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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.

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.

Non‐White people are more likely to develop systemic lupus erythematosus (SLE) yet are underrepresented in SLE clinical trials. The efficacy and safety of drugs may be influenced by ancestry, and ancestrally diverse study populations are necessary to optimize treatments across the full spectrum of patients. However, barriers to entry into clinical trials are amplified in non‐White populations. To address these issues, a conference was held in Bethesda, Maryland, from October 15–16, 2019, entitled "Increasing Ancestral Diversity in Systemic Lupus Erythematosus Clinical Studies: Overcoming the Barriers." Conference participants included people with lupus, lupus physicians, lupus clinical trialists, treatment developers from biotechnology, social scientists, patient advocacy groups, and US government representatives (The Office of Minority Health, Centers for Disease Control and Prevention, National Institutes of Health, and the Food and Drug Administration). For all these groups, the organizers of the conference purposefully included people of non‐White ancestry. Decreased participation of non‐White SLE patients in clinical research was evaluated through historical, societal, experiential, and pragmatic perspectives, and several interventional programs to increase non‐White patient participation in SLE and non‐SLE research were described and discussed. The presentations and discussions highlighted the need for changes at the societal, institutional, research team, referring physician, and patient education levels to achieve equitable ancestral representation in SLE clinical studies. [ABSTRACT FROM AUTHOR]

In our recent case report, the finding of lupus erythematosus (LE) cells in a bone marrow aspirate led to the diagnosis of systemic lupus erythematosus (SLE) and appropriate treatment, although the patient was not clinically suspected to have SLE. To determine whether LE cells are present in the bone marrow aspirates of SLE patients, but overlooked in routine bone marrow morphology review, bone marrow aspirates from 30 pediatric patients (15 with SLE and 15 with other diagnoses) evaluated by rheumatologists were reviewed. LE cells were found in the bone marrow aspirates of only 1 SLE patient and none in non-SLE patients. However, hematoxylin bodies were identified in 53% (8/15) of SLE patients. Neither hematoxylin bodies nor LE cells were found in the aspirates from patients with other disorders. Three additional pediatric patients identified prospectively were found to have hematoxylin bodies in the bone marrow aspirates. Although the diagnosis was not initially suspected, 2 of the 3 patients were subsequently diagnosed with SLE. All patients with hematoxylin bodies and SLE had antinuclear antibody titers ≥1:640 with a homogeneous staining pattern. In addition, bone marrow aspirates of 9 adult patients were reviewed, and neither LE cells nor hematoxylin bodies were identified. In summary, hematoxylin bodies were present in the bone marrow aspirates of many pediatric SLE patients, while LE cells were rare. The finding of hematoxylin bodies in pediatric bone marrow aspirates is a helpful and specific diagnostic clue that may lead to the diagnosis of SLE when other clinical features are nonspecific. [ABSTRACT FROM AUTHOR]

Objective Systemic 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. Methods Fifteen 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. Results Evidence 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 (r2 = 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. Conclusion Our 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. [ABSTRACT FROM AUTHOR]

Objective Several confirmed genetic susceptibility loci for lupus have been described. To date, no clear evidence for genetic epistasis in lupus has been established. The aim of this study was to test for gene-gene interactions in a number of known lupus susceptibility loci. Methods Eighteen single-nucleotide polymorphisms tagging independent and confirmed lupus susceptibility loci were genotyped in a set of 4,248 patients with lupus and 3,818 normal healthy control subjects of European descent. Epistasis was tested by a 2-step approach using both parametric and nonparametric methods. The false discovery rate (FDR) method was used to correct for multiple testing. Results We detected and confirmed gene-gene interactions between the HLA region and CTLA4, IRF5, and ITGAM and between PDCD1 and IL21 in patients with lupus. The most significant interaction detected by parametric analysis was between rs3131379 in the HLA region and rs231775 in CTLA4 (interaction odds ratio 1.19, Z = 3.95, P = 7.8 × 10−5 [FDR ≤0.05], P for multifactor dimensionality reduction = 5.9 × 10−45). Importantly, our data suggest that in patients with lupus, the presence of the HLA lupus risk alleles in rs1270942 and rs3131379 increases the odds of also carrying the lupus risk allele in IRF5 (rs2070197) by 17% and 16%, respectively ( P = 0.0028 and P = 0.0047, respectively). Conclusion We provide evidence for gene-gene epistasis in systemic lupus erythematosus. These findings support a role for genetic interaction contributing to the complexity of lupus heritability. [ABSTRACT FROM AUTHOR]

Background During pregnancy, maternal cells pass into the fetus, where they can persist for many years after birth. We investigated the presence of maternal cells in neonatal lupus syndrome (NLS), an autoimmune disease that develops in utero. The most serious complication of NLS is inflammation of the atrioventricular node leading to congenital heart block CHB). Methods In a blinded case-control study, maternal (female) cells were detected and quantified in male NLS and control heart-tissue samples. We used fluorescence in-situ hybridisation to label X and Y chromosomes. Studies in transplantation suggest that donor cells can differentiate into somatic tissue cells. Therefore, we asked whether maternal cells transferred in utero have cellular plasticity. To simultaneously identify and characterise maternal cells, we developed a technique by which multiple phenotypic markers could be detected concurrently with fluorescence in-situ hybridisation in the same cells of a tissue section. Findings Maternal cells were found in 15 of 15 sections of NLS heart tissue, ranging from 0.025% to 2.2% of total cells. By contrast, maternal cells were found in two of eight control sections (0--0.1%). Very few maternal cells expressed the haemopoietic cell marker CD45. Most expressed sarcomeric actin, a specific marker for cardiac myocytes. Interpretation Our findings suggest that differentiated tissuespecific maternal microchimerism can occur in neonates. Thus, semiallogeneic maternal cells could be the target of an immune response. Alternatively, maternal cells could contribute to a secondary process of tissue repair. [ABSTRACT FROM AUTHOR]

Background. Persistent circulating microchimerism with allogeneic cells can be derived from transplanted solid organs, blood transfusions, or maternal-fetal exchange. Male microchimerism has been detected in women with SLE who have given birth to sons, but also in nulligravid women with putative sources including unrecognized pregnancy or a vanished twin. We hypothesized that male microchimerism in pre-pubescent girls may be attributed to older siblings. Methods. Peripheral blood mononuclear cells from 81 pediatric SLE patients and 34 age-matched controls were assayed for microchimerism by Real-Time QPCR amplification of the Y-chromosome derived DYS14 and HLA and GST sequences. As autoimmune comparison groups, 40 children with scleroderma and 29 with juvenile idiopathic arthritis (JIA) were studied. Male cells were detected in tissue by fluorescence in situ hybridization for Y-chromosome sequences. Disease activity was measured by the SLE Disease Activity Index. Results. Male microchimerism was detected with increased frequency in SLE, (34% of SLE patients compared with 11.8% of healthy controls p = 0.02). The mean levels of DNA were not significantly higher (32 genome equivalents per million (gEq/M) in SLE vs. 15.5 gEq/M in controls, p = 0.14). In pre-pubertal girls who could never have been pregnant, the level of male microchimerism tended to be higher in SLE, but the difference was not significant. Male DNA was detected in 40% of pre-pubertal SLE patients compared with 14.3% of controls (p = 0.15), with a mean of 35.4 gEq/M in SLE vs. 13.1 gEq/M in controls, (p = 0.2). Male cells were detected in one of seven female kidney biopsy samples assayed, derived from a 5 y-old girl with newly- diagnosed SLE. Male DNA was not elevated in children with scleroderma or JIA compared with controls. No association was found between microchimerism levels and disease activity, race, prematurity, or prior transfusion. In four of six patients with male microchimerism a non-shared GST or HLA sequence carried by an older brother was also detected. Conclusion. Girls with SLE harbor male microchimerism in the blood, and in one affected kidney. In some cases the source may be indirectly from an older brother through the mother. Loss of tolerance to non-shared male antigens could lead to chronic activation of host T lymphocytes, with subsequent autoimmunity through a mechanism of epitope spreading, similar to the graft-vs.-host disease seen after stem cell transplantation. [ABSTRACT FROM AUTHOR]