Abstract
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of complex etiology that primarily affects women of childbearing age. The development of SLE is attributed to the breach of immunological tolerance and the interaction between SLE-susceptibility genes and various environmental factors, resulting in the production of pathogenic autoantibodies. Working in concert with the innate and adaptive arms of the immune system, lupus-related autoantibodies mediate immune-complex deposition in various tissues and organs, leading to acute and chronic inflammation and consequent end-organ damage. Over the past two decades or so, the impact of genetic susceptibility on the development of SLE has been well demonstrated in a number of large-scale genetic association studies which have uncovered a large fraction of genetic heritability of SLE by recognizing about a hundred SLE-susceptibility loci. Integration of genetic variant data with various omics data such as transcriptomic and epigenomic data potentially provides a unique opportunity to further understand the roles of SLE risk variants in regulating the molecular phenotypes by various disease-relevant cell types and in shaping the immune systems with high inter-individual variances in disease susceptibility. In this review, the catalogue of SLE susceptibility loci will be updated, and biological signatures implicated by the SLE-risk variants will be critically discussed. It is optimistically hoped that identification of SLE risk variants will enable the prognostic and therapeutic biomarker armamentarium of SLE to be strengthened, a major leap towards precision medicine in the management of the condition.
Highlights
High quality data which demonstrated that lupus patients who are pregnant or on hormonal replacement therapy experience more frequent disease flares further strengthen the relationship between female sex hormones and the pathogenesis of Systemic lupus erythematosus (SLE) [8,9,10]
While these studies on interferon-inducible genes (IFNIG) highlight the substantial involvement of genetic polymorphism in SLE susceptibility and resultant differences of clinical manifestations in SLE patients of different ancestral backgrounds, it offers a unique opportunity to materialize more personalized treatment in such a clinically heterogeneous disease
Through a powerful hypothesis-free approach to scanning susceptibility loci of common complex traits with genome-wide association studies (GWAS), around 100 lupus-susceptibility loci have been identified in large scale cohorts, which further improves our understanding of the genetic architecture of SLE
Summary
Systemic lupus erythematosus (SLE) is a highly complex and heterogeneous autoimmune condition that mainly affects women in their reproductive years [1,2]. Despite our partial understanding of the clinical and immunological behavior of the disease, the onset of SLE is postulated to be triggered by environmental and hormonal factors in genetically susceptible individuals [5,6]. Transgenic male mice overexpressing the genes on the X chromosome were endowed with an increased susceptibility to develop lupus-like manifestations when they were treated with pristane [14]. Such observations highlight the importance of CD40 in the pathogenesis of SLE at the genetic rather than the protein level since the overexpressed CD40L gene is X-linked
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