Biological insights into systemic lupus erythematosus through an immune cell-specific transcriptome-wide association study

Abstract

ObjectiveGenome-wide association studies (GWAS) have identified >100 risk loci for systemic lupus erythematosus (SLE), but the disease genes at most loci remain unclear, hampering translation of these genetic discoveries. We aimed to prioritise genes underlying the 110 SLE loci that were identified in the latest East Asian GWAS meta-analysis.MethodsWe built gene expression predictive models in blood B cells, CD4+ and CD8+ T cells, monocytes, natural killer cells and peripheral blood cells of 105 Japanese individuals. We performed a transcriptome-wide association study (TWAS) using data from the latest genome-wide association meta-analysis of 208 370 East Asians and searched for candidate genes using TWAS and three data-driven computational approaches.ResultsTWAS identified 171 genes for SLE (p<1.0×10–5); 114 (66.7%) showed significance only in a single cell type; 127 (74.3%) were in SLE GWAS loci. TWAS identified a strong association between CD83 and SLE (p<7.7×10–8). Meta-analysis of genetic associations in the existing 208 370 East Asian and additional 1498 cases and 3330 controls found a novel single-variant association at rs72836542 (OR=1.11, p=4.5×10–9) around CD83. For the 110 SLE loci, we identified 276 gene candidates, including 104 genes at recently-identified SLE novel loci. We demonstrated in vitro that putative causal variant rs61759532 exhibited an allele-specific regulatory effect on ACAP1, and that presence of the SLE risk allele decreased ACAP1 expression.ConclusionsCell-level TWAS in six types of immune cells complemented SLE gene discovery and guided the identification of novel genetic associations. The gene findings shed biological insights into SLE genetic associations.

Pathogenesis of systemic lupus erythematosus: risks, mechanisms and therapeutic targets

“…Specific SNPs have pointed to molecular pathways, mechanisms and therapeutic targets that underlie disease pathogenesis (table 1). A meta-analysis expanded the documented lupus-associated genetic loci based on analysis of more than 10 000 newly genotyped SLE cases, more than 180 000 controls and existing datasets from east Asian cohorts, with only 3.6% representing coding variants 37 54. A transancestral analysis identified quantitative trait loci in EA and AA individuals, with EA risk genes enriched in functions related to the innate immune response, while AA-associated genes were enriched in pathways related to T-cell and B-cell activation and cellular stress 55.…”

The Recent Evolution of the Application of Single-Cell Analysis in Kidney Diseases: A bibliometric analysis

“…Although we know the major potential and powerful applications of the single-cell analysis technology [34,130], there are still many other significant multi-methods, multi-models and multi-omics aspects that facilitate scholars to easily explore the much more complicated kidney diseases research domain and deserve more attention and exploration, such as the combination or integration application between SCA techniques and CRISPR screening [131][132][133], other multi-omics platforms [130,[134][135][136], nanotechnology [107,[137][138][139], stem cell/exosomes [53,58,107,134,[140][141][142][143][144][145], Genome-wide association studies (GWAS) [21,105,[146][147][148][149][150][151], machine-learning [95,135,152,153], as well as the mendelian randomization approach (MRA) [117,148,154], and so on. The combination or integration of various single-cell technologies and other techniques, methods or models allows for a more comprehensive understanding of pathophysiological mechanisms and biological processes behind kidney disease to obtain or improve new or traditional diagnostic/treatment approaches.…”

Pathogenesis and novel therapeutics of regulatory T cell subsets and interleukin-2 therapy in systemic lupus erythematosus

“…Epigenetic modifications, which can be influenced by both genetic and environmental factors, also impact T-cell function in SLE. The interaction between genetics, T cell abnormalities, and environmental factors also plays a critical role in in the onset and exacerbation of the disease (16). Natural Tregs-mediated immune regulation is mediated primarily by cell contact and suppressive cytokines (Table 1A).…”