Pathogenic Gene Spectrum and Clinical Implication in Chinese Patients with Lupus Nephritis

Abstract

Background Lupus nephritis is a rare immunological disorder. Genetic factors are considered important in its causation. We aim to systematically investigate the rare pathogenic gene variants in patients with lupus nephritis. Methods Whole-exome sequencing was used to screen pathogenic gene variants in 1886 probands with lupus nephritis. Variants were interpreted on the basis of known pathogenic variants or the American College of Medical Genetics and Genomics guidelines and studied by functional analysis, including RNA sequencing, quantitative PCR, cytometric bead array, and Western blotting. Results Mendelian form of lupus nephritis was confirmed in 71 probands, involving 63 variants in 39 pathogenic genes. The detection yield was 4%. The pathogenic genes enriched in nuclear factor kappa-B (NF-κB), type I interferon, phosphatidylinositol-3-kinase/serine/threonine kinase Akt (PI3K/AKT), Ras GTPase/mitogen-activated protein kinase (RAS/MAPK), and Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways. Clinical manifestation patterns were diverse among different signaling pathways. More than 50% of the pathogenic gene variants were reported to be associated with lupus or lupus nephritis for the first time. The identified pathogenic gene variants of lupus nephritis overlapped with those of autoinflammatory and immunodeficiency diseases. Inflammatory signatures, such as cytokine levels of IL-6, IL-8, IL-1β, IFNα, IFNγ, and IP10 in serum and transcriptional levels of interferon-stimulated genes in blood, were significantly higher in patients with pathogenic gene variants compared with controls. The overall survival rate of patients with pathogenic gene variants was lower than those without pathogenic gene variants. Conclusions A small fraction of patients with lupus nephritis had identifiable pathogenic gene variants, primarily in NF-κB, type I interferon, PI3K/AKT, JAK/STAT, RAS/MAPK, and complement pathways.

Aberrant expression of C1q, IL-6 and β-catenin in class VI lupus nephritis

“…The difference might be caused by different genetic background, time, diet and environment during the generation of mouse model. In addition, a study of IL-6-de cient BALB/C mice in pristance-induced lupus, an alternative murine lupus model, revealed that autoantibody development in this lupus model is IL-6-dependent [13]. It is true that IL-6-de ciency in MRL-Fas lpr mice reduced the level of C1q in both urine and kidney compared with MRL-Fas lpr mice in this study.…”

“…Indeed, beyond the realm of autoantibodies and immune complex deposition, a compelling body of evidence underscores the pivotal role of cytokines in the intricate tapestry of SLE pathogenesis [12] . Among these cytokines, the interleukin-6 (IL-6)/IL-6 receptor (IL-6R) signaling has garnered signi cant attention due to its robust link with LN activity in individuals with SLE [13,14] . In the context of LN, the primary source of IL-6 are the in ltrating in ammatory cells within kidneys, predominantly macrophages and monocytes [15] .…”