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Combined periodontitis GWAS identifies LINC01541 as a regulator of innate immunity in the oral mucosa
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DOI：10.1093/hmg/ddag039.png)
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Abstract
En 中文
Periodontitis is a complex inflammatory disease in which chronic immune activation drives destruction of periodontal soft tissues and alveolar bone. Although early-onset forms show high heritability, much genetic risk remains unresolved. To identify shared genetic signals across early- and later-onset periodontitis, we combined two European genome-wide association study datasets (3183 cases, 10 326 controls) and applied Fisher’s combined probability test (FCOMB) and effect-size-based genome-wide association meta-analysis (GWAMA) across > 7 million variants to capture shared signals with either heterogeneous or more concordant effect sizes. We confirmed known associations at SIGLEC5 and DEFA1A3 and identified several additional suggestive loci. Among these, FCOMB highlighted the strongest signal at the long non-coding RNA LINC01541 (rs11876034, P = 1.7 × 10−6). We evaluated the biological relevance of LINC01541 by repressing it in gingival fibroblasts using CRISPR interference. Knockdown led to significant downregulation of inflammatory mediators, including CSF2 and CSF3, regulators of neutrophil recruitment, members of the interleukin (IL) family (IL1B, IL36B, IL36RN), and chemokines (CXCL5, CXCL8, CCL20). Six of the top ten differentially expressed genes belonged to an epithelial keratinization expression cluster. Gene-set enrichment analyses following linc01541 knockdown demonstrated repression of cytokine signaling, with IL-10 signaling most affected (padj = 5.3 × 10−14; AUC = 0.81), alongside activation of cell-cycle pathways (padj = 3.3 × 10−24; AUC = 0.73). We demonstrated the utility of aggregating heterogeneous samples to detect modest but biologically meaningful genetic effects. The convergence of the genetic association at LINC01541 with functional evidence suggests that this lncRNA modulates an upstream mucosal inflammatory axis relevant to periodontal pathogenesis.
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