Objective Systemic 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 more than 30 SLE susceptibility genes. One of these genes, TNIP1, encodes the ABIN1 protein. ABIN1 functions in the immune system by restricting the NF-κB signaling. In order to better understand the genetic factors that influence association with SLE in genes that regulate the NF-κB pathway, we analyzed a dense set of genetic markers spanning TNIP1 and TAX1BP1, as well as the TNIP1 homolog, TNIP2, in case-control sets of diverse ethnic origins. Methods We fine-mapped TNIP1, TNIP2, and TAX1BP1 in a total of 8372 SLE cases and 7492 healthy controls from European-ancestry, African-American, Hispanic, East Asian, and African-American Gullah populations. Levels of TNIP1 mRNA and ABIN1 protein were analyzed using quantitative RT-PCR and Western blotting, respectively, in EBV-transformed human B cell lines. Results We found significant associations between genetic variants within TNIP1 and SLE but not in TNIP2 or TAX1BP1. After resequencing and imputation, we identified two independent risk haplotypes within TNIP1 in individuals of European-ancestry that were also present in African-American and Hispanic populations. These risk haplotypes produced lower levels of TNIP1 mRNA and ABIN1 protein suggesting they harbor hypomorphic functional variants that influence susceptibility to SLE by restricting ABIN1 expression. Conclusion Our results confirmed 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.

MetS may contribute to the development of accelerated atherosclerosis in SLE.

Objective. To assess the hypothesis that B27 or a gene(s) in close proximity (e.g., within or near the major histocompatibility complex [MHC]) represents a diseasecausing ankylosing spondylitis (AS) gene, and therefore contributes directly to the pathogenesis of this disorder.Methods. MHC haplotypes were determined by both serologic and molecular analyses in 15 multiplecase AS families from Toronto and Newfoundland. Segregation of MHC haplotypes with AS within these families was examined by linkage and identity-bydescent analyses. Submitted for publication October 4, 1993; accepted in revised form February 27, 1994. linkage between AS and the MHC, the maximal logarithm of odds (LOD) score being 3.48 at a recombination frequency (0) of 0.05. In a second analysis in which the population association of the MHC gene HLA-B27 with AS was taken into account, the maximal LOD score was 7.5 at 0 = 0.05. Identity-by-descent analyses showed a significant departure from random segregation among affected avuncular (P < 0.05) and cousin (P < 0.01) pairs. The presence of HLA-B40 in HLA-B27 positive individuals increased the risk for disease more than 3-fold, confirming previous reports. Disease susceptibility modeling suggested an autosomal dominant pattern of inheritance, with penetrance of approximately 20%.Conclusion. These data provide the first conclusive demonstration of linkage between the MHC region and AS, and confirm that genes within this region contribute directly to the genetic susceptibility for AS.

Objective. To determine the potential role of the CD24 A57V gene polymorphism in systemic lupus erythematosus (SLE).Methods. We studied 3 cohorts of Caucasian patients and controls. The Spanish cohort included 696 SLE patients and 539 controls, the German cohort included 257 SLE patients and 317 controls, and the Swedish cohort included 310 SLE patients and 247 controls. The CD24 A57V polymorphism was genotyped by polymerase chain reaction, using a predeveloped TaqMan allele discrimination assay. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated.Results. In the Spanish cohort there was a statistically significant difference in the distribution of the CD24 V allele between SLE patients and controls (OR 3.6 [95% CI 2.13-6.16], P < 0.0001). In addition, frequency of the CD24 V/V genotype was increased in SLE patients compared with controls (OR 3.7 [95% CI 2.16-6.34], P < 0.00001). We sought to replicate this association with SLE in a German population and a Swedish population. A similar trend was found in the German group. The CD24 V/V genotype and the CD24 V allele were more frequent in SLE patients than in controls, although this difference was not statistically significant. No differences were observed in the Swedish group. A meta-analysis of the Spanish and German cohorts demonstrated that the CD24 V allele has a risk effect in SLE patients (pooled OR 1.25 [95% CI 1.08-1.46], P ‫؍‬ 0.003). In addition, homozygosity for the CD24 V risk allele significantly increased the effect (pooled OR 2.19 [95% CI 1.50-3.22], P ‫؍‬ 0.00007).Conclusion. These findings suggest that the CD24 A57V polymorphism plays a role in susceptibility to SLE in a Spanish population.Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease with a complex pathogenesis involving multiple genetic and environmental factors. The disease is characterized by enhanced autoantibody production, abnormalities of immune/inflammatory system function, and inflammation in several organs. Al-

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.