included in the main multivariable regression model. After adjusting for discoid rash, nailfold infarcts, photosensitivity and Raynaud’s phenomenon (significant in the univariable analyses), disease activity over time [Hazard ratio (HR)=1.17; 95% Confidence interval (CI) 1.09–1.26)] was associated with a shorter time-to-integument damage whereas hydroxychloroquine use (HR=0.23, 95% CI 0.12–0.47) and Texan-Hispanic (HR=0.35; 95% CI 0.14–0.87) and Caucasian ethnicities (HR=0.37; 95% CI 0.14–0.99) were associated with a longer time. Results of the alternative models were consistent with those of the main model albeit in model 2 the association with hydroxychloroquine was not significant.

Conclusions

Our data indicate that hydroxychloroquine use is possibly associated with a delay in integument damage development in patients with SLE.

Summary

The objective of this study was to determine the factors associated with the occurrence of arterial vascular events in a multiethnic systemic lupus erythematosus (SLE) cohort. The PROFILE cohort, comprised of SLE patients (n=1,333) of defined ethnicity from five different U.S. institutions, was studied to determine demographic, clinical and biological variables associated with vascular events. An arterial vascular event (first episode) was either a myocardial infarction, angina pectoris and/or a vascular procedure for myocardial infarction, stroke, claudication and/or evidence of gangrene. Patient characteristics were analyzed by univariable and multivariable Cox proportional hazards regression analyses. One-hundred twenty-three (9.8%) patients had at least one incident arterial event. Age at cohort enrollment (HR= 1.04, 95% CI 1.03-1.06), smoking (HR= 2.20, 95% CI 1.40-3.46), and the CRP2* C alleles (HR= 1.91, 95%CI 1.04-3.49) were associated with a shorter time-to-the occurrence of arterial vascular events. Some clinical manifestations of disease activity were associated with a shorter time-to-occurrence [psychosis (HR= 2.21, 95% CI 1.10-4.44), seizures (HR= 1.85, 95% CI 1.00-3.24) and anemia (HR= 1.83, 95% CI 1.02-3.31)], but others were not [arthritis (HR= 0.32, 95% CI 0.18-0.58)]. In conclusion, older patients, especially in the context of a predisposing environmental factor (smoking) and severe clinical manifestations, are at higher risk of having arterial vascular events. The genetic contribution of the variation at the CRP locus was not obscured by demographic or clinical variables. Awareness of these factors should lead to more effective management strategies of patients at risk for arterial vascular events.

Background

Renal involvement is a serious manifestation of systemic lupus erythematosus (SLE); it may portend a poor prognosis as it may lead to end-stage renal disease (ESRD). The purpose of this study was to determine the factors predicting the development of renal involvement and its progression to ESRD in a multi-ethnic SLE cohort (PROFILE).

Methods and Findings

PROFILE includes SLE patients from five different United States institutions. We examined at baseline the socioeconomic–demographic, clinical, and genetic variables associated with the development of renal involvement and its progression to ESRD by univariable and multivariable Cox proportional hazards regression analyses. Analyses of onset of renal involvement included only patients with renal involvement after SLE diagnosis (n = 229). Analyses of ESRD included all patients, regardless of whether renal involvement occurred before, at, or after SLE diagnosis (34 of 438 patients). In addition, we performed a multivariable logistic regression analysis of the variables associated with the development of renal involvement at any time during the course of SLE.

In the time-dependent multivariable analysis, patients developing renal involvement were more likely to have more American College of Rheumatology criteria for SLE, and to be younger, hypertensive, and of African-American or Hispanic (from Texas) ethnicity. Alternative regression models were consistent with these results. In addition to greater accrued disease damage (renal damage excluded), younger age, and Hispanic ethnicity (from Texas), homozygosity for the valine allele of FcγRIIIa (FCGR3A*GG) was a significant predictor of ESRD. Results from the multivariable logistic regression model that included all cases of renal involvement were consistent with those from the Cox model.

Conclusions

Fcγ receptor genotype is a risk factor for progression of renal disease to ESRD. Since the frequency distribution of FCGR3A alleles does not vary significantly among the ethnic groups studied, the additional factors underlying the ethnic disparities in renal disease progression remain to be elucidated.

Fcγ receptor genotype is a risk factor for progression of renal disease to ESRD but does not explain the ethnic disparities in renal disease progression.

Editors' Summary

Background.

Systemic lupus erythematosis (SLE, commonly known as “lupus”) is an illness of many manifestations that appear to result from the immune system attacking components of the body's own cells. One of the unfortunate effects of SLE is kidney damage, which can, in a minority of patients, progress to kidney failure (formally called “end-stage renal disease,” or ESRD). Compared to White Americans, other ethnic groups tend to develop renal complications of lupus more often and with worse outcomes.

Why Was This Study Done?

It is unclear why some people with lupus develop kidney problems. The purpose of this US-based study was to confirm the factors that increase the risk of kidney damage and kidney failure, particularly in racial and ethnic minority patients, and to determine which of these factors accelerate the pace of kidney disease. Knowing these risk factors could allow the development and targeting of interventions, such as screening tests and preventive treatments, to prevent long-term loss of kidney function in patients with lupus.

What Did the Researchers Do and Find?

The researchers measured a number of factors in a multi-ethnic group of 1,008 patients with lupus, almost half of whom had some degree of kidney involvement. They found that those who developed kidney damage after being diagnosed with lupus tended to be younger, to have had lupus for a longer time, and to have experienced more effects of lupus in general than those who did not have kidney involvement. Those who developed kidney problems were also more likely to have been unemployed, to have had fewer years of formal education, and to have had high blood pressure before developing kidney involvement. African-American and Texan Hispanic individuals with lupus were more likely to develop kidney involvement, and tended to develop it more rapidly, than White Americans or Puerto Rican Hispanic ethnicity. Actual kidney failure (ESRD requiring dialysis or kidney transplantation) was more likely to occur among Texan Hispanics with kidney involvement than in the other ethnic groups. Diabetes and high blood pressure were not found to predict ESRD, but people with a particular variant of a protein that helps antibodies bind to cells (know as Fc-gamma receptor IIIa, or FcγRIIIa) were found to be more likely to develop ESRD, and to develop it more quickly.

What Do These Findings Mean?

These results suggest that the emergence and progression of kidney disease in patients with lupus depends on medical, genetic, and socioeconomic factors. Because no single test or intervention can be expected to address all of these factors, those treating patients with lupus must remain aware of the complexity of their patients lives at a variety of levels. In particular, ethnic disparities in the risk of serious kidney disease remain to be addressed.

Additional Information.

Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030396.

MedlinePlus page on lupus

Lupus Foundation of America

American College of Rheumatology pages on lupus

Wikipedia entry on lupus (note: Wikipedia is a free Internet encyclopedia that anyone can edit)

It is generally believed that susceptibility to both organ-specific and systemic autoimmune diseases is under polygenic control. Although multiple genes have been implicated in each type of autoimmune disease, few are known to have a significant impact on both. Here, we investigated the significance of polymorphisms in the human gene CD24 and the susceptibility to multiple sclerosis (MS) and systemic lupus erythematosus (SLE). We used cases/control studies to determine the association between CD24 polymorphism and the risk of MS and SLE. In addition, we also considered transmission disequilibrium tests using family data from two cohorts consisting of a total of 150 pedigrees of MS families and 187 pedigrees of SLE families. Our analyses revealed that a dinucleotide deletion at position 1527∼1528 (P1527del) from the CD24 mRNA translation start site is associated with a significantly reduced risk (odds ratio = 0.54 with 95% confidence interval = 0.34–0.82) and delayed progression (p = 0.0188) of MS. Among the SLE cohort, we found a similar reduction of risk with the same polymorphism (odds ratio = 0.38, confidence interval = 0.22–0.62). More importantly, using 150 pedigrees of MS families from two independent cohorts and the TRANSMIT software, we found that the P1527del allele was preferentially transmitted to unaffected individuals (p = 0.002). Likewise, an analysis of 187 SLE families revealed the dinucleotide-deleted allele was preferentially transmitted to unaffected individuals (p = 0.002). The mRNA levels for the dinucleotide-deletion allele were 2.5-fold less than that of the wild-type allele. The dinucleotide deletion significantly reduced the stability of CD24 mRNA. Our results demonstrate that a destabilizing dinucleotide deletion in the 3′ UTR of CD24 mRNA conveys significant protection against both MS and SLE.

Author Summary

When an individual's immune system attacks self tissues or organs, he/she develops autoimmune diseases. Although it is well established that multiple genes control susceptibility to autoimmune diseases, most of the genes remain unidentified. In addition, although different autoimmune diseases have a common immunological basis, a very small number of genes have been identified that affect multiple autoimmune diseases. Here we show that a variation in CD24 is a likely genetic factor for the risk and progression of two types of autoimmune diseases, including multiple sclerosis (MS), an organ-specific autoimmune disease affecting the central nervous system, and systemic lupus erythematosus, a systemic autoimmune disease. Our data indicated that if an individual's CD24 gene has a specific two-nucleotide deletion in the noncoding region of CD24 mRNA, his/her risk of developing MS or SLE is reduced by 2- to 3-fold. As a group, MS patients with the two-nucleotide deletion will likely have a slower disease progression. Biochemical analysis indicated that the deletion leads to rapid decay of CD24 mRNA, which should result in reduced synthesis of the CD24 protein. Our data may be useful for the treatment and diagnosis of autoimmune diseases.