Recent advances in the genetics of systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the production of antinuclear autoantibodies and the inflammatory infiltration of many organ systems. SLE is a complex disorder in which multiple genetic variants, together with environmental and hormonal factors, contribute to disease risk. In this article, we summarize our current understanding of the genetic contribution to SLE in light of recent genome-wide association studies, which have brought the total number of confirmed SLE susceptibility loci to 29. In the second section, we explore the functional implications of these risk loci and, in particular, highlight the role that many of these genes play in the Toll-like receptor and type I interferon signaling pathways. Finally, we discuss the genetic overlap between SLE and other autoimmune and inflammatory conditions as several risk loci are shared among multiple disorders, suggesting common underlying pathogenic mechanisms. Keywordsgenome-wide association studies; pathogenesis; systemic lupus erythematosus; Toll-like receptor signaling; type I interferon signaling Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease that predominantly affects women of childbearing age. The incidence of SLE in the general US population is approximately one in 2000, with a nine-to-one female gender bias and a two-tofourfold greater prevalence in non-Caucasian compared with Caucasian populations [1]. In SLE, the tissue deposition of autoantibodies and immune complexes (ICs) leads to destructive inflammation in many organ systems, including the skin, blood elements, joints, kidneys, serosa, CNS and other tissues. The clinical manifestations of SLE are diverse, with renal inflammation (glomerulonephritis) being the most common cause of morbidity and mortality. A hallmark of SLE is the production of autoantibodies directed against intracellular antigens, many of which are associated with the nucleic acids DNA or RNA [2]. The cellular and

MicroRNAs in lupus

“…Although studies investigating common genetic variants in lupus have revealed a number of susceptibility loci, the cumulative effect size of these loci accounts for a small fraction of disease heritability (8). Epigenetic dysregulation likely compounds genetic susceptibility (9) in the generation of autoantibodies and disease (10–14), evidenced by low lupus penetrance (25–45%) in monozygotic twins (15), alterations of histone modifications and DNA methylation in lupus patients, and autoimmunity in mice with miRNA dysregulation (16–20). …”

Overexpression of Fkbp11, a feature of lupus B cells, leads to B cell tolerance breakdown and initiates plasma cell differentiation

“…GWAS of SLE patients have identified more than 30 genetic polymorphisms that are associated with SLE, but the combination of these variants differs from patient to patient. These SLE susceptibility genes could affect different steps of SLE development including B cell tolerance breakdown leading to autoantibody production (e.g., PTPN22, BANK1, BLK, LYN ), defective clearance of immune complexes and apoptotic debris (e.g., ITGAM, Fc gamma R, Complement ), T cell activation (e.g., PTPN22, CTLA4 ) or organ damage (e.g., Complement, IRF5, TNFAIP3 ) 1,2.…”

Coping and Quality of Life in Patients with Systemic Lupus Erythematosus: A Review

“…The cellular and molecular mechanisms governing inflammation in sle remain uncertain (Flesher, Sun, Behrens, Graham, & Criswell, 2010). However, genetic, environmental and hormonal factors are hypothesized to play a key role in prevalence, disease severity and course in different patients (Squatrito et al, 2014;Flesher et al, 2010).…”

“…However, genetic, environmental and hormonal factors are hypothesized to play a key role in prevalence, disease severity and course in different patients (Squatrito et al, 2014;Flesher et al, 2010).…”