Unveiling the Intricate Causal Nexus Between 91 Circulating Inflammatory Proteins and Perianal Abscess Through a Comprehensive Bidirectional Two-Sample Mendelian Randomization Analysis

We read with great interest the article titled “Unveiling the Intricate Causal Nexus Between 91 Circulating Inflammatory Proteins and Perianal Abscess Through a Comprehensive Bidirectional Two-Sample Mendelian Randomization Analysis,” [1] which offers valuable insights into the complex relationship between circulating inflammatory proteins and the risk of perianal abscess (PA). The authors' use of a comprehensive bidirectional Mendelian randomization (MR) approach is commendable, as it minimizes confounding and reverse causation, providing more robust evidence than traditional observational studies. Their identification of both risk-associated and protective inflammatory proteins sheds new light on the potential pathophysiological mechanisms of PA and highlights possible biomarkers for future clinical applications.

First, we acknowledge the careful selection of 91 inflammatory proteins and the use of multiple sensitivity analyses to ensure the robustness of the findings. However, the GWAS datasets were predominantly derived from European ancestry populations, and some protein exposures had relatively modest sample sizes. Moreover, potential confounders such as lifestyle factors, comorbid conditions, or environmental exposures were not fully accounted for in the MR framework. These limitations may affect the strength and generalizability of the causal inferences [2]. We suggest that future work consider incorporating larger, multi-ethnic datasets and performing multivariable MR to adjust for potential residual confounding and improve external validity.

Second, it is commendable that the study individually assessed numerous inflammatory proteins, revealing both risk factors (e.g., IL-18R1, IL-33) and protective factors (e.g., IL-2, PD-L1). Nonetheless, treating each protein as an independent exposure may oversimplify the intricate interplay between inflammatory pathways. In reality, many cytokines function in networks, where synergistic or antagonistic effects may shape disease risk. Employing multivariable or mediation MR models could help clarify whether certain proteins act as upstream regulators or downstream mediators within shared inflammatory pathways [3]. Such an approach would provide a more mechanistic understanding of how inflammatory cascades collectively contribute to PA development.

Lastly, while the study established causal associations, the clinical phenotype of PA was considered as a binary outcome. PA itself has heterogeneous presentations, ranging from simple abscesses to recurrent or fistula-associated forms, which may have distinct inflammatory profiles. Stratifying PA cases by clinical subtype or severity, could yield more nuanced insights into which inflammatory proteins are most relevant to disease progression [4]. Furthermore, functional validation in patient-derived tissue or animal models would help bridge the gap between genetic associations and biological mechanisms.

In conclusion, this study makes an important contribution by identifying novel inflammatory proteins associated with PA risk and demonstrating the utility of bidirectional MR in elucidating causal pathways. We applaud the authors' efforts and hope that future research will expand these findings by incorporating more diverse populations, exploring protein interaction networks, and refining clinical phenotypes to enhance translational relevance.

Menghan Zhou: writing – original draft. Shuning Liu: investigation, methodology. Junpeng Guo: writing – review and editing, supervision.

This is a review article therefore no additional ethical approval was required.

The authors declare no conflicts of interest.

The lead / Corresponding author (Menghan Zhou) affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.