article · International Journal of Molecular Sciences
Systemic lupus erythematosus is a complex autoimmune condition, and lupus nephritis is among its most frequent and severe complications. An analysis of the global genetic architecture reveals that systemic lupus erythematosus and lupus nephritis share significant genetic overlap, with most identified susceptibility loci driving broader immune dysregulation rather than kidney-specific vulnerability. Key pathways involved include antigen presentation, type I interferon signalling, B-cell activation, and immune complex clearance. While a few loci such as PDGFRA, HAS2, and SLC5A11 show renal links, APOL1 variants specifically correlate with kidney disease progression in individuals of African ancestry. Current genomic datasets remain heavily concentrated on European, Asian, and admixed groups, leaving continental African populations markedly underrepresented despite their elevated disease burden and high genetic diversity. Closing this data divide is vital to discover causal variants and understand distinct disease mechanisms across diverse groups.
Lupus nephritis can lead to severe kidney failure, yet global genetic studies have largely neglected African populations where the illness is especially aggressive. Capturing genetic diversity across understudied groups is essential to understand why certain patients suffer worse organ damage. Broadening genetic research helps identify distinct biological risks, paving the way for more accurate risk profiling and tailored therapies for patients affected by severe autoimmune complications.
This early-stage review highlights genetic targets relevant to future diagnostic assays and precision medicine strategies for managing lupus nephritis. Diagnostic developers and pharmaceutical researchers could eventually use markers such as APOL1 variants to identify high-risk patients and guide targeted interventions. However, these tools remain far from clinical implementation, requiring expanded high-resolution genomic datasets and functional validation in continental African cohorts before viable commercial tests can emerge.
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Systemic lupus erythematosus (SLE) is a complex autoimmune disease with a strong genetic component, and lupus nephritis (LN) represents one of its most common and severe organ-specific manifestations. This review synthesises current evidence on the genetic architecture of SLE and LN, with a particular focus on identifying shared and distinct genetic susceptibility loci and highlighting knowledge and data gaps in highly burdened African populations. Across studies, most risk loci, including HLA-DRB1, TNFSF4, IRF5, STAT4, TNFAIP3, BANK1, BLK, ITGAM, and FcγR2A/FcγR3A, converge on key immune pathways such as antigen presentation, type I IFN signalling, B-cell activation, and immune complex clearance. The findings support a substantial genomic overlap between SLE and LN, with most variants contributing to systemic immune dysregulation rather than kidney-specific susceptibility. A limited number of loci, including PDGFRA, HAS2, and SLC5A11, have been implicated in renal involvement, while APOL1 G1/G2 risk variants are associated with renal disease progression and adverse kidney outcomes among individuals of African ancestry. Despite these advances, relatively few loci have been definitively linked to LN independent of SLE, reflecting both biological overlap and limitations in study design. Moreover, the existing literature is heavily skewed toward European, Asian, and admixed populations, with minimal representation of continental African cohorts. Given the high genetic diversity and disproportionate disease burden in African populations, this represents a critical knowledge gap. Improved inclusion of diverse populations, coupled with high-resolution genomic and functional studies, will be essential to refine causal variant identification and enhance understanding of disease mechanisms. Ultimately, insights into population-specific genetic risk may enable earlier identification of high-risk individuals and support the development of precision medicine strategies for SLE, specifically LN.
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DOI: 10.3390/ijms27167383
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