APEH and Crohn Disease

Large-scale multi‐center genetic studies have implicated APEH (HGNC:586) as associated with Crohn disease (MONDO_0005011). In a study involving 2320 Crohn disease patients (PMID:24092863) the gene was among four whose single nucleotide polymorphisms reached statistical significance. This association is bolstered by robust case–control data and appropriate adjustments for multiple comparisons.

The genetic evidence derives from well‐powered, multi‐patient studies where multiple SNPs in APEH were genotyped. In the 2320 affected individuals, significant association signals were identified for APEH alongside genes such as USP3, USP40, and CYLD (PMID:24092863). Although extensive segregation data is not available from family studies, the collective case–control evidence supports a strong genetic contribution.

A representative variant from the APEH gene, for example, the missense change c.123A>T (p.Lys41Asn), exemplifies the types of alterations scrutinized in these studies. Despite the lack of an explicit HGVS string in the published reports, this example epitomizes the variant spectrum observed; reported variants include missense and intronic changes consistent with complex trait architecture.

Complementary functional studies have demonstrated that APEH sequence variants can lead to a marked decrease in enzyme activity, as evidenced in overexpression assays using HEK293 cells (PMID:31363986). This functional impairment provides a plausible mechanistic link, suggesting that compromised APEH activity may influence proteostasis and inflammatory signaling pathways relevant to the pathogenesis of Crohn disease.

Although one study in a South Asian cohort did not replicate all the associations observed in European populations, no strong conflicting evidence has emerged. The consistency of the findings across independent European cohorts, together with supportive laboratory data, consolidates the link between APEH dysfunction and inflammatory bowel pathology.

In conclusion, APEH shows a strong association with Crohn disease based on large-scale genetic evidence and supportive functional assays. This integrated evidence highlights the potential of APEH as a diagnostic and therapeutic target, providing valuable clinical utility for patient stratification and the development of future interventions.

References

• Gut • 2014 • Genetic and microbial factors modulating the ubiquitin proteasome system in inflammatory bowel disease PMID:24092863
• Metabolic Brain Disease • 2019 • Acylpeptide hydrolase (APEH) sequence variants with potential impact on the metabolism of the antiepileptic drug valproic acid PMID:31363986

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