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

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 based on known pathogenic variants or the American College of Medical Genetics and Genomics (ACMG) guideline, and studied by functional analysis including RNA sequencing, quantitative PCR, Cytometric Bead Array, western blotting, etc.

RESULTS: Mendelian-form lupus nephritis was confirmed in 71 probands, involving 63 variants in 39 pathogenic genes. The detection yield was 4%. The pathogenic genes enriched in NF-κB, type I interferon, PI3K/AKT, RAS/MAPK, and JAK/STAT pathways. The 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. 73% of the mutations were novel. The identified pathogenic gene variants of lupus nephritis were overlapped with those of autoinflammatory diseases, and immunodeficiency. 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 to 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 have identifiable pathogenic gene variants, primarily in the NF-κB, type I interferon, PI3K/AKT, JAK/STAT, RAS/MAPK, and complement pathways.