Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (∼50% of these regions have multiple independent associations); these include 24 novel SLE regions (P<5 × 10−8), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE.
Oxidized low-density lipoprotein (oxLDL) interacts with beta2-glycoprotein I (beta2-GPI) via oxLDL-derived specific ligands (oxLig-1) forming complexes. The prevalence and significance of oxLDL/alpha2-GPI complexes and antibodies to oxLig-1/alpha2-GPI were evaluated in patients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). The oxLDL/beta2-GPI complex was 69% positive (above mean + 3 SD of control subjects) in 97 consecutive patients with SLE, 62% in 40 patients with SLE with secondary APS, and 60% in 50 control patients with SLE without APS. IgG anti-oxLig-1/beta2-GPI antibody was positive in 31 (32%) of 97 consecutive patients with SLE, in 26 (65%) of 40 patients with SLE with secondary APS, and in 6 (19%) of 32 control patients with SLE. Anti-oxLig-1/beta2-GPI antibodies were 93.7% specific with a positive predictive value of 90.0% for APS, better than anticardiolipin antibodies (80.0% specific, 71.4% predictive value). These results confirm that oxLDL/beta2-GPI complexes are common in SLE and suggest a possible immunogenic role in APS. In contrast, IgG anti-oxLig-1/beta2-GPI antibodies not only are associated with but also are clinically useful risk factors for APS.
Immunoregulatory cytokine interleukin-10 (IL-10) is elevated in sera from patients with systemic lupus erythematosus (SLE) correlating with disease activity. The established association of IL10 with SLE and other autoimmune diseases led us to fine map causal variant(s) and to explore underlying mechanisms. We assessed 19 tag SNPs, covering the IL10 gene cluster including IL19, IL20 and IL24, for association with SLE in 15,533 case and control subjects from four ancestries. The previously reported IL10 variant, rs3024505 located at 1 kb downstream of IL10, exhibited the strongest association signal and was confirmed for association with SLE in European American (EA) (P = 2.7×10−8, OR = 1.30), but not in non-EA ancestries. SNP imputation conducted in EA dataset identified three additional SLE-associated SNPs tagged by rs3024505 (rs3122605, rs3024493 and rs3024495 located at 9.2 kb upstream, intron 3 and 4 of IL10, respectively), and SLE-risk alleles of these SNPs were dose-dependently associated with elevated levels of IL10 mRNA in PBMCs and circulating IL-10 protein in SLE patients and controls. Using nuclear extracts of peripheral blood cells from SLE patients for electrophoretic mobility shift assays, we identified specific binding of transcription factor Elk-1 to oligodeoxynucleotides containing the risk (G) allele of rs3122605, suggesting rs3122605 as the most likely causal variant regulating IL10 expression. Elk-1 is known to be activated by phosphorylation and nuclear localization to induce transcription. Of interest, phosphorylated Elk-1 (p-Elk-1) detected only in nuclear extracts of SLE PBMCs appeared to increase with disease activity. Co-expression levels of p-Elk-1 and IL-10 were elevated in SLE T, B cells and monocytes, associated with increased disease activity in SLE B cells, and were best downregulated by ERK inhibitor. Taken together, our data suggest that preferential binding of activated Elk-1 to the IL10 rs3122605-G allele upregulates IL10 expression and confers increased risk for SLE in European Americans.
Objective To examine the role of place of residency in the expression and outcomes of SLE in a multi-ethnic Latin American cohort. Patients and Methods SLE patients (<2 years of diagnosis) from 34 centers constitute this cohort. Residency was dichotomized into rural and urban, cut-off: 10,000 inhabitants. Socio-demographic, clinical/laboratory, and mortality rates were compared between them using descriptive tests. The influence of place of residency on disease activity at diagnosis and renal disease was examined by multivariable regression analyses. Results 122 (8.6%) of 1426 patients were rural residents. Their median age (onset, diagnosis) were 23.5 and 25.5 years; 85 (69.7%) patients were Mestizos, 28 (22.9%) Caucasians and 9 (7.4%) African-Latin Americans. Rural residents were more frequently younger at diagnosis, Mestizo and uninsured; they also had fewer years of education and a lower socioeconomic status, exhibited hypertension and renal disease more frequently, and had higher levels of disease activity at diagnosis; they used methotrexate, cyclophosphamide pulses, and hemodialysis more frequently than urban patients. Disease activity over time, renal damage, overall damage and the proportion of deceased patients were comparable in both, rural and urban patients.. In multivariable analyses, rural residency was associated with high levels of disease activity at diagnosis (OR 1.65, 95% CI 1.06–2.57) and renal disease occurrence (OR 1.77, 95% CI 1.00–3.11). Conclusions Rural residency associates with Mestizo ethnicity, lower socioeconomic status, and renal disease occurrence. It also plays a role on disease activity at diagnosis and kidney involvement but not on the other end-points examined.
We aimed to evaluate the immunodiagnostic values of autoantibodies to a panel of six tumor-associated antigens (TAAs) in the detection of patients with breast cancer. This study determines whether a panel of multiple TAAs would enhance antibody detection and be a useful approach in breast cancer detection and diagnosis. The panel of multiple TAAs was composed of six TAAs including Imp1, p16, Koc, survivin, cyclin B1, and c-myc full-length recombinant proteins. Enzyme-linked immunosorbent assay (ELISA) was used to detect antibodies against these six TAAs in 49 sera from patients with breast cancer, 35 sera from patients with benign breast tumor, and 38 sera from normal individuals. Antibody frequency to any individual TAA in breast cancer was variable and ranged from 12.2 to 18.4%. With the successive addition of TAAs to a final total of six antigens, there was a stepwise increase of positive antibody reactions reaching a sensitivity of 67.3% and a specificity of 92.2% in breast cancer. Positive and negative likelihood ratios were 8.52 and 0.36, respectively, which showed that the clinical diagnostic value of a parallel assay of six TAAs was high. Positive and negative predictive values were, respectively, 91.7 and 68.6%, indicating that the parallel assay of six TAAs raised the diagnostic accuracy greatly. Agreement rate and kappa value were 78.1% and 0.57, respectively, which indicated that the observed value of this assay had a middle range of coincidence with the actual value. The data from this study further support our previous hypothesis that the detection of autoantibodies for diagnosis of a certain type of cancer can be enhanced by using a panel of several carefully selected TAAs as target antigens and a panel of multiple TAAs would be a useful approach in the detection and diagnosis of breast cancer.
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