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Uncertain generalizability of CTSB–EAC/BE findings beyond European ancestry

Determine whether the inverse association between cathepsin B protein levels and/or CTSB gene expression and the risk of esophageal adenocarcinoma and Barrett's esophagus observed in European ancestry cohorts generalizes to populations of non-European ancestry.

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Background

The paper’s primary analyses draw on GWAS and other datasets mainly from individuals of European ancestry, including INTERVAL proteomics, GTEx expression reference panels, and meta-analyses for EAC/BE. The authors acknowledge that ancestry-specific genetic architectures and environmental exposures may affect transferability of causal estimates.

This open question focuses on validating and replicating the reported inverse CTSB–EAC/BE association in diverse populations to assess external validity and potential differences in effect size or direction across ancestries.

References

As a result, the generalizability of the findings to other populations remains uncertain and requires further investigation.

— Defining the relationship between cathepsin B and esophageal adenocarcinoma: conjoint analysis of Mendelian randomization, transcriptome-wide association studies, and single-cell RNA sequencing data (2504.01270 - Li et al., 2 Apr 2025) in Discussion (Limitations)