Update on the Genetics of Systemic Lupus Erythematosus: Genome-Wide Association Studies and Beyond

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.

Keywords: SLE; epigenetics; genetics; genome; lupus.

Figure 1

Forest plot of associations of human leukocyte antigen (HLA) classical alleles with susceptibility to systemic lupus erythematosus (SLE) in four populations. A total of 45 HLA two-field classical alleles in 6 HLA genes including (A) HLA-DRB1 (13 alleles), (B) HLA-DQB1 (9 alleles), (C) HLA-DQA1 (11 alleles) and (D) HLA class I genes (2 HLA-A alleles, 6 HLA-B alleles and 4 HLA-C alleles) have been associated with risk of SLE at the association significance threshold p < 5.0 × 10^–6 in at least one of four populations including European, East Asian, Hispanic and African ancestry [79,95]. The circles and error bars represent odds ratios and 95% confidence intervals, respectively. Circle sizes are proportional to allele frequencies in patients with SLE in European (orange), East Asian (green), Hispanic (blue), and African-American (purple) population. EUR: European ancestry; EAS: East Asian ancestry; HIS: Hispanic ancestry; AFN: African-American ancestry.

Figure 2

SLE susceptibility loci discovered over the past five years. Non-HLA loci associated with SLE susceptibility with p < 5.0 × 10⁻⁸ in previous studies, especially from 2014 to 2019, are listed with citation of references.