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Leptin is abnormally elevated in the plasma of patients with systemic lupus erythematosus (SLE), where it is thought to promote and/or sustain pro-inflammatory responses. Whether this association could reflect an increased genetic susceptibility to develop SLE is not known, and studies of genetic associations with leptin-related polymorphisms in SLE patients have been so far inconclusive. Here we genotyped DNA samples from 15,706 SLE patients and healthy matched controls from four different ancestral groups, to correlate polymorphisms of genes of the leptin pathway to risk for SLE. It was found that although several SNPs showed weak associations, those associations did not remain significant after correction for multiple testing. These data do not support associations between defined leptin-related polymorphisms and increased susceptibility to develop SLE.

Genetic variants at chromosomal region 11q23.3, near the gene ETS1, have been associated with systemic lupus erythematosus (SLE), or lupus, in independent cohorts of Asian ancestry. Several recent studies have implicated ETS1 as a critical driver of immune cell function and differentiation, and mice deficient in ETS1 develop an SLE-like autoimmunity. We performed a fine-mapping study of 14,551 subjects from multi-ancestral cohorts by starting with genotyped variants and imputing to all common variants spanning ETS1. By constructing genetic models via frequentist and Bayesian association methods, we identified 16 variants that are statistically likely to be causal. We functionally assessed each of these variants on the basis of their likelihood of affecting transcription factor binding, miRNA binding, or chromatin state. Of the four variants that we experimentally examined, only rs6590330 differentially binds lysate from B cells. Using mass spectrometry, we found more binding of the transcription factor signal transducer and activator of transcription 1 (STAT1) to DNA near the risk allele of rs6590330 than near the non-risk allele. Immunoblot analysis and chromatin immunoprecipitation of pSTAT1 in B cells heterozygous for rs6590330 confirmed that the risk allele increased binding to the active form of STAT1. Analysis with expression quantitative trait loci indicated that the risk allele of rs6590330 is associated with decreased ETS1 expression in Han Chinese, but not other ancestral cohorts. We propose a model in which the risk allele of rs6590330 is associated with decreased ETS1 expression and increases SLE risk by enhancing the binding of pSTAT1.

Exploiting genotyping, DNA sequencing, imputation and trans-ancestral mapping, we used Bayesian and frequentist approaches to model the IRF5-TNPO3 locus association, now implicated in two immunotherapies and seven autoimmune diseases. Specifically, in systemic lupus erythematosus (SLE), we resolved separate associations in the IRF5 promoter (all ancestries) and with an extended European haplotype. We captured 3230 IRF5-TNPO3 high-quality, common variants across 5 ethnicities in 8395 SLE cases and 7367 controls. The genetic effect from the IRF5 promoter can be explained by any one of four variants in 5.7 kb (P-valuemeta = 6 × 10(-49); OR = 1.38-1.97). The second genetic effect spanned an 85.5-kb, 24-variant haplotype that included the genes IRF5 and TNPO3 (P-valuesEU = 10(-27)-10(-32), OR = 1.7-1.81). Many variants at the IRF5 locus with previously assigned biological function are not members of either final credible set of potential causal variants identified herein. In addition to the known biologically functional variants, we demonstrated that the risk allele of rs4728142, a variant in the promoter among the lowest frequentist probability and highest Bayesian posterior probability, was correlated with IRF5 expression and differentially binds the transcription factor ZBTB3. Our analytical strategy provides a novel framework for future studies aimed at dissecting etiological genetic effects. Finally, both SLE elements of the statistical model appear to operate in Sjögren's syndrome and systemic sclerosis whereas only the IRF5-TNPO3 gene-spanning haplotype is associated with primary biliary cirrhosis, demonstrating the nuance of similarity and difference in autoimmune disease risk mechanisms at IRF5-TNPO3.

Efforts to identify lupus-associated causal variants in the FAM167A/BLK locus on 8p21 are hampered by highly associated noncausal variants. In this report, we used a trans-population mapping and sequencing strategy to identify a common variant (rs922483) in the proximal BLK promoter and a tri-allelic variant (rs1382568) in the upstream alternative BLK promoter as putative causal variants for association with systemic lupus erythematosus. The risk allele (T) at rs922483 reduced proximal promoter activity and modulated alternative promoter usage. Allelic differences at rs1382568 resulted in altered promoter activity in B progenitor cell lines. Thus, our results demonstrated that both lupus-associated functional variants contribute to the autoimmune disease association by modulating transcription of BLK in B cells and thus potentially altering immune responses.

ObjectiveLittle is known about the genetic etiology of systemic lupus erythematosus (SLE) in individuals of African ancestry, despite its higher prevalence and greater disease severity. Overproduction of nitric oxide (NO) and reactive oxygen species are implicated in the pathogenesis and severity of SLE, making NO synthases and other reactive intermediate-related genes biological candidates for disease susceptibility. We analyzed variation in reactive intermediate genes for association with SLE in 2 populations with African ancestry.MethodsA total of 244 single-nucleotide polymorphisms (SNP) from 53 regions were analyzed in non-Gullah African Americans (AA; 1432 cases and 1687 controls) and the genetically more homogeneous Gullah of the Sea Islands of South Carolina (133 cases and 112 controls). Single-marker, haplotype, and 2-locus interaction tests were computed for these populations.ResultsThe glutathione reductase gene GSR (rs2253409; p = 0.0014, OR 1.26, 95% CI 1.09-1.44) was the most significant single SNP association in AA. In the Gullah, the NADH dehydrogenase NDUFS4 (rs381575; p = 0.0065, OR 2.10, 95% CI 1.23-3.59) and NO synthase gene NOS1 (rs561712; p = 0.0072, OR 0.62, 95% CI 0.44-0.88) were most strongly associated with SLE. When both populations were analyzed together, GSR remained the most significant effect (rs2253409; p = 0.00072, OR 1.26, 95% CI 1.10-1.44). Haplotype and 2-locus interaction analyses also uncovered different loci in each population.ConclusionThese results suggest distinct patterns of association with SLE in African-derived populations; specific loci may be more strongly associated within select population groups.

ObjectivesThe 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.MethodsWe fine-mapped ≥136 SNPs in a ∼227 kb region on Xq28, containing IRAK1, MECP2 and seven adjacent genes (L1CAM, AVPR2, ARHGAP4, NAA10, RENBP, HCFC1 and TMEM187), for association with SLE in 15 783 case-control subjects derived from four different ancestral groups.ResultsMultiple SNPs showed strong association with SLE in European Americans, Asians and Hispanics at p

ObjectiveSystemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production and altered type I interferon expression. Genetic surveys and genome-wide association studies have identified >30 SLE susceptibility genes. One of these genes, TNIP1, encodes the ABIN1 protein. ABIN1 functions in the immune system by restricting NF-κB signaling. The present study was undertaken to investigate the genetic factors that influence association with SLE in genes that regulate the NF-κB pathway.MethodsWe analyzed a dense set of genetic markers spanning TNIP1 and TAX1BP1, as well as the TNIP1 homolog TNIP2, in case-control populations of diverse ethnic origins. TNIP1, TNIP2, and TAX1BP1 were fine-mapped in a total of 8,372 SLE cases and 7,492 healthy controls from European-ancestry, African American, Hispanic, East Asian, and African American Gullah populations. Levels of TNIP1 messenger RNA (mRNA) and ABIN1 protein in Epstein-Barr virus-transformed human B cell lines were analyzed by quantitative reverse transcription-polymerase chain reaction and Western blotting, respectively.ResultsWe found significant associations between SLE and genetic variants within TNIP1, but not in TNIP2 or TAX1BP1. After resequencing and imputation, we identified 2 independent risk haplotypes within TNIP1 in individuals of European ancestry that were also present in African American and Hispanic populations. Levels of TNIP1 mRNA and ABIN1 protein were reduced among subjects with these haplotypes, suggesting that they harbor hypomorphic functional variants that influence susceptibility to SLE by restricting ABIN1 expression.ConclusionOur results confirm the association signals between SLE and TNIP1 variants in multiple populations and provide new insight into the mechanism by which TNIP1 variants may contribute to SLE pathogenesis.

ObjectiveSystemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with significant immune system aberrations resulting from complex heritable genetics as well as environmental factors. We undertook to study the role of TRAF6 as a candidate gene for SLE, since it plays a major role in several signaling pathways that are important for immunity and organ development.MethodsFifteen single-nucleotide polymorphisms (SNPs) across TRAF6 were evaluated in 7,490 SLE patients and 6,780 control subjects from different ancestries. Population-based case-control association analyses and meta-analyses were performed. P values, false discovery rate q values, and odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated.ResultsEvidence of associations was detected in multiple SNPs. The best overall P values were obtained for SNPs rs5030437 and rs4755453 (P = 7.85 × 10(-5) and P = 4.73 × 10(-5) , respectively) without significant heterogeneity among populations (P = 0.67 and P = 0.50, respectively, in Q statistic). In addition, SNP rs540386, which was previously reported to be associated with rheumatoid arthritis (RA), was found to be in linkage disequilibrium with these 2 SNPs (r(2) = 0.95) and demonstrated evidence of association with SLE in the same direction (meta-analysis P = 9.15 × 10(-4) , OR 0.89 [95% CI 0.83-0.95]). The presence of thrombocytopenia improved the overall results in different populations (meta-analysis P = 1.99 × 10(-6) , OR 0.57 [95% CI 0.45-0.72], for rs5030470). Finally, evidence of family-based association in 34 African American pedigrees with the presence of thrombocytopenia was detected in 1 available SNP (rs5030437) with a Z score magnitude of 2.28 (P = 0.02) under a dominant model.ConclusionOur data indicate the presence of association of TRAF6 with SLE, consistent with the previous report of association with RA. These data provide further support for the involvement of TRAF6 in the pathogenesis of autoimmunity.

Maternal cells have recently been found in the circulation and tissues of mothers' immune-competent children, including in adult life, and is referred to as maternal microchimerism (MMc). Whether MMc confers benefits during development or later in life or sometimes has adverse effects is unknown. Type 1 diabetes (T1D) is an autoimmune disease that primarily affects children and young adults. To identify and quantify MMc, we developed a panel of quantitative PCR assays targeting nontransmitted, nonshared maternal-specific HLA alleles. MMc was assayed in peripheral blood from 172 individuals, 94 with TID, 54 unaffected siblings, and 24 unrelated healthy subjects. MMc levels, expressed as the genome equivalent per 100,000 proband cells, were significantly higher in TID patients than unaffected siblings and healthy subjects. Medians and ranges, respectively, were 0.09 (0-530), 0 (0-153), and 0 (0-7.9). Differences between groups were evident irrespective of HLA genotypes. However, for patients with the TID-associated DQB1*0302-DRB1*04 haplotype, MMc was found more often when the haplotype was paternally (70%) rather than maternally transmitted (14%). In other studies, we looked for female islet [beta] cells in four male pancreases from autopsies, one from a T1D patient, employing FISH for X and Y chromosomes with concomitant CD45 and [beta] cell insulin staining. Female islet [beta] cells (presumed maternal) formed 0.39-0.96% of the total, whereas female hematopoietic cells were very rare. Thus, T1D patients have higher levels of MMc in their circulation than unaffected siblings and healthy individuals, and MMc contributes to islet [beta] cells in a mother's progeny. quantitative PCR | chimerism | autoimmunity | pancreas | HLA

Abstract Systemic juvenile idiopathic arthritis (sJIA) is a systemic inflammatory disease characterized by arthritis, spiking fever and a skin rash that is frequently complicated by macrophage activation syndrome (MAS), a life-threatening disorder. We report a 22-month-old girl with sJIA who developed severe MAS but was successfully treated with corticosteroids, cyclosporin A, and non-steroidal anti-inflammatory drugs by monitoring serum IL-18 levels. IL-18 is an extremely useful cytokine for monitoring the activity of sJIA and MAS, and serum IL-18 can be used as an indicator for the effectiveness of treatment and the decision to discontinue therapy.