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1.  Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci 
Nature genetics  2008;40(2):204-210.
Systemic lupus erythematosus (SLE) is a common systemic autoimmune disease with complex etiology but strong clustering in families (λS = ~30). We performed a genome-wide association scan using 317,501 SNPs in 720 women of European ancestry with SLE and in 2,337 controls, and we genotyped consistently associated SNPs in two additional independent sample sets totaling 1,846 affected women and 1,825 controls. Aside from the expected strong association between SLE and the HLA region on chromosome 6p21 and the previously confirmed non-HLA locus IRF5 on chromosome 7q32, we found evidence of association with replication (1.1 × 10−7 < Poverall < 1.6 × 10−23; odds ratio 0.82–1.62)in four regions: 16p11.2 (ITGAM), 11p15.5 (KIAA1542), 3p14.3 (PXK) and 1q25.1 (rs10798269). We also found evidence for association (P < 1 × 10−5) at FCGR2A, PTPN22 and STAT4, regions previously associated with SLE and other autoimmune diseases, as well as at ≥9 other loci (P < 2 × 10−7). Our results show that numerous genes, some with known immune-related functions, predispose to SLE.
doi:10.1038/ng.81
PMCID: PMC3712260  PMID: 18204446
2.  Immune opsonins modulate BLyS/BAFF release in a receptor-specific fashion* 
TNF ligand superfamily member 13B (B-lymphocyte stimulator (BLyS), B cell activating factor (BAFF)) promotes primary B cell proliferation and immunoglobulin production. While the soluble form of BLyS/BAFF is thought to be the primary biologically active form, little is known about the regulation of its cleavage and processing. We provide evidence that Fcγ receptor cross-linking triggers a rapid release of soluble, biologically active BLyS/BAFF from myeloid cells. Surprisingly, this function is primarily mediated by FcγRI, but not FcγRIIa as defined by specific mAb, and can be initiated by both IgG and C reactive protein (CRP) as ligands. The generation of a B cell proliferation and survival factor by both innate and adaptive immune opsonins through engagement of an Fcγ receptor, which can also enhance antigen uptake and presentation, provides a unique opportunity to facilitate antibody production. These results provide a mechanism by which Fcγ receptors can elevate circulating BLyS levels and promote autoantibody production in immune complex mediated autoimmune diseases.
PMCID: PMC3684394  PMID: 18606652
Fc Receptors; Monocytes/Macrophages; Human; Autoimmunity
3.  TIME to SEIZURE OCCURRENCE and DAMAGE in PROFILE, a MULTIETHNIC SLE COHORT 
Lupus  2008;17(3):177-184.
SUMMARY
The objective of this study was to determine risk factors predicting seizures and damage due to seizures in a multi-ethnic systemic lupus erythematosus (SLE) cohort (PROFILE) which includes SLE patients (n=1295) from five different US institutions. Only patients with seizures after SLE diagnosis (incident) were included in the analyses of clinical seizures, 80/1295, 6.2%; but all patients (prevalent and incident) in the analyses of damage due to seizures 51/1295, 3.9%. We examined socioeconomic-demographic, clinical and genetic variables predictive of clinical seizures and damage from seizures by Cox Proportional Hazard Ratios (HR) and 95% Confidence Intervals (CI). Independent predictors of a shorter time to occurrence of clinical seizures were younger age (HR=1.0; 95% CI 0.9–1.0), having Hispanic-Texan ethnicity (HR=2.7; 95% CI 1.3–5.7) or African-American ethnicity (HR=1.8; 95% CI 1.0–3.1, and the prior occurrence of a cerebrovascular accident [CVA] (HR=3.3; 95% CI 1.6–7.1) or an episode of psychosis (HR=2.4; 95% CI 1.1–5.0), while the prior occurrence of photosensitivity (HR=0.5; 95% CI 0.3–0.9).was the only independent predictor of a longer time to the clinical occurrence of seizures Independent predictors of a shorter time to occurrence of damage due to seizures were younger age (HR=1.0 95% CI 0.9–1.0), male gender (HR=2.4; 95% CI 1.1–5.4), and the occurrence of a prior CVA (HR=2.7; 95% CI 1.0–7.0 or an episode of psychosis (HR=4.7; 95% CI 2.3–9.9). No allele from the candidate genes examined (HLA-DRB1, HLA-DQB1, FCGR2A, FCGR3A, or FCG3B) predicted clinical seizures or damage due to seizures.
doi:10.1177/0961203307086639
PMCID: PMC2787620  PMID: 18372357
4.  Features Associated With, and the Impact of, Hemolytic Anemia in Patients With Systemic Lupus Erythematosus: LX, Results From a Multiethnic Cohort 
Arthritis and rheumatism  2008;59(9):1332-1340.
Objective
To examine the clinical and genetic correlates of hemolytic anemia and its impact on damage accrual and mortality in systemic lupus erythematosus (SLE) patients.
Methods
SLE patients (American College of Rheumatology [ACR] criteria) of Hispanic (Texan or Puerto Rican), African American, and Caucasian ethnicity from the LUMINA (LUpus in MInorities, NAture versus nurture) cohort were studied. Hemolytic anemia was defined as anemia with reticulocytosis (ACR criterion). The association between degrees of hemolytic anemia and socioeconomic/demographic, clinical, pharmacologic, immunologic, psychological, and behavioral variables was examined by univariable and multivariable (proportional odds model) analyses. Genetic variables (FCGR and Fas/Fas ligand polymorphisms) were examined by 2 degrees of freedom test of association and Cochran-Armitage trend tests. The impact of hemolytic anemia on damage accrual and mortality was examined by multivariable linear and Cox regression analyses, respectively.
Results
Of 628 patients studied, 90% were women, 19% were Texan Hispanic, 16% were Puerto Rican Hispanic, 37% were African American, and 28% were Caucasian. Sixty-five (10%) patients developed hemolytic anemia at some time during the disease course, 83% at or before diagnosis. Variables independently associated with degrees of hemolytic anemia were African American ethnicity, thrombocytopenia, and the use of azathioprine. Hemolytic anemia was associated with damage accrual after adjusting for variables known to affect this outcome; however, hemolytic anemia was not associated with mortality.
Conclusion
The association of hemolytic anemia with thrombocytopenia suggests a common mechanism in their pathophysiology. Hemolytic anemia is an early disease manifestation and is associated with African American ethnicity and the use of azathioprine; it appears to exert an impact on damage but not on mortality.
doi:10.1002/art.24020
PMCID: PMC2760833  PMID: 18759263
5.  IgA1-secreting cell lines from patients with IgA nephropathy produce aberrantly glycosylated IgA1 
Aberrant glycosylation of IgA1 plays an essential role in the pathogenesis of IgA nephropathy. This abnormality is manifested by a deficiency of galactose in the hinge-region O-linked glycans of IgA1. Biosynthesis of these glycans occurs in a stepwise fashion beginning with the addition of N-acetylgalactosamine by the enzyme N-acetylgalactosaminyltransferase 2 and continuing with the addition of either galactose by β1,3-galactosyltransferase or a terminal sialic acid by a N-acetylgalactosamine–specific α2,6-sialyltransferase. To identify the molecular basis for the aberrant IgA glycosylation, we established EBV-immortalized IgA1-producing cells from peripheral blood cells of patients with IgA nephropathy. The secreted IgA1 was mostly polymeric and had galactose-deficient O-linked glycans, characterized by a terminal or sialylated N-acetylgalactosamine. As controls, we showed that EBV-immortalized cells from patients with lupus nephritis and healthy individuals did not produce IgA with the defective galactosylation pattern. Analysis of the biosynthetic pathways in cloned EBV-immortalized cells from patients with IgA nephropathy indicated a decrease in β1,3-galactosyltransferase activity and an increase in N-acetylgalactosamine–specific α2,6-sialyltransferase activity. Also, expression of β1,3-galactosyltransferase was significantly lower, and that of N-acetylgalactosamine–specific α2,6-sialyltransferase was significantly higher than the expression of these genes in the control cells. Thus, our data suggest that premature sialylation likely contributes to the aberrant IgA1 glycosylation in IgA nephropathy and may represent a new therapeutic target.
doi:10.1172/JCI33189
PMCID: PMC2157566  PMID: 18172551

Results 1-5 (5)