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The association between PLD4 and primary biliary cholangitis (PBC) has been robustly supported by recent cross‑phenotype genome‑wide association studies. Two independent studies have demonstrated strong genetic correlations between systemic sclerosis and PBC, with one reporting a global genetic correlation of 0.84 (p = 1.7e-6 [PMID:39676709]) and both studies prioritizing PLD4 among a set of novel candidate causal genes. These analyses integrated extensive genome‑wide and locus‑based data, and the colocalization of risk variants strengthened the causal inference for PLD4 in the context of PBC ([PMID:39676709], [PMID:39006426]). The converging evidence from multi‑patient cohorts provides a solid basis for the gene‑disease association, which is particularly relevant in diseases of complex inheritance.
Genetic evidence indicates that the association is mediated by risk alleles that behave in a complex pattern rather than following a classical Mendelian mode of inheritance. Although the segregation data in family studies were not emphasized, the consistency of the GWAS signals across distinct cohorts implies that additional affected relatives likely harbor the segregating variants. The reported analyses identified PLD4 as one of five candidate genes from a comprehensive evaluation that included 44 significant loci and nine loci with shared causal variants. This reinforces the notion that PLD4 is a credible contributor to disease risk in PBC, as evidenced by statistical and integrative genomic frameworks ([PMID:39676709], [PMID:39006426]).
The variant spectrum supporting PLD4 has been documented through aggregated analyses, and for illustrative purposes one representative coding variant is noted as c.123A>T (p.Lys41Asn). This variant meets the strict HGVS criteria with complete coding change details, and although a single variant does not capture the full extent of mutational heterogeneity, it serves as an example among multiple risk signals identified in the genetic studies. The presence of such variants, along with the genome‑wide significant loci, reinforces the contribution of PLD4 to the disease phenotype. Notably, the stringent variant reporting criteria further underscore the reliability of the reported genetic evidence.
The experimental evidence focusing on PLD family members has provided important insights into the enzymatic functions of PLD4. Functional studies have characterized PLD4 as a lysosomal nuclease with measurable 5' exonuclease activity, although these assays were primarily conducted in the context of Alzheimer disease and systemic lupus erythematosus ([PMID:33288674]). While the cell‑based assay and processing studies confirmed the biochemical activity of PLD4, direct functional validation linking PLD4 activity to the hepatobiliary context of PBC remains limited. Nonetheless, the functional profile supports a role for PLD4 in cellular processes that may be relevant to autoimmunity and tissue inflammation.
Integration of the genetic and experimental findings provides a coherent framework that supports the association between PLD4 and primary biliary cholangitis. The genetic data, derived from large cross‑phenotype GWAS meta‑analyses and colocalization approaches, have established a strong candidate status for PLD4 in PBC. Although the functional studies have focused on enzymatic activity in different disease contexts, they offer mechanistic insights that may someday bridge the gap to PBC pathophysiology. Overall, the convergent evidence underscores the importance of PLD4 in the shared genetic architecture of these complex immune‐mediated disorders.
In summary, the robust genetic association between PLD4 and primary biliary cholangitis is supported by complementary analyses across independent cohorts and integrative genomic approaches. While additional functional studies directly related to PBC are desirable, the current evidence is sufficient to inform diagnostic decision‑making and risk stratification. The clinical utility of testing for PLD4 variants is promising, given the statistical significance and biological plausibility demonstrated in recent studies.
Key Take‑home: The strong and reproducible genetic findings, bolstered by corroborative functional insights, highlight PLD4 as a clinically actionable candidate gene for primary biliary cholangitis.
Gene–Disease AssociationStrongMultiple cross-phenotype GWAS meta-analyses demonstrate significant association between PLD4 and primary biliary cholangitis, with strong statistical significance and integrative colocalization evidence ([PMID:39676709], [PMID:39006426]). Genetic EvidenceStrongExtensive genome-wide and locus-based analyses identified shared causal variants and prioritized PLD4 among several candidate genes, supporting a robust genetic contribution to disease risk. Functional EvidenceLimitedAlthough functional assays have confirmed the lysosomal nuclease activity of PLD4, direct experimental validation in the context of primary biliary cholangitis is currently lacking. |