Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by the production of autoantibodies against nuclear antigens, leading to inflammation and multi-organ involvement. The pathogenesis of SLE, while not fully understood, is influenced by genetic, environmental, and immunological factors. Recent advances have highlighted the role of long non-coding RNAs (lncRNAs) in the pathogenesis of SLE. LncRNAs, crucial members of the non-coding RNA family, are RNA transcripts exceeding 200 nucleotides without protein-coding capability (Kapranov et al., 2007). Identified as immune regulators, their dysregulation plays a role in autoimmune diseases, including SLE (Tsai et al., 2020).

Previous studies have demonstrated abnormalities in lncRNA expression in SLE patients. In peripheral blood mononuclear cells (PBMCs), 8,868 lncRNAs showed differential expression between SLE patients and healthy donors, with 3,657 upregulated and 5,211 downregulated (Luo et al., 2018). Similarly, in monocyte-derived dendritic cells (moDCs), 163 lncRNAs exhibited differential expression between SLE and controls (Wang et al., 2018). The versatile role of lncRNA in immunity and inflammation is highlighted by its correlation with SLE disease activity. Specifically, the expression levels of ENST00000604411.1, ENST00000501122.2, NEAT1 in moDCs, and lnc7514 in PBMCs positively correlated with clinical disease activity (Wang et al., 2018; Zhang et al., 2016; Wang et al., 2019). In patients positive for anti-dsDNA, lnc7514 levels were markedly lower than in those negative for anti-dsDNA (Wang et al., 2019). Furthermore, lnc3643 expression levels were associated with C-reactive protein and erythrocyte sedimentation rates in SLE patients (Wang et al., 2019).

Evidence from genome-wide association studies (GWAS) and candidate gene analyses has highlighted the association of single nucleotide polymorphisms (SNPs) with susceptibility to SLE. The variant rs13259960, situated in an intronic enhancer region of SLEAR, has been linked to increased susceptibility to SLE (P = 1.03 × 10⁻¹¹), influencing SLEAR expression that correlates positively with cell death in the peripheral blood of SLE patients (Fan et al., 2020). Similarly, the risk alleles rs205764 and rs547311, located in the promoter region of linc00513, are known to elevate linc00513 expression by enhancing promoter activity, contributing to SLE. Linc00513 acts as a positive regulator of the type I interferon pathway and correlates positively with the IFN score in SLE patients (Xue et al., 2018).

We reviewed previous GWAS data with a focus on lncRNA-coding genes (Sun et al., 2016). Among the Chinese Han population from Beijing, rs80213143 at LOC100130476 emerged as a locus significantly associated with increased susceptibility to systemic lupus erythematosus (SLE) (p = 2.5 × 10⁻⁷, OR 2.63, 95% CI 1.80–3.84). Furthermore, this study replicated the genetic association between rs80213143 and SLE susceptibility and explored the role of LOC100130476 in the pathogenesis and progression of SLE.

In this study, we demonstrated a robust association between the rs80213143 variant at the LOC100130476 locus and susceptibility to SLE. Notably, the risk C allele was not only linked to an increased overall risk for SLE (p < 2.04 × 10⁻¹⁴) but was also significantly associated with more severe renal involvement. Carriers of the C allele exhibited higher levels of 24-h proteinuria and elevated serum creatinine, indicating a potential role of this variant in the pathogenesis of LN. Although trends toward earlier disease onset and increased prevalence of mucocutaneous, neurologic, and serositis manifestations were observed in C allele carriers, these associations did not reach statistical significance, warranting further investigation in larger cohorts. It should be noted that the association signal for rs80213143 in the discovery cohort did not reach the conventional genome-wide significance threshold; however, the finding was consistently replicated in an independent cohort and further strengthened by meta-analysis, providing robust genetic evidence for the involvement of this locus in SLE susceptibility.

The SNP rs80213143 is located within the TNFAIP3 gene region on chromosome 6, a well-established risk haplotype for SLE and other immune-mediated diseases (Ray et al., 2020). Previous studies have reported associations between rs80213143 and several immune-related disorders, including rheumatoid arthritis (Ray et al., 2020), asthma (Ray et al., 2020), and systemic sclerosis (Terao et al., 2017), suggesting its potential functional role in immune dysregulation. However, rs80213143 has not been directly associated with SLE. Although other variants within the TNFAIP3 haplotype have been linked to SLE, the specific role of rs80213143 remains underexplored. This study is the first to demonstrate a statistically significant association between rs80213143 and both SLE and LN, addressing a critical gap in the genetic landscape of SLE.

LOC100130476, located at chromosome 6q23.3, encodes wound and keratinocyte migration-associated lncRNA 2 (WAKMAR2, named by Herter, et al.) and was reported involved in the pathogenesis of gastric cardia adenocarcinoma, malignant progression of esophageal squamous cell carcinoma, and the inflammation of human chronic wounds (Guo et al., 2016a; Guo et al., 2016b; Herter et al., 2019). The methylation-mediated downregulation of LOC100130476 was detected and might function as a tumor suppressor gene in gastric cardia adenocarcinoma (Guo et al., 2016b). Aberrant hypermethylation of the CpG sites in exon one downregulated the expression of LOC100130476 which was associated with poor esophageal squamous cell carcinoma patient survival (Guo et al., 2016a). Recent advances revealed the protective role of WAKMAR2 in skin wound healing process by restriction of the production of inflammatory chemokines in keratinocytes (Herter et al., 2019). Our findings extend the biological significance of LOC100130476 by linking its genetic variation to autoimmunity, suggesting that alterations in its expression or function may contribute to SLE pathogenesis. Located in LncRNA coding regions, the variant rs13259960, rs205764 and rs547311 were reported associated with increased SLE susceptibility by modulated the expression of SLEAR and linc00513, respectively (Fan et al., 2020; Xue et al., 2018). Advancements in the field indicate that an increasing number of studies suggested genetic variations in the regions of lncRNAs are implicated in susceptibility to SLE. Given the complexity of genetic regulation and the possibility of additional functional variants within this region, further comprehensive studies—including broader sequencing and fine-mapping—are needed to clarify the causal variants and their biological significance.

Subsequently, we explored the potential functional implications of rs80213143. Annotations from RegulomeDB indicate that the rs80213143 locus is situated within a transcription factor binding region. The transition from G to C at this locus affects the binding affinity with various transcription factors, thereby influencing regulatory motifs and leading to reduced binding scores. The C allele, identified as the risk allele at the rs80213143 locus, is associated with a reduced binding capacity to the transcription factors Hand1_1, Hand1_2, RP58, and TAL1_known2. Hand1 and ZBT18 function as transcriptional repressors, with Hand1 notably inhibiting SOX15, and ZBT18 affecting development and cell processes like myogenesis and neuron survival (UniProt Consortium, 2023). Therefore, the decreased binding with these repressive transcription factors by the risk allele C suggested an association with increased gene expression. Following an analysis of the transcriptome across various immune cell subtypes, we observed that the rs80213143 locus did not exert a QTL effect in all immune cell subtypes. Notably, its impact on expression was primarily observed in subsets of monocytes, neutrophils, and T cells. This suggested that rs80213143 might contribute to the pathogenesis of SLE by modulating expression specifically within these immune cell populations. The QTL analysis suggests that the allele C of rs80213143 on RP11-356I2.4 is responsive to sun exposure, implying that this variant could contribute to the pathogenesis of SLE by modulating gene expression levels in an environment-dependent manner.

In the present study, LOC100130476 expression was significantly upregulated in SLE patients, with the highest levels observed in patients with lupus nephritis. Given the clinical heterogeneity of lupus nephritis, the interpretation of this expression difference requires caution. Renal dysfunction itself may influence gene expression profiles in both peripheral blood and renal tissues. As the present analyses were cross-sectional and included LN patients with varying degrees of renal impairment, causality cannot be inferred from these data alone. The observed upregulation of LOC100130476 may therefore reflect either a contributing factor to LN pathogenesis or a secondary consequence of renal injury. Future studies focusing on LN patients with preserved renal function, as well as longitudinal analyses correlating gene expression with renal function parameters, will be necessary to clarify the temporal and causal relationship between LOC100130476 expression and renal involvement.

In the past few years, the correlation between the expression of lncRNA and renal impairment in SLE were revealed. In SLE patients with kidney injury, the expression of LNC-DC was significantly elevated, while the downregulations of linc0949 and lncRNA TUG1 was markedly lower (Wu et al., 2017; Cao et al., 2020). A negative correlation was identified between TUG1 levels and 24-h urinary protein (Cao et al., 2020). Moreover, the level of lncRNA TUG1 was a potential clinical diagnostic tool to distinguish lupus nephritis patients from SLE patients without renal impairment (Cao et al., 2020). Given the number of clinical manifestations examined and the absence of predefined a priori hypotheses, the genotype–phenotype association analyses should be regarded as exploratory in nature. After strict correction for multiple testing, the observed associations with renal manifestations would not remain statistically significant and therefore require validation in independent cohorts.

Furthermore, we explored LOC100130476’s role in SLE and LN, revealing its influence on crucial disease pathways. Our analysis revealed significant enrichment in pathways related to T cell receptor, antigen presentation, interferon, and apoptosis, pointing to LOC100130476’s potential in driving SLE pathogenesis. Additionally, LOC100130476 was linked to LN through pathways of leukocyte-mediated immunity, inflammatory responses, pathways related to the extracellular matrix and tissue repair, and the PI3K signaling network, indicating its key role in LN’s pathogenic mechanisms.

Our study suggested that LOC100130476 may have played a promotional role in the pathogenesis of SLE and LN. Given its specific impact on autoimmune conditions, this suggested a targeted role in disease progression. However, the precise functional mechanisms of rs80213143 remain to be elucidated. Future studies could employ functional experiments, such as CRISPR/Cas9 gene editing or in vitro cell model validation, to systematically investigate the regulatory effects of rs80213143 on LOC100130476 expression and downstream immune pathways. These experiments will help clarify the independent contribution of rs80213143 to SLE and LN pathogenesis.

In conclusion, our comprehensive analysis establishes a genetic link between the rs80213143 variant at LOC100130476 and SLE susceptibility, particularly highlighting its impact on renal involvement. These findings enhance our understanding of the molecular mechanisms underlying SLE and lupus nephritis (LN). Moreover, LOC100130476 holds potential as a biomarker for lupus nephritis, which could aid in better diagnosis or monitoring of disease progression. Future studies focused on further elucidating the regulatory mechanisms and functional consequences of this variant will be important for advancing our understanding of its role in SLE and LN.