Pervasive Sharing of Causal Genetic Risk Factors Contributes to Clinical and Molecular Overlap between Sjögren's Disease and Systemic Lupus Erythematosus.

SjD (Sjögren's Disease) and SLE (Systemic Lupus Erythematosus) are similar diseases. There is extensive overlap between the two in terms of both clinical features and pathobiologic mechanisms. Shared genetic risk is a potential explanation of this overlap.

Modeling of horizontal pleiotropy identifies possible causal gene expression in systemic lupus erythematosus.

Background: Systemic lupus erythematosus (SLE) is a chronic autoimmune condition with complex causes involving genetic and environmental factors. While genome-wide association studies (GWASs) have identified genetic loci associated with SLE, the functional genomic elements responsible for disease development remain largely unknown. Mendelian Randomization (MR) is an instrumental variable approach to causal inference based on data from observational studies, where genetic variants are employed as instrumental variables (IVs).

Comparative analysis of the repertoire of insulin-reactive B cells in type 1 diabetes-prone and resistant mice.

Seropositivity for autoantibodies against multiple islet antigens is associated with development of autoimmune type 1 diabetes (T1D), suggesting a role for B cells in disease. The importance of B cells in T1D is indicated by the effectiveness of B cell-therapies in mouse models and patients. B cells contribute to T1D by presenting islet antigens, including insulin, to diabetogenic T cells that kill pancreatic beta cells.

Polygenic autoimmune disease risk alleles impacting B cell tolerance act in concert across shared molecular networks in mouse and in humans.

Most B cells produced in the bone marrow have some level of autoreactivity. Despite efforts of central tolerance to eliminate these cells, many escape to periphery, where in healthy individuals, they are rendered functionally non-responsive to restimulation through their antigen receptor a process termed anergy. Broad repertoire autoreactivity may reflect the chances of generating autoreactivity by stochastic use of germline immunoglobulin gene segments or active mechanisms may select autoreactive cells during egress to the naïve peripheral B cell pool.

Systemic lupus erythematosus as a genetic disease.

Systemic lupus erythematosus is the prototypical systemic autoimmune disease, as it is characterized both by protean multi-organ system manifestations and by the uniform presence of pathogenic autoantibodies directed against components of the nucleus. Prior to the modern genetic era, the diverse clinical manifestations of SLE suggested to many that SLE patients were unlikely to share a common genetic risk basis. However, modern genetic studies have revealed that SLE usually arises when an environmental exposure occurs in an individual with a collection of genetic risk variants passing a liability threshold.

SLE non-coding genetic risk variant determines the epigenetic dysfunction of an immune cell specific enhancer that controls disease-critical microRNA expression.

Since most variants that impact polygenic disease phenotypes localize to non-coding genomic regions, understanding the consequences of regulatory element variants will advance understanding of human disease mechanisms. Here, we report that the systemic lupus erythematosus (SLE) risk variant rs2431697 as likely causal for SLE through disruption of a regulatory element, modulating miR-146a expression. Using epigenomic analysis, genome-editing and 3D chromatin structure analysis, we show that rs2431697 tags a cell-type dependent distal enhancer specific for miR-146a that physically interacts with the miR-146a promoter.

Inhibitory Receptor Trap: A Platform for Discovery of Inhibitory Receptors That Utilize Inositol Lipid and Phosphotyrosine Phosphatase Effectors.

Among the areas of most impactful recent progress in immunology is the discovery of inhibitory receptors and the subsequent translation of this knowledge to the clinic. Although the original and canonical member of this family is FcγRIIB, more recent studies defined PD1 as an inhibitory receptor that constrains T cell immunity to tumors. These studies led to development of "checkpoint blockade" immunotherapies (CBT) for cancers in which PD1 interactions with its ligand are blocked.

Characterization of cxorf21 Provides Molecular Insight Into Female-Bias Immune Response in SLE Pathogenesis.

Ninety percent of systemic lupus erythematosus (SLE) patients are women. X chromosome-dosage increases susceptibility to SLE and primary Sjögren's syndrome (pSS). Chromosome X open reading frame 21 escapes X-inactivation and is an SLE risk gene of previously unknown function.

GWAS and enrichment analyses of non-alcoholic fatty liver disease identify new trait-associated genes and pathways across eMERGE Network.

Background: Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver illness with a genetically heterogeneous background that can be accompanied by considerable morbidity and attendant health care costs. The pathogenesis and progression of NAFLD is complex with many unanswered questions. We conducted genome-wide association studies (GWASs) using both adult and pediatric participants from the Electronic Medical Records and Genomics (eMERGE) Network to identify novel genetic contributors to this condition.

Lysosomal pH Is Regulated in a Sex Dependent Manner in Immune Cells Expressing .

and both contain risk alleles for systemic lupus erythematosus (SLE) and Sjögren's syndrome (pSS). The former escapes X inactivation. Our group predicts specific endolysosomal-dependent immune responses are driven by the protein products of these genes, which form a complex at the endolysosomal surface.

Lupus risk variants in the PXK locus alter B-cell receptor internalization.

Genome wide association studies have identified variants in PXK that confer risk for humoral autoimmune diseases, including systemic lupus erythematosus (SLE or lupus), rheumatoid arthritis and more recently systemic sclerosis. While PXK is involved in trafficking of epidermal growth factor Receptor (EGFR) in COS-7 cells, mechanisms linking PXK to lupus pathophysiology have remained undefined. In an effort to uncover the mechanism at this locus that increases lupus-risk, we undertook a fine-mapping analysis in a large multi-ancestral study of lupus patients and controls.

The effect of inversion at 8p23 on BLK association with lupus in Caucasian population.

Unlabelled: To explore the potential influence of the polymorphic 8p23.1 inversion on known autoimmune susceptibility risk at or near BLK locus, we validated a new bioinformatics method that utilizes SNP data to enable accurate, high-throughput genotyping of the 8p23.1 inversion in a Caucasian population.

Two functional lupus-associated BLK promoter variants control cell-type- and developmental-stage-specific transcription.

Efforts to identify lupus-associated causal variants in the FAM167A/BLK locus on 8p21 are hampered by highly associated noncausal variants. In this report, we used a trans-population mapping and sequencing strategy to identify a common variant (rs922483) in the proximal BLK promoter and a tri-allelic variant (rs1382568) in the upstream alternative BLK promoter as putative causal variants for association with systemic lupus erythematosus. The risk allele (T) at rs922483 reduced proximal promoter activity and modulated alternative promoter usage.

Prolidase deficiency breaks tolerance to lupus-associated antigens.

Aim: Prolidase deficiency is a rare autosomal recessive disease in which one of the last steps of collagen metabolism, cleavage of proline-containing dipeptides, is impaired. Only about 93 patients have been reported with about 10% also having systemic lupus erythematosus (SLE).

Methods: We studied a large extended Amish pedigree with four prolidase deficiency patients and three heterozygous individuals for lupus-associated autoimmunity.

Differential colonization with segmented filamentous bacteria and Lactobacillus murinus do not drive divergent development of diet-induced obesity in C57BL/6 mice.

Alterations in the gut microbiota have been proposed to modify the development and maintenance of obesity and its sequelae. Definition of underlying mechanisms has lagged, although the ability of commensal gut microbes to drive pathways involved in inflammation and metabolism has generated compelling, testable hypotheses. We studied C57BL/6 mice from two vendors that differ in their obesogenic response and in their colonization by specific members of the gut microbiota having well-described roles in regulating gut immune responses.

Evaluation of TRAF6 in a large multiancestral lupus cohort.

Objective: Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with significant immune system aberrations resulting from complex heritable genetics as well as environmental factors. We undertook to study the role of TRAF6 as a candidate gene for SLE, since it plays a major role in several signaling pathways that are important for immunity and organ development.

Methods: Fifteen single-nucleotide polymorphisms (SNPs) across TRAF6 were evaluated in 7,490 SLE patients and 6,780 control subjects from different ancestries.

Obesity and the gut microbiome: Striving for causality.

The gut microbiome has been proposed to play a causal role in obesity. Here, we review the historical context for this hypothesis, highlight recent key findings, and critically discuss issues central to further progress in the field, including the central epistemological problem for the field: how to define causality in the relationship between microbiota and obesity phenotypes. Definition of such will be critical for the field to move forward.

Identification of ATPAF1 as a novel candidate gene for asthma in children.

Background: Asthma is a common disease of children with a complex genetic origin. Understanding the genetic basis of asthma susceptibility will allow disease prediction and risk stratification.

Objective: We sought to identify asthma susceptibility genes in children.

The role of genetic variation near interferon-kappa in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by increased type I interferons (IFNs) and multiorgan inflammation frequently targeting the skin. IFN-kappa is a type I IFN expressed in skin. A pooled genome-wide scan implicated the IFNK locus in SLE susceptibility.

MDM2 polymorphism increases susceptibility to childhood acute myeloid leukemia: a report from the Children's Oncology Group.

Background: The variant polymorphism in the gene MDM2, SNP309, leads to increased level of mdm2 protein and subsequent downregulation of p53 tumor suppressor pathway. Presence of this single nucleotide polymorphism (SNP) has been associated with earlier tumorigenesis in patients with Li-Fraumeni syndrome, as well as decreased survival in patients with CLL. In addition, cells homozygous (G/G) for SNP 309 were found to have 10-fold increase resistance to topoisomerase II inhibitors in vitro.

Genetic susceptibility to SLE: new insights from fine mapping and genome-wide association studies.

Genome-wide association studies and fine mapping of candidate regions have rapidly advanced our understanding of the genetic basis of systemic lupus erythematosus (SLE). More than 20 robust associations have now been identified and confirmed, providing insights at the molecular level that refine our understanding of the involvement of host immune response processes. In addition, genes with unknown roles in SLE pathophysiology have been identified.

Identification of IFRD1 as a modifier gene for cystic fibrosis lung disease.

Lung disease is the major cause of morbidity and mortality in cystic fibrosis, an autosomal recessive disease caused by mutations in CFTR. In cystic fibrosis, chronic infection and dysregulated neutrophilic inflammation lead to progressive airway destruction. The severity of cystic fibrosis lung disease has considerable heritability, independent of CFTR genotype.