Several Critical Cell Types, Tissues, and Pathways Are Implicated in Genome-Wide Association Studies for Systemic Lupus Erythematosus

Abstract

We aimed to elucidate the cell types, tissues, and pathways influenced by common variants in systemic lupus erythematosus (SLE). We applied a nonparameter enrichment statistical approach, termed SNPsea, in 181 single nucleotide polymorphisms (SNPs) that have been identified to be associated with the risk of SLE through genome-wide association studies (GWAS) in Eastern Asian and Caucasian populations, to manipulate the critical cell types, tissues, and pathways. In the two most significant cells’ findings (B lymphocytes and CD14+ monocytes), we subjected the GWAS association evidence in the Han Chinese population to an enrichment test of expression quantitative trait locus (QTL) sites and DNase I hypersensitivity, respectively. In both Eastern Asian and Caucasian populations, we observed that the expression level of SLE GWAS implicated genes was significantly elevated in xeroderma pigentosum B cells (P ≤ 1.00 × 10−6), CD14+ monocytes (P ≤ 2.74 × 10−4) and CD19+ B cells (P ≤ 2.00 × 10−6), and plasmacytoid dendritic cells (pDCs) (P ≤ 9.00 × 10−6). We revealed that the SLE GWAS-associated variants were more likely to reside in expression QTL in B lymphocytes (q1/q0 = 2.15, P = 1.23 × 10−44) and DNase I hypersensitivity sites (DHSs) in CD14+ monocytes (q1/q0 = 1.41, P = 0.08). We observed the common variants affected the risk of SLE mostly through by regulating multiple immune system processes and immune response signaling. This study sheds light on several immune cells and responses, as well as the regulatory effect of common variants in the pathogenesis of SLE.

IFN-γ Mediates the Development of Systemic Lupus Erythematosus

“…The role of single and cluster genes in the development and pathogenesis of SLE is described [ 22 ]. Recent technological advancements such as GWAS and microarray have expanded our understanding on gene expression, including those associated with the pathogenesis of SLE [ 23 ]. The previous studies however focused on the expression signature of blood IFN- α [ 24 – 26 ].…”

The Potential Role of Trained Immunity in Autoimmune and Autoinflammatory Disorders

“…The production of a number of antinuclear antibodies is the most prominent and well-known process, and they are used for diagnostic purposes. However, monocytes and macrophages also play a prominent role in the disease activity, which increasingly becomes a topic of research ( 53 – 55 ). In SLE patients, macrophages are characterized by a proinflammatory status and show an increased production of proinflammatory cytokines, such as IFNα, TNFα, and IL-6 ( 56 – 58 ).…”

“…Of these DHS, 4,583 showed SLE-specific changes for H3K4me3 and 1,714 for H3K27me3 at promoter sites. At enhancer site theses numbers were 12,109 and 3,046, respectively ( 55 ). Transcription factor binding motifs analysis revealed PU.1 and CEBPB as main transcription factors related to the H3K4me3 induced genomic areas, just as seen for β-glucan-induced training ( 10 ).…”

“…Transcription factor binding motifs analysis revealed PU.1 and CEBPB as main transcription factors related to the H3K4me3 induced genomic areas, just as seen for β-glucan-induced training ( 10 ). Also BLIMP1 and interferon-related transcription factors as STAT1/6, and IRF1/4/8 were defined ( 55 ).…”

DNA-reactive B cells in lupus

“…Recent studies investigating the cell-type specific expression of these risk alleles has revealed that these genes are most highly expressed in B cells, monocytes, and plasmacytoid dendritic cells [37,38]. This suggests that genetic risk factors can contribute to both B cell-intrinsic and B cell-extrinsic triggering of the disease (Figure 2).…”