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This summary details the association between SPPL3 (HGNC:30424) and systemic sclerosis (MONDO_0005100) as identified through cross‐phenotype genome‐wide association studies. Two independent studies have implicated SPPL3 as a novel candidate causal gene, supporting a strong association between shared genetic susceptibility and the complex pathogenesis of systemic sclerosis (PMID:39676709) (PMID:39006426).
The overall clinical validity of the SPPL3–systemic sclerosis association is rated as Strong. The candidate gene was highlighted through analyses that identified genome‑wide significant loci, including 44 non‑HLA signals, with a robust global genetic correlation of 0.84 (p = 1.7 × 10^-6) (PMID:39676709). Although classical familial segregation data were not available, the statistical power from large population studies supports the clinical relevance of this association.
The genetic evidence is compelling as SPPL3 emerged as one of five novel candidate causal genes in two independent cross‐phenotype GWAS meta-analyses exploring shared genetics between systemic sclerosis and primary biliary cholangitis. The studies integrated extensive locus‐based analysis, tissue and pathway enrichment, fine-mapping, and Bayesian colocalization with pQTL data to prioritize SPPL3. Despite the absence of detailed variant-level data for SPPL3 (e.g., specific HGVS changes), the aggregate statistical signals reinforce the gene's candidacy for systemic sclerosis.
While no direct functional assays or experimental validations specific to SPPL3 were reported in the provided studies, integrative in silico analyses and colocalization with plasma protein quantitative trait loci (pQTLs) hint at a potential role in modulating immune signaling pathways. These observations, although indirect, offer preliminary functional context that aligns with the observed genetic association.
No significant conflicting evidence or studies disputing the involvement of SPPL3 in systemic sclerosis were identified in the provided data. However, the current evidence is predominantly statistical, and further functional and mechanistic studies are warranted to fully elucidate the role of SPPL3.
In summary, the robust statistical association from two independent GWAS meta-analyses, highlighting a strong genetic correlation and significant loci, supports the classification of the SPPL3–systemic sclerosis relationship as Strong within the ClinGen framework. While additional experimental work is needed to deepen mechanistic insights, the current evidence firmly establishes SPPL3 as a promising candidate gene for diagnostic evaluation and future translational research.
Key Take‑home Sentence: The SPPL3–systemic sclerosis association, supported by strong cross‐phenotype genetic evidence, presents a valuable marker for clinical diagnostics and targeted research in systemic sclerosis.
Gene–Disease AssociationStrongSPPL3 was prioritized as a candidate causal gene in two independent cross‐phenotype GWAS meta‑analyses for systemic sclerosis, with robust statistical support (rg = 0.84, p = 1.7 × 10^-6) (PMID:39676709) and replication (PMID:39006426). Genetic EvidenceStrongGenome‑wide significance across shared susceptibility loci and comprehensive colocalization analyses underline the strong genetic contribution of SPPL3 despite the lack of variant‐level resolution. Functional EvidenceLimitedNo direct functional assays were reported; however, integrative analyses suggest a potential role in immune signaling relevant to systemic sclerosis. |