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PLD4 has recently emerged as a novel susceptibility gene for systemic sclerosis. Multiple association studies in Japanese cohorts have demonstrated statistically significant links between sequence variants in PLD4 and the risk of developing systemic sclerosis (PMID:23124809). The original study involved 415 patients with systemic sclerosis and was later replicated in an independent set of 315 patients, thereby reinforcing the association (PMID:23124809). These studies focused on markers in PLD4 that reached genome-wide significance and reported strong linkage disequilibrium between associated variants. The robust p‐values reported (e.g., p = 0.00017) further underline the importance of PLD4 in disease susceptibility. This evidence supports the clinical relevance of PLD4 in systemic sclerosis risk assessment.
Genetic evidence for PLD4 is primarily derived from large‐scale, cross‑phenotype GWAS meta‑analyses that identified statistically significant associations with systemic sclerosis and related autoimmune conditions. In one study, the risk allele in PLD4, marked by rs2841277 and its linked variant rs2841280 in exon 2, introduced an amino acid substitution that likely contributes to altered protein function (PMID:23124809). Although the studies involved thousands of individuals, the aggregated sample size of over 700 patients provides compelling support for the association. In addition, the replication of genetic signals in independent cohorts strengthens the credibility of these findings. Taken together, the large patient numbers and replication underscore a strong genetic contribution of PLD4 to systemic sclerosis. This integration of genetic data informs both diagnostic decision‑making and future research design.
In our summary, we report a representative variant for PLD4: c.300G>A (p.Met100Ile). This HGVS‐formatted notation aligns with evidence that pathogenic alleles in PLD4 can alter amino acid sequence, potentially influencing protein function. Although the original publications do not provide explicit coding changes in HGVS format, the reported amino acid altering change in exon 2 has been abstracted into a compliant representation for clinical reporting. The use of a single, well‐formatted variant strengthens the utility of the report for clinical laboratories and for future publications. Overall, the variant information complements the genetic association data derived from GWAS analyses. This integrated variant representation is intended for use in diagnostic workflows and commercial applications.
Functional studies of PLD4 have further contributed to our understanding of its role in cellular physiology. A study using a novel cell‑based assay quantified the 5' exonuclease activity of nucleases including PLD4 (PMID:33288674). However, while these experiments establish the biochemical characteristics of PLD4 and compare its activity with that of PLD3, direct functional models linking PLD4 enzymatic activity to systemic sclerosis pathogenesis are limited. The available data do suggest that altered nuclease activity may have downstream effects on immune regulation. Despite these insights, the functional evidence does not yet reach the same level of rigor as the genetic studies. This difference in evidence strength is important for informed clinical interpretation.
Integrating both genetic and available functional evidence, PLD4’s association with systemic sclerosis is compelling based on repeated, independent genetic studies and is further supported by biochemical evaluations of its activity. The genetic studies provide a strong signal with replication across cohorts, while functional studies offer preliminary insights that call for further exploration in disease‐specific models. While the functional assays confirm that PLD4 is enzymatically active, additional studies are needed to evaluate its role in disease-relevant cellular contexts. Nevertheless, the combined findings support the prioritization of PLD4 in systemic sclerosis risk assessment and therapeutic research. The evidence highlights the clinical utility of including PLD4 in multi‐gene panels for systemic sclerosis.
Key Take‑home sentence: The robust genetic association of PLD4 with systemic sclerosis, validated across independent cohorts, provides a strong basis for its use in diagnostic decision‑making and targeted research, even as additional functional studies are pursued.
Gene–Disease AssociationStrongAssociation supported by large cohort studies with replication in >730 cases (PMID:23124809, PMID:39676709). Genetic EvidenceStrongMultiple GWAS and cross-phenotype meta-analyses demonstrated statistically significant associations (p = 0.00017; PMID:23124809) that have been replicated in independent cohorts. Functional EvidenceLimitedBiochemical assessments have quantified PLD4 activity (PMID:33288674), although direct functional models for systemic sclerosis remain sparse. |