Multiple polymorphisms in the TNFAIP3 region are independently associated with systemic lupus erythematosus.
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ABSTRACT:
SUBMITTER: Musone SL
PROVIDER: S-EPMC3897246 | biostudies-literature | 2008 Sep
REPOSITORIES: biostudies-literature
Publications
Multiple polymorphisms in the TNFAIP3 region are independently associated with systemic lupus erythematosus.
Musone Stacy L SL Taylor Kimberly E KE Lu Timothy T TT Nititham Joanne J Ferreira Ricardo C RC Ortmann Ward W Shifrin Nataliya N Petri Michelle A MA Kamboh M Ilyas MI Manzi Susan S Seldin Michael F MF Gregersen Peter K PK Behrens Timothy W TW Ma Averil A Kwok Pui-Yan PY Criswell Lindsey A LA
Nature genetics 20080901 9
The TNFAIP3 (tumor necrosis factor alpha-induced protein 3) gene encodes a ubiquitin editing enzyme, A20, that restricts NF-kappaB-dependent signaling and prevents inflammation. We show that three independent SNPs in the TNFAIP3 region (rs13192841, rs2230926 and rs6922466) are associated with systemic lupus erythematosus (SLE) among individuals of European ancestry. These findings provide critical links between A20 and the etiology of SLE. ...[more]
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Project description:Systemic lupus erythematosus (SLE) is an autoimmune disease influenced by genetic and environmental factors. We carried out a genome-wide association scan and replication study and found an association between SLE and a variant in TNFAIP3 (rs5029939, meta-analysis P = 2.89 x 10(-12), OR = 2.29). We also found evidence of two independent signals near TNFAIP3 associated with SLE, including one previously associated with rheumatoid arthritis (RA). These results establish that variants near TNFAIP3 contribute to differential risk of SLE and RA.
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Project description:Systemic lupus erythematosus (SLE, MIM152700) is an autoimmune disease characterized by self-reactive antibodies resulting in systemic inflammation and organ failure. TNFAIP3, encoding the ubiquitin-modifying enzyme A20, is an established susceptibility locus for SLE. By fine mapping and genomic re-sequencing in ethnically diverse populations, we fully characterized the TNFAIP3 risk haplotype and identified a TT>A polymorphic dinucleotide (deletion T followed by a T to A transversion) associated with SLE in subjects of European (P = 1.58 × 10(-8), odds ratio = 1.70) and Korean (P = 8.33 × 10(-10), odds ratio = 2.54) ancestry. This variant, located in a region of high conservation and regulatory potential, bound a nuclear protein complex composed of NF-?B subunits with reduced avidity. Further, compared with the non-risk haplotype, the haplotype carrying this variant resulted in reduced TNFAIP3 mRNA and A20 protein expression. These results establish this TT>A variant as the most likely functional polymorphism responsible for the association between TNFAIP3 and SLE.
| S-EPMC3103780 | biostudies-literature
Project description:Systemic lupus erythematosus (SLE) is associated with severe cardiovascular complications. The T50 score is a novel functional blood test quantifying calcification propensity in serum. High calcification propensity (or low T50) is a strong and independent determinant of all-cause mortality in various patient populations.A total of 168 patients with ? 4 American College of Rheumatology (ACR) diagnostic criteria from the Swiss Systemic lupus erythematosus Cohort Study (SSCS) were included in this analysis. Serum calcification propensity was assessed using time-resolved nephelometry.The cohort mainly consisted of female (85%), middle-aged (43±14 years) Caucasians (77%). The major determinants of T50 levels included hemoglobin, serum creatinine and serum protein levels explaining 43% of the variation at baseline. Integrating disease activity (SELENA-SLEDAI) into this multivariate model revealed a significant association between disease activity and T50 levels. In a subgroup analysis considering only patients with active disease (SELENA-SLEDAI score ?4) we found a negative association between T50 and SELENA-SLEDAI score at baseline (Spearman's rho -0.233, P = 0.02).Disease activity and T50 are closely associated. Moreover, T50 levels identify a subgroup of SLE patients with ongoing systemic inflammation as mirrored by increased disease activity. T50 could be a promising biomarker reflecting SLE disease activity and might offer an earlier detection tool for high-risk patients.
| S-EPMC5783342 | biostudies-literature
Project description:T cells from patients with systemic lupus erythematosus (SLE) express increased amounts of PP2Ac, which contributes to decreased production of interleukin-2 (IL-2). Because IL-2 is important in the regulation of several aspects of the immune response, it has been proposed that PP2Ac contributes to the expression of SLE. This study was designed to determine whether genetic variants of PPP2AC are linked to the expression of SLE and specific clinical manifestations and account for the increased expression of PP2Ac.We conducted a trans-ethnic study of 8,695 SLE cases and 7,308 controls of 4 different ancestries. Eighteen single-nucleotide polymorphisms (SNPs) across PPP2CA were genotyped using an Illumina custom array. PPP2CA expression in SLE and control T cells was analyzed by real-time polymerase chain reaction.A 32-kb haplotype comprising multiple SNPs of PPP2CA showed significant association with SLE in Hispanic Americans, European Americans, and Asians, but not in African Americans. Conditional analyses revealed that SNP rs7704116 in intron 1 showed consistently strong association with SLE across Asian, European American, and Hispanic American populations (odds ratio 1.3 [95% confidence interval 1.14-1.31], meta-analysis P=3.8×10(-7)). In European Americans, the largest ethnic data set studied, the risk A allele of rs7704116 was associated with the presence of renal disease, anti-double-stranded DNA, and anti-RNP antibodies. PPP2CA expression was ?2-fold higher in SLE patients carrying the rs7704116 AG genotype than those carrying the GG genotype (P=0.007).Our data provide the first evidence of an association between PPP2CA polymorphisms and elevated PP2Ac transcript levels in T cells, which implicates a new molecular pathway for SLE susceptibility in European Americans, Hispanic Americans, and Asians.
| S-EPMC3163110 | biostudies-literature
Project description:ObjectivesMethyl-CpG-binding protein 2 (MECP2) and interleukin-1 receptor-associated kinase (IRAK1) are encoded by adjacent X-linked genes and recognized for their role in regulation of inflammation. The present case control study was conducted to detect the genetic association between MECP2 (rs1734791) and IRAK1 (rs1059703) single nucleotide polymorphisms (SNPs) and susceptibility to systemic lupus erythematosus (SLE), and the possible association of these SNPs and severity of SLE.Material and methodsFifty patients with SLE and 100 healthy controls were included in this study. Systemic Lupus International Collaborating Clinics (SLICC) criteria were used to classify SLE patients and the activity of the disease was assessed by SLEDAI score. Disease severity was assessed by the SLICC damage index (SLICC DI). Genetic association of both SNPs with SLE was assessed by Taq Man allelic discrimination technique.ResultsAnalyses of MECP2 (rs1734791) SNP genotypes revealed that homozygous TT genotype was significantly higher in the control group than SLE patients (p < 0.001, odds ratio [OR] = 0.120). Frequency of allele (A) was significantly higher in SLE patients, (p < 0.001, OR = 0.334). SLE patients had significantly higher frequency of the homozygous AA and heterozygous AG genotype of IRAK1 (rs1059703) SNP in comparison to healthy controls (p = 0.0029, OR = 4.17 and 6.30 respectively). T+G and T+A of rs1734791 and rs1059703 SNPs are protective haplotypes (OR = 0.47 and 0.3, p = 0.0046 and < 0.012 respectively). No significant association between either SNP and disease activity or severity was found.ConclusionsThere is a possible genetic association between both rs1734791 and rs1059703 SNPs and susceptibility to SLE, while no significant association between either SNP and disease activity or severity was detected.
| S-EPMC6911245 | biostudies-literature
Project description: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 and 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.
| S-EPMC2714407 | biostudies-literature
Project description:Functional characterization of causal variants present on risk haplotypes identified through genome-wide association studies (GWAS) is a primary objective of human genetics. In this report, we evaluate the function of a pair of tandem polymorphic dinucleotides, 42 kb downstream of the promoter of TNFAIP3, (rs148314165, rs200820567, collectively referred to as TT>A) recently nominated as causal variants responsible for genetic association of systemic lupus erythematosus (SLE) with tumor necrosis factor alpha inducible protein 3 (TNFAIP3). TNFAIP3 encodes the ubiquitin-editing enzyme, A20, a key negative regulator of NF-κB signaling. A20 expression is reduced in subjects carrying the TT>A risk alleles; however, the underlying functional mechanism by which this occurs is unclear. We used a combination of electrophoretic mobility shift assays (EMSA), mass spectrometry (MS), reporter assays, chromatin immunoprecipitation-PCR (ChIP-PCR) and chromosome conformation capture (3C) EBV transformed lymphoblastoid cell lines (LCL) from individuals carrying risk and non-risk TNFAIP3 haplotypes to characterize the effect of TT>A on A20 expression. Our results demonstrate that the TT>A variants reside in an enhancer element that binds NF-κB and SATB1 enabling physical interaction of the enhancer with the TNFAIP3 promoter through long-range DNA looping. Impaired binding of NF-κB to the TT>A risk alleles or knockdown of SATB1 expression by shRNA, inhibits the looping interaction resulting in reduced A20 expression. Together, these data reveal a novel mechanism of TNFAIP3 transcriptional regulation and establish the functional basis by which the TT>A risk variants attenuate A20 expression through inefficient delivery of NF-κB to the TNFAIP3 promoter. These results provide critical functional evidence supporting a direct causal role for TT>A in the genetic predisposition to SLE.
| S-EPMC3764111 | biostudies-literature
Project description:Linkage disequilibrium poses a major challenge to the functional characterization of specific disease-associated susceptibility variants. Precision genome-editing technologies have provided new opportunities to address this challenge. As proof of concept, we employed TALEN (transcription activation-like effector nuclease)-mediated genome editing to specifically disrupt the TT>A enhancer region to mimic candidate causal variants identified in the systemic lupus erythematosus-associated susceptibility gene, tumor necrosis factor-α-induced protein 3 (TNFAIP3), in an isogenic HEK293T cell line devoid of other linkage disequilibrium-associated variants. Targeted disruption of the TT>A enhancer impaired its interaction with the TNFAIP3 promoter by long-range DNA looping, thereby reducing TNFAIP3 gene expression. Loss of TNFAIP3 mRNA and its encoded protein, A20, impaired tumor necrosis factor-α-induced receptor-mediated downregulation of nuclear factor-κB signaling, a hallmark of autoimmunity. Results demonstrate that the TT>A enhancer variants contribute to causality and function independently of other variants to disrupt TNFAIP3 expression. Furthermore, we believe this approach can be implemented to independently examine other candidate casual variants in the future.
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Project description:ObjectiveAlthough the number of convincingly established genetic associations with systemic lupus erythematosus (SLE) has increased sharply over the last few years, refinement of these associations is required, and their potential roles in gene-gene interactions need to be further investigated. Recent genome-wide association studies (GWAS) in SLE have produced renewed interest in B cell/T cell responses and the NF-κB signaling pathway. The aim of this study was to search for possible gene-gene interactions based on identified single-nucleotide polymorphisms (SNPs), in using an approach based on the role of signaling pathways.MethodsThe SNPs in BLK, TNFSF4, TRAF1, TNFAIP3, and REL were replicated in order to evaluate genetic associations with SLE. TaqMan genotyping was conducted in 804 Chinese patients with SLE and 722 matched control subjects. A multiple logistic regression model was used to estimate the multiplicative interaction effect of the SNPs, and additive interactions were analyzed by 2×2 factorial designs. Data from a previously published GWAS conducted by the International Consortium on the Genetics of Systemic Lupus Erythematosus were derived for comparison and validation.ResultsSingle-marker analysis validated the association of BLK rs2736340 (P=4.25×10(-6)) as well as TNFSF4 rs2205960 (P=2.82×10(-5)) and TNFAIP3 rs5029939 (P=1.92×10(-3)) with SLE susceptibility in Chinese. Multiplicative interaction analysis indicated that BLK had an interactive effect with TNFSF4 in Chinese patients with SLE (P=6.57×10(-4)). Additive interaction analysis revealed interactions between TRAF1 and TNFAIP3 in both Chinese (P=2.18×10(-3)) and Caucasians (P=2.86×10(-4)). In addition, multiple tendencies toward interactions were observed, and an additive effect was observed as the number of risk genotypes increased.ConclusionThe results of this study provide evidence of the possible gene-gene interactions of BLK, TNFSF4, TRAF1, TNFAIP3, and REL in SLE, which may represent a synergic effect of T cells and B cells through the NF-κB pathway in determining immunologic aberration.
| S-EPMC3994469 | biostudies-literature
Project description:Recent genome-wide association studies demonstrated association of single nucleotide polymorphisms (SNPs) in the TNFAIP3 region at 6q23 with systemic lupus erythematosus (SLE) in European-American populations. In this study, we investigated whether SNPs in the TNFAIP3 region are associated with SLE also in a Japanese population. A case-control association study was performed on the SNPs rs13192841, rs2230926, and rs6922466 in 318 Japanese SLE patients and 444 healthy controls. Association of rs2230926 G allele with SLE was replicated in Japanese (allelic association P = .033, odds ratio [OR] 1.47, recessive model P = .023, OR 8.52). The association was preferentially observed in the SLE patients with nephritis. When the TNFAIP3 mRNA levels of the HapMap samples were examined using GENEVAR database, the presence of TNFAIP3 rs2230926 G allele was associated with lower mRNA expression of TNFAIP3 (P = .013). These results indicated that TNFAIP3 is a susceptibility gene to SLE both in the Caucasian and Asian populations.
| S-EPMC2896654 | biostudies-literature