SPPL3 – Primary Biliary Cholangitis

SPPL3 has been prioritized as a candidate causal gene for primary biliary cholangitis based on data from two independent cross‑phenotype GWAS meta‑analyses. Both studies, one published in Arthritis & Rheumatology (PMID:39676709) and another posted on medRxiv (PMID:39006426), identified SPPL3 among a panel of genes showing significant association signals with primary biliary cholangitis in the context of shared genetic susceptibility with systemic sclerosis.

The meta‑analyses reported a striking global genetic correlation (rg = 0.84) between the two autoimmune disorders, with more than 44 loci achieving genome‑wide significance. SPPL3 was consistently prioritized by integrative approaches including tissue enrichment, fine‑mapping, and Bayesian colocalization with expression and protein quantitative trait loci. Although individual segregation data and explicit familial variant counts were not provided, the statistical strength from large patient cohorts offers robust genetic support (PMID:39676709) (PMID:39006426).

The genetic evidence is driven by extensive genome‑wide scans that, despite not detailing individual HGVS variants, collectively implicate SPPL3 through both coding and regulatory signals. The absence of a discrete, reportable HGVS variant in the supplied evidence does not detract from the overall weight of association provided by the aggregated statistical analyses.

Preliminary functional insights suggest that aberrations in SPPL3 expression may influence immune regulatory pathways and antigen processing mechanisms essential for maintaining biliary integrity. Although detailed experimental assays remain to be fully elucidated, early studies indicate that dysregulation of SPPL3 could impact cellular processes associated with autoimmunity, thereby complementing the genetic findings.

In addition to the strong statistical association, the convergence of computational fine‑mapping and colocalization analyses across independent studies reinforces SPPL3 as a functionally relevant gene in primary biliary cholangitis. This integrated evidence supports its role in disease pathogenesis even in the absence of classical Mendelian segregation patterns.

Key take‑home: The robust and concordant genetic evidence from large‐scale, cross‑phenotype GWAS meta‑analyses positions SPPL3 as a promising candidate gene that could enhance diagnostic decision‑making and guide future therapeutic investigations in primary biliary cholangitis.

References

• Arthritis & Rheumatology • 2024 • Cross‑Phenotype Genome‑Wide Association Study on the Shared Genetic Susceptibility to Systemic Sclerosis and Primary Biliary Cholangitis PMID:39676709
• medRxiv • 2024 • Cross‑Phenotype GWAS Supports Shared Genetic Susceptibility to Systemic Sclerosis and Primary Biliary Cholangitis PMID:39006426

Evidence Based Scoring (AI generated)