No abstract

No abstract

Osteopontin (SPP1) is an important bone matrix mediator found to have key roles in inflammation and immunity. SPP1 genetic polymorphisms and increased osteopontin protein levels have been reported to be associated with SLE in small patient collections. The present study evaluates association between SPP1 polymorphisms and SLE in a large cohort of 1141 unrelated SLE patients [707 European-American (EA) and 434 African-American (AA)], and 2009 unrelated controls (1309 EA and 700 AA). Population-based case-control association analyses were performed. To control for potential population stratification, admixture adjusted logistic regression, genomic control (GC), structured association (STRAT), and principal components analysis (PCA) were applied. Combined analysis of 2 ethnic groups, showed the minor allele of 2 SNPs (rs1126616T and rs9138C) significantly associated with higher risk of SLE in males (P = 0.0005, OR = 1.73, 95% CI = 1.28–2.33), but not in females. Indeed, significant gene-gender interactions in the 2 SNPs, rs1126772 and rs9138, were detected (P = 0.001 and P = 0.0006, respectively). Further, haplotype analysis identified rs1126616T-rs1126772A-rs9138C which demonstrated significant association with SLE in general (P = 0.02, OR = 1.30, 95%CI 1.08–1.57), especially in males (P = 0.0003, OR = 2.42, 95%CI 1.51–3.89). Subgroup analysis with single SNPs and haplotypes also identified a similar pattern of gender-specific association in AA and EA. GC, STRAT, and PCA results within each group showed consistent associations. Our data suggest SPP1 is associated with SLE, and this association is especially stronger in males. To our knowledge, this report serves as the first association of a specific autosomal gene with human male lupus.

Objective. Interleukin-21 (IL-21) is a member of the type I cytokine superfamily that has a variety of effects on the immune system, including B cell activation, plasma cell differentiation, and immunoglobulin production. The expression of IL-21 receptor (IL-21R) is reduced in the B cells of patients with systemic lupus erythematosus (SLE), while serum IL-21 levels are increased both in lupus patients and in some murine lupus models. We recently reported that polymorphisms within the IL21 gene are associated with increased susceptibility to SLE. The aim of this study was to examine the genetic association between single-nucleotide polymorphisms (SNPs) within IL21R and SLE.Methods. We genotyped 17 SNPs in the IL21R gene in 2 large cohorts of lupus patients (a Europeanderived cohort and a Hispanic cohort) and in ethnically matched healthy controls.Results. We identified and confirmed the association between rs3093301 within the IL21R gene and SLE in the 2 cohorts (meta-analysis odds ratio 1.16 [95% confidence interval 1.08-1.25], P ‫؍‬ 1.0 ؋ 10 ؊4 ).Conclusion. Our findings indicate that IL21R is a novel susceptibility gene for SLE.

Several SNP in IFNG are associated with SLE susceptibility, and the risk allele of an associated SNP (rs2430561) located in an NF-kappaB binding site has elevated IFNG expression versus the non-risk allele, supporting that elevated IFNG expression is associated with increased SLE susceptibility.

Observations of familial aggregation (λs=8-29) and a 40% identical twin concordance rate prompted recent

Objective. Systemic lupus erythematosus (SLE) isMethods. Fifty-six single-nucleotide polymorphisms (SNPs) across STAT1 and STAT4 on chromosome 2 were genotyped using the Illumina platform, as part of an extensive association study in a large collection of 9,923 lupus patients and control subjects from different racial groups. DNA samples were obtained from the peripheral blood of patients with SLE and control subjects. Principal components analyses and population-based case-control association analyses were performed, and the P values, false discovery rate q values, and odds ratios with 95% confidence intervals were calculated.

Over the past 40 years more than 100 genetic risk factors have been defined in systemic lupus erythematosus through a combination of case studies, linkage analyses of multiplex families, and case-control analyses of single genes. Multiple investigators have examined patient cohorts gathered from around the world, and although we doubt that all of the reported associations will be replicated, we have probably already discovered many of the genes that are important in lupus pathogenesis, including those encoding human leukocyte antigen-DR, Fcγ receptor 3A, protein tyrosine phosphatase nonreceptor 22, cytotoxic T lymphocyte associated antigen 4, and mannose-binding lectin. In this review we will present what is known, what is disputed, and what remains to be discovered in the world of lupus genetics. IntroductionSystemic lupus erythematosus (SLE) has long been appreciated to arise from both genetic and environmental factors. Although environmental factors, such as the EpsteinBarr virus, are clearly important [1], this review focuses on genetic factors that are involved in SLE. Evidence for the genetic origins of the disease come from the observation of familial aggregation [2] (up to 10% of patients with SLE have another family member with the disease) and increased concordance in monozygotic twins [3]. The patterns of inheritance are complex, however, and it is generally thought that variations in a number of genes are involved, each contributing a small amount to the overall genetic risk [4]. Two major strategies have been used to search for the 'lupus genes': genome-wide screening, using multiplex families and linkage analysis; and candidate gene studies, usually performed on trios or case-control collections. With either strategy, a high threshold is necessary to establish genetic risk, and follow-up testing of an independent cohort is required to confirm the results. Genome-wide linkage studies for systemic lupus erythematosusThe genetic basis of SLE is well established, but the genetic transmission of SLE has proven to be highly complex. Consequently, gene identification has been accomplished for only a handful of genes. Genome-wide linkage scanning is a comprehensive and unbiased approach to identifying chromosomal loci that may be linked to complex diseases [5]. Testing for genome-wide linkage is fundamentally a statistical process that evaluates for co-inheritance of genetic markers (such as DNA polymorphisms) with the disease phenotype in families with multiple affected members. Consistent coinheritance of the marker with the disease in families means that they are 'linked' and indicates that the actual disease gene is in close proximity. As with other complex diseases, genome scans for SLE susceptibility genes suffer from low power to detect true-positive linkages. Causes of this include relatively small study populations in some studies and common causative alleles with low penetrance.Several different study designs have been used for genomewide scanning to identify novel susceptibility loci for...