Role of Serum Metabolites in Mediating the Effect of Circulating Inflammatory Proteins on NK/T Cell Lymphoma.

Abstract

Introduction: NK/T Cell Lymphomas (NKTCL) are highly aggressive types of Non-Hodgkin's Lymphoma (NHL) that have a predilection for Asian and South American populations. Identifying new drug targets or prognostic markers is essential for developing future strategies for NKTCL treatment.

Methods: This study employed a two-step and bidirectional Mendelian Randomization (MR) study with an Inverse Variance Weighted (IVW) approach to investigate the potential association of Circulating Inflammatory Proteins (CIPs) with NKTCL and the mediation effect of serum metabolites in the relationship between CIPs and NKTCL. Data on 91 CIPs from a proteomic study of 14,824 individuals conducted with the Olink Target platform were collected. Genetic information for NKTCL was obtained from the finngen_ R10_CD2_TNK_LYMPHOMA, including 363 cases and 324,650 controls. Data for 1,091 plasma metabolites and 309 metabolite ratios (Ebi-a- GCST90199621 to Ebia- GCST90201020) were derived from the GWAS Catalog.

Results: MR analyses identified 4 plasma proteins significantly associated with NKTCL. Increased levels of TGF-α and TNFRSF9 were associated with increased NKTCL risk, with Odds Ratios (OR) of 1.6388 (95% CI 1.0158-2.6440) and 1.6863 (95% CI 1.1757-2.4187), respectively. Conversely, LIF-R (OR 0.6265, 95% CI 0.4427-0.8866) and SULT1A1 (OR 0.5425, 95% CI 0.3758-0.7833) exhibited protective effects. Notably, none of these proteins showed evidence of reverse causality. Furthermore, the mediation MR suggested that the effect of TNFRSF9 on NKTCL (total effect IVW: OR = 1.6863, 95% CI 1.1757-2.4187, P = 0.010) was partially mediated by Isobutyrylcarnitine (C4) levels (0.739, 95% CI 0.609-0.895, P = 0.002), accounting for 5.77% of the total effect.

Discussion: This MR study suggests that CIPs may be associated with NKTCL pathogenesis and proposes that metabolite-mediated pathways represent a potential novel mechanistic link. It provides preliminary evidence consistent with serum metabolites playing a role as mediators in this relationship. These findings highlight the therapeutic potential of targeting specific metabolic pathways in NKTCL.

Conclusion: Our proteome-wide MR analysis suggests an association between CIPs and NKTCL, which may be mediated by serum metabolites.