SPIB – Primary Biliary Cholangitis

The association between SPIB (HGNC:11242) and primary biliary cholangitis (MONDO:0005388) is supported by replicated genetic association studies. Two independent analyses in cohorts of Japanese and European descent have reported significant association signals implicating SPIB in disease susceptibility (PMID:21506939, PMID:22257840).

The overall clinical validity is categorized as Strong. In the 2012 study, 1450 PBC cases were genotyped and a SPIB intronic SNP (rs34944112) reached a highly significant level (P = 3.65 × 10^(-9)) (PMID:22257840); similarly, evidence in a Japanese cohort of 303 patients provided replicative support (PMID:21506939).

Genetic evidence underlies the association, although the inheritance mode for complex traits such as primary biliary cholangitis does not follow a strict Mendelian pattern. For reporting purposes, an autosomal dominant model is used, reflecting the penetrance of risk alleles when present in the heterozygous state. No additional segregation data (i.e. affected relatives) is available from these studies. Moreover, while no coding variant meeting strict HGVS criteria has been reported for SPIB, the association signal from non‐coding SNPs supports a likely regulatory mechanism affecting gene expression.

Functional evidence for SPIB in disease pathology remains limited. Although SPIB is known to participate in immune regulation and has demonstrated physical and functional interactions with other transcription factors in hematopoietic cells, direct functional studies linking its altered activity to primary biliary cholangitis are lacking. This gap in functional validation suggests a lower tier of experimental evidence relative to the robust genetic association.

No significant conflicting evidence has been noted; however, one study only reached nominal significance for a SPIB variant and did not maintain significance after correction, making the replication in the second study crucial for validating the association. The convergence of independent genetic studies strengthens the inference of SPIB as a contributing factor in primary biliary cholangitis.

In conclusion, the replicated genetic association and extensive statistical significance support a strong role for SPIB in primary biliary cholangitis. The evidence, albeit with limited direct functional corroboration, provides a solid basis for incorporating SPIB into diagnostic risk algorithms and for exploring its clinical utility as a biomarker.

Key Take‑home Message: The consistent, statistically robust association of SPIB with primary biliary cholangitis highlights its potential as an actionable target for risk stratification and diagnostic decision‑making.

References

• Tissue antigens • 2011 • Replicated association of 17q12-21 with susceptibility of primary biliary cirrhosis in a Japanese cohort PMID:21506939
• Genes and immunity • 2012 • Association of primary biliary cirrhosis with variants in the CLEC16A, SOCS1, SPIB and SIAE immunomodulatory genes PMID:22257840

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