Abstract
BACKGROUNDS: Systemic lupus erythematosus (SLE) is an autoimmune disease with multi-organ involvement, and lupus nephritis (LN) is a severe manifestation. Long non-coding RNAs (lncRNAs) have been implicated in regulating immune responses in autoimmune diseases. LOC100130476, a lncRNA located on chromosome 6q23.3, has been linked to inflammation and cancer progression, but its role in SLE and LN remains unclear. METHODS: We studied the association between the rs80213143 variant at LOC100130476 and SLE susceptibility in a Chinese Han cohort, using SNP genotyping and Bonferroni correction for multiple comparisons. Functional annotations were conducted to explore the effects of rs80213143 on transcription factor binding and gene expression. eQTL analysis was performed to assess the variant's impact on immune cell gene expression. RESULTS: Within LOC100130476, the strongest association was observed at rs80213143 (p = 2.5 × 10(-7)), which was successfully replicated (p = 2.64 × 10(-9)) in an independent cohort. The combined analysis of both discovery and replication cohorts reinforced the genetic association (p(meta) = 2.04 × 10(-14)). The risk C allele was linked to more severe renal involvement, including higher 24-h proteinuria and serum creatinine levels. Functional annotations indicated that rs80213143 potentially influences immune cell functionality through regulatory motif alterations. The expression of LOC100130476 was abnormally upregulated in the whole blood of SLE patients, particularly in lupus nephritis patients. Moreover, the expression of LOC100130476 was significantly upregulated in the biopsy samples of lupus nephritis patients. Differentially expressed genes in whole blood between SLE patients and healthy donors, positively associated with LOC100130476 expression, were significantly enriched in pathways involving T cell receptor signaling, antigen presentation, interferon response, and apoptosis. Furthermore, LOC100130476 showed positive associations with genes differentially expressed between LN patients' renal biopsy tissues and adjacent normal renal tissues, enriched in leukocyte-mediated immunity, inflammatory responses, extracellular matrix and tissue repair pathways, and the PI3K signaling network. CONCLUSION: The rs80213143 variant in LOC100130476 is associated with SLE susceptibility and renal involvement. Its elevated expression in lupus nephritis suggests it may be an important factor in disease pathogenesis and a potential biomarker for lupus nephritis.