IL-10 Gene Polymorphisms and Susceptibility to Systemic Lupus Erythematosus: A Meta-Analysis

Background

A number of observational studies have been conducted to investigate the association of the IL-10 gene polymorphisms with systemic lupus erythematosus (SLE) susceptibility. However, their results are conflicting.

Method

We searched published case-control studies on the IL-10 polymorphisms and SLE in PubMed, EMBASE and Chinese Biomedical Literature Database. A meta-analysis was conducted using a fixed-effect or random-effect model based on between-study heterogeneity.

Results

A total of 42 studies with 7948 cases and 11866 controls were included in this meta-analysis. Among Caucasians, the CA27 allele of the IL10.G microsatellites (OR 2.38, 95% CI 1.01–5.62), the G allele of the IL-10 -1082G/A polymorphism (G vs. A: OR 1.21, 95% CI 1.02–1.44; GG vs. AA: OR 1.45, 95% CI 1.16–1.82; GG+GA vs. AA: OR 1.16, 95% CI 1.03–1.29) and its associated haplotype -1082G/−819C/−592C (OR 1.25, 95% CI 1.10–1.42) were associated with increased SLE susceptibility without or with unimportant between-study heterogeneity. Removing studies deviating from Hardy-Weinberg equilibrium (HWE) hardly changed these results. Among Asians, the CA21 allele of the IL-10.G microsatellites (OR 1.28, 95% CI 1.02–1.60) and the -1082G/−819C/−592C haplotype (OR 1.24, 95% CI 1.00–1.53) were associated with increased SLE susceptibility, but with substantial between-study heterogeneity or sensitive to HWE status. Removing studies deviating from HWE also produced statistically significant associations of the IL-10 -1082G/A (GG vs. AA: OR 3.21, 95% CI 1.24–8.28; GG vs. AA+GA: OR 2.85, 95% CI 1.19–6.79) and -592C/A polymorphisms (CC+CA vs. AA: OR 0.69, 95% CI 0.51–0.94) with SLE among Asians.

Conclusion

This meta-analysis showed that the IL10.G microsatellites, the IL-10 -1082G/A and -592C/A polymorphisms and the haplotype -1082G/−819C/−592C are associated with SLE susceptibility. Besides, this is the first time to report an association between the CA27 allele of the IL-10.G microsatellites and SLE among Caucasians. Further studies are needed to confirm these findings.     

Mortality in Systemic Lupus Erythematosus: A 10-Year Review

During the years 1963-72 33 patients with systemic lupus erythematosus (S.L.E.) died. Of these 30 case records were available for analysis. For the same period 167 patients with S.L.E. were admitted. It was ascertained that of the 30 deaths 22 were directly attributable to the disease itself and 8 were related to complications of therapy. The three commonest causes of death were neurological involvement (11 patients), renal failure (9 patients), and infection (8 patients).     

Functional Relevance for Associations between Genetic Variants and Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a serious prototype autoimmune disease characterized by chronic inflammation, auto-antibody production and multi-organ damage. Recent association studies have identified a long list of loci that were associated with SLE with relatively high statistical power. However, most of them only established the statistical associations of genetic markers and SLE at the DNA level without supporting evidence of functional relevance. Here, using publically available datasets, we performed integrative analyses (gene relationship across implicated loci analysis, differential gene expression analysis and functional annotation clustering analysis) and combined with expression quantitative trait loci (eQTLs) results to dissect functional mechanisms underlying the associations for SLE. We found that 14 SNPs, which were significantly associated with SLE in previous studies, have cis-regulation effects on four eQTL genes (HLA-DQA1, HLA-DQB1, HLA-DQB2, and IRF5) that were also differentially expressed in SLE-related cell groups. The functional evidence, taken together, suggested the functional mechanisms underlying the associations of 14 SNPs and SLE. The study may serve as an example of mining publically available datasets and results in validation of significant disease-association results. Utilization of public data resources for integrative analyses may provide novel insights into the molecular genetic mechanisms underlying human diseases.     

Serological and Genetic Evidence for Altered Complement System Functionality in Systemic Lupus Erythematosus: Findings of the GAPAID Consortium

Systemic lupus erythematosus is a chronic autoimmune disease with multifactorial ethiopathogenesis. The complement system is involved in both the early and late stages of disease development and organ damage. To better understand autoantibody mediated complement consumption we examined ex vivo immune complex formation on autoantigen arrays. We recruited patients with SLE (n = 211), with other systemic autoimmune diseases (n = 65) and non-autoimmune control subjects (n = 149). Standard clinical and laboratory data were collected and serum complement levels were determined. The genotype of SNP rs1143679 in the ITGAM gene was also determined. Ex vivo formation of immune complexes, with respect to IgM, IgG, complement C4 and C3 binding, was examined using a functional immunoassay on autoantigen microarray comprising nucleic acids, proteins and lipids. Complement consumption of nucleic acids increased upon binding of IgM and IgG even when serum complement levels were decreased due to consumption in SLE patients. A negative correlation between serum complement levels and ex vivo complement deposition on nucleic acid autoantigens is demonstrated. On the contrary, complement deposition on tested protein and lipid autoantigens showed positive correlation with C4 levels. Genetic analysis revealed that the non-synonymous variant rs1143679 in complement receptor type 3 is associated with an increased production of anti-dsDNA IgG antibodies. Notwithstanding, homozygous carriers of the previously reported susceptible allele (AA) had lower levels of dsDNA specific IgM among SLE patients. Both the non-synonymous variant rs1143679 and the high ratio of nucleic acid specific IgG/IgM were associated with multiple organ involvement. In summary, secondary complement deficiency in SLE does not impair opsonization of nucleic-acid-containing autoantigens but does affect other antigens and potentially other complement dependent processes. Dysfunction of the receptor recognizing complement opsonized immune complexes promotes the development of class-switched autoantibodies targeting nucleic acids.     

Systemic Lupus Erythematosus: Old and New Susceptibility Genes versus Clinical Manifestations

Systemic Lupus Erythematosus (SLE) is one of the most relevant world-wide autoimmune disorders. The formation of autoantibodies and the deposition of antibody-containing immune complexes in blood vessels throughout the body is the main pathogenic mechanism of SLE leading to heterogeneous clinical manifestations and target tissue damage. The complexity of etiology and pathogenesis in SLE, enclosing genetic and environmental factors, apparently is one of the greatest challenges for both researchers and clinicians. Strong indications for a genetic background in SLE come from studies in families as well as in monozygotic and dizygotic twins, discovering several SLE-associated loci and genes (e.g. IRF5, PTPN22, CTLA4, STAT4 and BANK1). As SLE has a complex genetic background, none of these genes is likely to be entirely responsible for triggering autoimmune response in SLE even if they disclosure a potentially novel molecular mechanisms in the pathogenesis'' disease. The clinical manifestations and disease severity varies greatly among patients, thus several studies try to associate clinical heterogeneity and prognosis with specific genetic polymorphisms in SLE associated genes. The continue effort to describe new predisposing or modulating genes in SLE is justified by the limited knowledge about the pathogenesis, assorted clinical manifestation and the possible prevention strategies. In this review we describe newly discovered, as well as the most studied genes associated to SLE susceptibility, and relate them to clinical manifestations of the disease.     

Analysis of Gender Differences in Genetic Risk: Association of TNFAIP3 Polymorphism with Male Childhood-Onset Systemic Lupus Erythematosus in the Japanese Population

Background

Systemic lupus erythematosus (SLE) is a systemic multisystem autoimmune disorder influenced by genetic background and environmental factors. Our aim here was to replicate findings of associations between 7 of the implicated single nucleotide polymorphisms (SNPs) in IRF5, BLK, STAT4, TNFAIP3, SPP1, TNIP1 and ETS1 genes with susceptibility to childhood-onset SLE in the Japanese population. In particular, we focused on gender differences in allelic frequencies.

Methodology/Principal Findings

The 7 SNPs were genotyped using TaqMan assays in 75 patients with childhood-onset SLE and in 190 healthy controls. The relationship between the cumulative number of risk alleles and SLE manifestations was explored in childhood-onset SLE. Logistic regression was used to test the effect of each polymorphism on susceptibility to SLE, and Wilcoxon rank sum testing was used for comparison of total risk alleles. Data on rs7574865 in the STAT4 gene and rs9138 in SPP1 were replicated for associations with SLE when comparing cases and controls (corrected P values ranging from 0.0043 to 0.027). The rs2230926 allele of TNFAIP3 was associated with susceptibility to SLE in males, but after Bonferroni correction there were no significant associations with any of the other four SNPs in IRF5, BLK, TNIP1 and ETS1 genes. The cumulative number of risk alleles was significantly increased in childhood-onset SLE relative to healthy controls (P = 0.0000041). Male SLE patients had a slightly but significantly higher frequency of the TNFAIP3 (rs2230926G) risk allele than female patients (odds ratio [OR] = 4.05, 95% confidence interval [95%CI] = 1.46–11.2 P<0.05).

Conclusions

Associations of polymorphisms in STAT4 and SPP1 with childhood-onset SLE were confirmed in a Japanese population. Although these are preliminary results for a limited number of cases, TNFAIP3 rs2230926G may be an important predictor of disease onset in males. We also replicated findings that the cumulative number of risk alleles was significantly increased in childhood-onset SLE.     

Candidate Gene Identification for Systemic Lupus Erythematosus Using Network Centrality Measures and Gene Ontology

Systemic lupus erythematosus (SLE) commonly accredited as “the great imitator” is a highly complex disease involving multiple gene susceptibility with non-specific symptoms. Many experimental and computational approaches have been used to investigate the disease related candidate genes. But the limited knowledge of gene function and disease correlation and also lack of complete functional details about the majority of genes in susceptible locus, encumbrances the identification of SLE related candidate genes. In this paper, we have studied the human immunome network (undirected) using various graph theoretical centrality measures integrated with the gene ontology terms to predict the new candidate genes. As a result, we have identified 8 candidate genes, which may act as potential targets for SLE disease. We have also carried out the same analysis by replacing the human immunome network with human immunome signaling network (directed) and as an outcome we have obtained 5 candidate genes as potential targets for SLE disease. From the comparison study, we have found these two approaches are complementary in nature.     

Animal Models of Human Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a human autoimmune disease of unknown etiology. Clinical, serologic, immunologic, and pathologic findings are highly variable in different patients and at different times in the same patient. Murine and canine animal models of SLE have been found with clinicopathologic abnormalities resembling those observed in humans. Each animal model has unique characteristics; taken together they reflect the spectrum of disease in human SLE.Investigations in the animals have suggested that genetic, hormonal, immunologic, viral, and other environmental factors contribute to and modify the expression of disease. Where analogous studies are available for humans, the same factors have been found to modify disease expression in a similar fashion. Together, these studies have helped to clarify the multifactorial basis for SLE.The best characterized abnormalities are immunologic. These include excessive B cell function with the formation of large amounts of autoantibodies, and T cell abnormalities which include defects in T cell regulatory function as well as certain T cell effector functions.The animal models of SLE also serve as convenient test subjects for newer therapeutic modalities. It is hoped that further study of the animal models will provide a more rational approach to therapeutic modulation of disease in humans with SLE.     

Further Evidence of Subphenotype Association with Systemic Lupus Erythematosus Susceptibility Loci: A European Cases Only Study

Introduction

Systemic Lupus Erythematosus (SLE) shows a spectrum of clinical manifestations that complicate its diagnosis, treatment and research. This variability is likely related with environmental exposures and genetic factors among which known SLE susceptibility loci are prime candidates. The first published analyses seem to indicate that this is the case for some of them, but results are still inconclusive and we aimed to further explore this question.

Methods

European SLE patients, 1444, recruited at 17 centres from 10 countries were analyzed. Genotypes for 26 SLE associated SNPs were compared between patients with and without each of 11 clinical features: ten of the American College of Rheumatology (ACR) classification criteria (except ANAs) and age of disease onset. These analyses were adjusted for centre of recruitment, top ancestry informative markers, gender and time of follow-up. Overlap of samples with previous studies was excluded for assessing replication.

Results

There were three new associations: the SNPs in XKR6 and in FAM167A-BLK were associated with lupus nephritis (OR = 0.76 and 1.30, P_corr = 0.007 and 0.03, respectively) and the SNP of MECP2, which is in chromosome X, with earlier age of disease onset in men. The previously reported association of STAT4 with early age of disease onset was replicated. Some other results were suggestive of the presence of additional associations. Together, the association signals provided support to some previous findings and to the characterization of lupus nephritis, autoantibodies and age of disease onset as the clinical features more associated with SLE loci.

Conclusion

Some of the SLE loci shape the disease phenotype in addition to increase susceptibility to SLE. This influence is more prominent for some clinical features than for others. However, results are only partially consistent between studies and subphenotype specific GWAS are needed to unravel their genetic component.     

The Clinical Significance of Vitamin D in Systemic Lupus Erythematosus: A Systematic Review

Background

Vitamin D deficiency is more prevalent among SLE patients than the general population. Over the past decade, many studies across the globe have been carried out to investigate the role of vitamin D in SLE from various clinical angles. Therefore, the aim of this systematic review is to summarise and evaluate the evidence from the published literature; focusing on the clinical significance of vitamin D in SLE.

Methods

The following databases were searched: MEDLINE, Scopus, Web of Knowledge and CINAHL, using the terms “lupus”, “systemic lupus erythematosus”, “SLE and “vitamin D”. We included only adult human studies published in the English language between 2000 and 2012.The reference lists of included studies were thoroughly reviewed in search for other relevant studies.

Results

A total of 22 studies met the selection criteria. The majority of the studies were observational (95.5%) and cross sectional (90.9%). Out of the 15 studies which looked into the association between vitamin D and SLE disease activity, 10 studies (including the 3 largest studies in this series) revealed a statistically significant inverse relationship. For disease damage, on the other hand, 5 out of 6 studies failed to demonstrate any association with vitamin D levels. Cardiovascular risk factors such as insulin resistance, hypertension and hypercholesterolaemia were related to vitamin D deficiency, according to 3 of the studies.

Conclusion

There is convincing evidence to support the association between vitamin D levels and SLE disease activity. There is paucity of data in other clinical aspects to make firm conclusions.     

非HLA类系统性红斑狼疮易感基因关联研究进展

系统性红斑狼疮(systemic lupus erythematosus,SLE)是一种复杂的多基因自身免疫疾病,遗传因素在其中起重要作用;除了人类白细胞抗原基因之外,多种非HLA基因也通过各种途径参与SLE免疫紊乱,其不同多态性及单倍型背景可能通过差异性遗传学效应影响SLE的发生与发展,因而探索相关基因的作用机制、基因间相互关系及其表达调控的网络信号通路对于深入了解SLE致病机制,指导其风险评估,开展个性化诊疗及预后等极为关键,是未来SLE研究的重大方向。     

Association between Polymorphisms of the IKZF3 Gene and Systemic Lupus Erythematosus in a Chinese Han Population

Objective

It has been reported that IKAROS family of zinc finger 3 (IKZF3)-deficient mice spontaneously develop human systemic lupus erythematosus (SLE)-like phenotypes and produce anti-dsDNA Ab leading to immune complex-mediated glomerulonephritis. Polymorphism of the IKZF3 gene corresponds with the susceptibility to several immune-related diseases. Our intention was to establish an association between polymorphisms in the IKZF3 gene and SLE in the Chinese Han population.

Methods

The study involved obtaining blood samples for DNA extraction and genotyping the 4 selected single-nucleotide polymorphisms (SNPs) in IKZF3, including rs12150079, rs9909593, rs907091, and rs2872507, by performing PCR restriction fragment length polymorphism analysis (PCR-RFLP). A group of 366 SLE patients were compared to 455 healthy controls.

Results

A significant decrease in frequencies of the rs907091 CC genotype and C allele appeared in the SLE patients unlike that observed in the controls (p = 0.001 and 0.015, respectively). The frequencies of the rs12150079 genotype and allele were different between the SLE patients and the control individuals, although the significance was only marginal (p = 0.046 and 0.049, respectively). In addition, a significantly low frequency of the GGCG haplotype was observed in the SLE patients, suggesting that it may provide protection against SLE (p = 0.011).

Conclusion

To the best of our knowledge, this is the first study to demonstrate an important association between polymorphisms in IKZF3 and SLE in the Chinese Han population. A strong association between rs907091 in the IKZF3 gene and SLE was identified.     

Systemic Lupus Erythematous and Malignancy Risk: A Meta-Analysis

Background

Pilot studies have estimated cancer incidence in patients with systemic lupus erythematous (SLE). However, the results have been inconclusive. To ascertain the correlation between SLE and malignancy more comprehensively and precisely, we conducted a meta-analysis.

Methods

PubMed, the Cochrane Library and Embase databases through June 2014, were searched to identify observational studies evaluating the association between SLE and malignancy. The outcomes from these studies were measured as relative risks (RRs). A random or fixed effects model was chosen to calculate the pooled RR according to heterogeneity test. Between-study heterogeneity was assessed by estimating I² index. Publication bias was assessed by Egger’s test.

Results

A total of 16 papers, including 59,662 SLE patients, were suitable for the meta-analysis. Of these papers, 15 reported RRs for overall malignancy, 12 for non-Hodgkin lymphoma (NHL) and lung cancer, 7 for bladder cancer, 6 for Hodgkin lymphoma (HL) and leukemia, 5 for skin melanoma, and liver and thyroid cancers, 4 for multiple myeloma (MM), and esophageal and vaginal/vulvar cancers and 3 for laryngeal and non-melanoma skin cancers. The pooled RRs were 1.28 (95% CI, 1.17–1.41) for overall cancer, 5.40 (95% CI, 3.75–7.77) for NHL, 3.26(95% CI, 2.17–4.88) for HL, 2.01(95% CI, 1.61–2.52) for leukemia, 1.45(95% CI, 1.04–2.03) for MM, 4.19(95% CI, 1.98–8.87) for laryngeal cancer, 1.59 (95% CI, 1.44–1.76) for lung cancer, 1.86(95% CI, 1.21–2.88) for esophageal cancer, 3.21(95% CI, 1.70–6.05) for liver cancer, 3.67(95% CI, 2.80–4.81) for vaginal/vulvar cancer, 2.11(95% CI, 1.12–3.99) for bladder cancer, 1.51(95% CI, 1.12–2.03) for non-melanoma skin cancer, 1.78(95% CI, 1.35–2.33) for thyroid cancer, and 0.65(95% CI, 0.50–0.85) for skin melanoma. Only the meta-analyses of overall malignancy, NHL, and liver and bladder cancers produced substantial heterogeneity (I², 57.6% vs 74.3% vs 67.7% vs 82.3%). No apparent publication bias was detected except for NHL studies.

Conclusions

Our data support an association between SLE and malignancy, not only demonstrating an increased risk for NHL, HL, leukemia, and some non-hematologic malignancies, including laryngeal, lung, liver, vaginal/vulvar, and thyroid malignancies, but also a reduced risk for skin melanoma. Although an increased risk of MM, and esophageal, bladder and non-melanoma skin cancers was identified from the accumulated data in these studies, this observation requires confirmation.     

The Coexistence of Antiphospholipid Syndrome and Systemic Lupus Erythematosus in Colombians

Objectives

To examine the prevalence and associated factors related to the coexistence of antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE) in a cohort of Colombian patients with SLE, and to discuss the coexistence of APS with other autoimmune diseases (ADs).

Method

A total of 376 patients with SLE were assessed for the presence of the following: 1) confirmed APS; 2) positivity for antiphospholipid (aPL) antibodies without a prior thromboembolic nor obstetric event; and 3) SLE patients without APS nor positivity for aPL antibodies. Comparisons between groups 1 and 3 were evaluated by bivariate and multivariate analysis.

Results

Although the prevalence of aPL antibodies was 54%, APS was present in just 9.3% of SLE patients. In our series, besides cardiovascular disease (AOR 3.38, 95% CI 1.11–10.96, p = 0.035), pulmonary involvement (AOR 5.06, 95% CI 1.56–16.74, p = 0.007) and positivity for rheumatoid factor (AOR 4.68, 95%IC 1.63–14.98, p = 0.006) were factors significantly associated with APS-SLE. APS also may coexist with rheumatoid arthritis, Sjögren''s syndrome, autoimmune thyroid diseases, systemic sclerosis, systemic vasculitis, dermatopolymyositis, primary biliary cirrhosis and autoimmune hepatitis.

Conclusions

APS is a systemic AD that may coexist with other ADs, the most common being SLE. Awareness of this polyautoimmunity should be addressed promptly to establish strategies for controlling modifiable risk factors in those patients.