Decreased SMG7 expression associates with lupus-risk variants and elevated antinuclear antibody production.

Objectives: Following up the systemic lupus erythematosus (SLE) genome-wide association studies (GWAS) identification of NMNAT2 at rs2022013, we fine-mapped its 150 kb flanking regions containing NMNAT2 and SMG7 in a 15 292 case-control multi-ancestry population and tested functions of identified variants.

Methods: We performed genotyping using custom array, imputation by IMPUTE 2.1.

Evidence of dynamically dysregulated gene expression pathways in hyperresponsive B cells from African American lupus patients.

Recent application of gene expression profiling to the immune system has shown a great potential for characterization of complex regulatory processes. It is becoming increasingly important to characterize functional systems through multigene interactions to provide valuable insights into differences between healthy controls and autoimmune patients. Here we apply an original systematic approach to the analysis of changes in regulatory gene interconnections between in Epstein-Barr virus transformed hyperresponsive B cells from SLE patients and normal control B cells.

Excess female siblings and male fetal loss in families with systemic lupus erythematosus.

Objective: Systemic lupus erythematosus (SLE) occurs more frequently among women than men. We aimed to determine whether the male-female ratio in SLE families is different from what would be expected by chance, and whether excess male fetal loss is found.

Methods: All patients with SLE met the revised American College of Rheumatology classification criteria, while unaffected subjects were shown not to satisfy these same criteria.

Juvenile spondyloarthropathies.

Spondyloarthropathy (or spondyloarthritis) can begin in childhood (defined as individuals less than 16 years of age). These diseases are distinct in childhood, when compared with adult-onset disease. Because of overlapping features, especially sacroiliac joint involvement, diagnostic difficulty may arise from Behcet's disease, as well as familial Mediterranean fever.

The genetics of systemic lupus erythematosus and implications for targeted therapy.

Observations of familial aggregation (λs=8-29) and a 40% identical twin concordance rate prompted recent work towards a comprehensive genetic analysis of systemic lupus erythematosus (SLE). Since 2007, the number of genetic effects known to be associated with human lupus has increased by fivefold, underscoring the complexity of inheritance that probably contributes to this disease. Approximately 35 genes associated with lupus have either been replicated in multiple samples or are near the threshold for genome-wide significance (p > 5 x 10⁻⁸).

Interferon-gamma gene polymorphisms associated with susceptibility to systemic lupus erythematosus.

Objective: Interferon-gamma (IFNG) is a type II interferon playing diverse roles in innate and adaptive immune systems. Elevated expression of IFNG has been associated with systemic lupus erythematosus (SLE). This study examined the association of IFNG polymorphisms with SLE susceptibility.

A polymorphism within IL21R confers risk for systemic lupus erythematosus.

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.

Osteopontin and systemic lupus erythematosus association: a probable gene-gender interaction.

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).

Current status of lupus genetics.

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, Fcgamma 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.

Localization and replication of the systemic lupus erythematosus linkage signal at 4p16: interaction with 2p11, 12q24 and 19q13 in European Americans.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by both population and phenotypic heterogeneity. Our group previously identified linkage to SLE at 4p16 in European Americans (EA). In the present study we replicate this linkage effect in a new cohort of 76 EA families multiplex for SLE by model-free linkage analysis.

The mannose-binding lectin gene polymorphisms and systemic lupus erythematosus: two case-control studies and a meta-analysis.

Objective: Mannose-binding lectin (MBL) enhances opsonization and activates complement. Dysfunctional alleles of MBL have been associated with low plasma concentrations of MBL and increased risk of systemic lupus erythematosus (SLE), but genotyping studies have shown inconsistent results. We performed case-control studies of the MBL polymorphisms in 2 Caucasian cohorts and a meta-analysis incorporating all published results of MBL genotyping in SLE to explore whether the MBL functional variants are associated with SLE.

Genetics of systemic lupus erythematosus: how far have we come?

There are two primary mechanisms for studying the genetic forces at work in systemic lupus erythematosus (SLE). Several groups have collected large numbers of pedigrees in which multiple family members have SLE for use in linkage studies. These linkage studies serve to isolate areas of the genome in which susceptibility genes lie.