ATG4A and Crohn Disease

The association between ATG4A and Crohn disease has been evaluated in multi‐patient studies, focusing on the presence of granulomas as a clinical marker. One study involving 307 Israeli Crohn disease patients did not find any significant association between ATG4A SNPs (rs807185) and granuloma formation (PMID:21122541). This study highlighted that despite the clinical relevance of granulomas, the allelic frequencies of the examined variants did not differ between granuloma‐positive and -negative patients.

In contrast, a subsequent study in a larger cohort of 464 surgically treated Crohn disease patients identified an association between granuloma formation and an ATG4A variant (rs5973822) alongside other autophagy‐related genes (PMID:22261526). This work suggested that granuloma presence might correlate with an aggressive disease course, implicating autophagy gene variants in the pathogenesis of Crohn disease.

Although neither study supplied a HGVS‑formatted variant description (e.g. one beginning with “c.” and containing a corresponding protein change), the conflicting genetic observations underscore the challenges in assigning a definitive diagnostic role to ATG4A in Crohn disease. The genetic evidence is mainly based on SNP associations with variable results and lacks supporting segregation data from familial studies.

Functional studies, not directly linked to Crohn disease but relevant to autophagy, reinforce the involvement of ATG4A in cellular degradation pathways. These experimental assessments—including protein interaction and autophagy modulation assays—demonstrate that ATG4A is critical in maintaining autophagic flux (PMID:30238850; PMID:40017376). However, these results do not fully reconcile the divergent clinical genetic findings.

The discordance between the association studies suggests a disputed clinical validity, with one report failing to confirm an association while another supports a link between ATG4A variants and a severe Crohn disease phenotype. This conflict, combined with a lack of clear Mendelian segregation and a sparse variant spectrum in the HGVS context, limits the strength of the genetic evidence.

In summary, while functional data support an important role for ATG4A in autophagy, the genetic data regarding its association with Crohn disease remain disputed. Clinicians and researchers should interpret ATG4A variants with caution, as additional evidence is needed to establish their clinical utility in diagnostic decision‑making.

Key take‑home: Despite promising functional insights, conflicting genetic association studies necessitate further investigation before ATG4A can be reliably used as a biomarker for aggressive Crohn disease.

References

• Journal of Crohn's & colitis • 2010 • Granulomas in Crohn's disease: are newly discovered genetic variants involved? PMID:21122541
• Journal of Crohn's & colitis • 2012 • Genetic variants in autophagy-related genes and granuloma formation in a cohort of surgically treated Crohn's disease patients. PMID:22261526
• Autophagy • 2019 • A cancer associated somatic mutation in LC3B attenuates its binding to E1-like ATG7 protein and subsequent lipidation. PMID:30238850
• Autophagy • 2025 • Cancer-associated mutations in autophagy-related proteins analyzed in yeast and human cells. PMID:40017376

Evidence Based Scoring (AI generated)