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3523 Large-Scale Metabolomic Mendelian Randomization Analysis Identifies Pyridoxate As a Key Factor in Graft-Versus-Host Disease

Program: Oral and Poster Abstracts
Session: 722. Allogeneic Transplantation: Acute and Chronic GVHD and Immune Reconstitution: Poster II
Hematology Disease Topics & Pathways:
Research, Fundamental Science
Sunday, December 8, 2024, 6:00 PM-8:00 PM

Xinghao Yu1,2*, Yiyin Chen1,2*, Lei Lei1,2*, Dandan Lin1,2*, Ying Shen1,2*, Chang Hou1,2*, Jia Chen1*, Yi Fan1*, Huimin Lu3*, Depei Wu, MD, PhD2,4 and Yang Xu, MD1,2*

1National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
2Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
3Department of outpatient and emergency, The First Affiliated Hospital of Soochow University, Suzhou, China
4The First Affiliated Hospital of Soochow University, Suzhou, China

Metabolites and their implications on prognosis following allogeneic hematopoietic stem cell transplantation (allo-HSCT), including graft-versus-host disease (GvHD) and relapse, remain largely unexplored. In discovery Mendelian randomization (MR) analysis, we used instrumental genetic variants identified from genome-wide association studies of 309 known metabolites to investigate potential causal associations. After multiple test corrections, four metabolites exhibited causal effects on allo-HSCT outcomes in a public cohort of 7,824 adults from two European population studies. Specifically, pyridoxate and 1-stearoylglycerophosphoethanolamine were associated with reduced GvHD risk, whereas glycochenodeoxycholate increased GvHD risk. Proline was linked to decreased relapse risk. Multiple sensitive methods, along with heterogeneity and horizontal pleiotropy tests, affirmed the robustness and stability of these findings. Multivariable MR analysis ruled out pleiotropic effects from potential confounders. Notably, the effects of pyridoxate remained robust upon further validation MR analysis from another independent dataset (N = 8,089 individuals), and pyridoxate levels consistently indicated its protective role against both acute and chronic GvHD, as well as relapse. Additionally, based on long-term follow-up cohort (NCT06143501), untargeted metabolomics study of 90 post-transplant patients over 4-6 weeks found that pyridoxine levels were maintained at higher levels in the non-GvHD group compared to the GvHD group (P = 0.019). Additional mediation MR analyses elucidated the direct and indirect effects of metabolites on GvHD through CD8+ T cells. Pathway analysis highlighted key biochemical processes and metabolic disturbances, including the regulatory roles of vitamin B6 derivatives. Our study offers novel insights into the pathogenesis and therapeutic strategies for GvHD and relapse after allo-HSCT, emphasizing the potential of pyridoxate and its metabolic pathways as therapeutic targets.

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH