Background:Tryptophan metabolism is involved in esophageal carcinogenesis.However,its genetic mechanisms remain unclear.This study aimed to investigate the effect of genetic variants that encode tryptophan metabolism ...Background:Tryptophan metabolism is involved in esophageal carcinogenesis.However,its genetic mechanisms remain unclear.This study aimed to investigate the effect of genetic variants that encode tryptophan metabolism on susceptibility to esophageal cancer(EC)and elucidate the mechanisms underlying genetic variation in EC progression.Methods:Age-and sex-matched cohorts of 167 patients with EC and 236 healthy controls were enrolled in this study.The concentrations of tryptophan and its metabolites were determined by self-assembled high-performance liquid chromatography-tandem mass spectrometry.High-throughput sequencing techniques were utilized to detect candidate coding genetic variants,and dominant genetic models were used to elucidate the genotypic associations.Results:Tryptophan metabolism was significantly imbalanced in patients with EC,with elevated indolepropionic acid(IPA)levels reducing the risk of EC susceptibility.ACSM2B rs73530508(A>G)mutation was associated with higher IPA levels in vivo(P?0.0004,false discovery rate[FDR]?0.0092)and significantly reduced the risk of EC susceptibility(odds ratio[OR]:0.576,Padj?0.0161).Mediation effect analysis indicated that singlenucleotide polymorphism may inhibit carcinogenesis by reducing IPA metabolism and excretion with a mediation effect of 45.54%.Conclusions:This study identifies the potential mechanism of ACSM2B rs73530508(A>G)in esophageal carcinogenesis and its role in driving increased IPA levels,thereby suppressing the risk of development.展开更多
基金funded by the 2022 Guangdong Province Clinical Drug Research Fund Project(Clinical Treatment Precision Medicine Special Project)(No:2022JZ21)the 2022 Bai Qiu En-Qiu Suo-Pharmacy Scientific Research Capacity Building Project(No:Z04JKM2021005)+3 种基金the 2022 Guangdong Science and Technology Innovation Strategic Project(“Major ProjcetstTask List”)Shan Fu Ke Letter[2022]124(No:STKJ202209072)the 2022 Special Fund for Hospital Pharmaceutical Research of Guangdong Province Hospital Association(No:YXKY202204)the 2023 Guangdong Provincial Hospital Pharmacist Youth Trust Research Fund(Qingyue Pharmacy Fund)(No:2023QNTJ14)the 2024 Guangdong Provincial Hospital Pharmaceutical Research Foundation(No:2024A05).
文摘Background:Tryptophan metabolism is involved in esophageal carcinogenesis.However,its genetic mechanisms remain unclear.This study aimed to investigate the effect of genetic variants that encode tryptophan metabolism on susceptibility to esophageal cancer(EC)and elucidate the mechanisms underlying genetic variation in EC progression.Methods:Age-and sex-matched cohorts of 167 patients with EC and 236 healthy controls were enrolled in this study.The concentrations of tryptophan and its metabolites were determined by self-assembled high-performance liquid chromatography-tandem mass spectrometry.High-throughput sequencing techniques were utilized to detect candidate coding genetic variants,and dominant genetic models were used to elucidate the genotypic associations.Results:Tryptophan metabolism was significantly imbalanced in patients with EC,with elevated indolepropionic acid(IPA)levels reducing the risk of EC susceptibility.ACSM2B rs73530508(A>G)mutation was associated with higher IPA levels in vivo(P?0.0004,false discovery rate[FDR]?0.0092)and significantly reduced the risk of EC susceptibility(odds ratio[OR]:0.576,Padj?0.0161).Mediation effect analysis indicated that singlenucleotide polymorphism may inhibit carcinogenesis by reducing IPA metabolism and excretion with a mediation effect of 45.54%.Conclusions:This study identifies the potential mechanism of ACSM2B rs73530508(A>G)in esophageal carcinogenesis and its role in driving increased IPA levels,thereby suppressing the risk of development.
