代謝物分佈的縱向變化及其與乙型肝炎相關肝細胞癌風險的

StephenW

Longitudinal change of metabolite profile and its relation to multiple risk factors for the risk of developing hepatitis B‐related hepatocellular carcinoma
Bo‐Yuan Huang
Min‐Ru Tsai
Jia‐Kai Hsu
Ching‐Yu Lin
Chih‐Lin Lin
Jui‐Ting Hu
Yi‐Wen Huang
Chun‐Jen Liu
Wan‐Jung Wu
Chih‐Feng Wu
Feng‐Yu Sung
Pei‐Jer Chen
Hao‐Jan Liang
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First published: 10 September 2020
https://doi.org/10.1002/mc.23255

Bo‐Yuan Huang, Min‐Ru Tsai, Jia‐Kai Hsu, and Ching‐Yu Lin contributed equally to this work.

Abstract

Despite considerable knowledge of viral pathogenesis, the pathophysiological changes related to the multifactorial, multistep process of hepatitis B virus (HBV)‐related hepatocellular carcinoma (HCC) development remains unclear. Longitudinal metabolomics study can reveal biological process for disease progression. We performed metabolite profiling with longitudinal prediagnostic plasma samples from two nested case‐control studies of hepatitis B surface antigen carriers participating in ultrasound screening for HCC, one within a government employee cohort (870 samples from 109 HCC cases and 107 controls) and the other within a hospital‐based cohort (266 samples from 63 HCC cases and 114 controls). Of the 34 measured metabolites, tyrosine, isoleucine, and glutamine were consistently associated with HCC. In analyses combining longitudinal data, a high metabolic risk score based on the three amino acids was robustly associated with increased risk of HCC (OR = 3.71, 95% confidence interval: 2.53–5.42), even after adjustment for clinical factors, or when assessed for different times up to ≥8 years before diagnosis. Similar association was observed in an independent, prospective analysis comprising 633 randomly selected individuals of the government employee cohort. More importantly, this metabolite signature was longitudinally influenced by HBV‐infection phase and involved in gradual progression to liver fibrosis and cirrhosis. Furthermore, mediation analysis showed that the score mediated substantial proportions of the associations of key viral factors, insulin resistance, and diabetes status with HCC risk. Our results suggest that an amino‐acid dysregulation metabotype may play a role in HBV‐related HCC development, and may also be linked to common pathways that mediate increased HCC risks.

StephenW

代謝物分佈的縱向變化及其與乙型肝炎相關肝細胞癌風險的多種危險因素的關係
黃伯元
蔡敏如
徐家凱
林青玉
林志霖
胡瑞婷
黃以文
劉春仁
吳萬榮
吳志峰
宋鳳玉
陳佩傑
梁浩然
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首次發布：2020年9月10日
https://doi.org/10.1002/mc.23255

黃伯元，蔡敏如，徐家凱和林靜玉對此工作做出了同樣的貢獻。

抽象

儘管對病毒的發病機理有相當的了解，但與乙型肝炎病毒（HBV）相關的肝細胞癌（HCC）發育的多因素，多步驟過程相關的病理生理變化仍不清楚。縱向代謝組學研究可以揭示疾病進展的生物學過程。我們對來自兩項嵌套的參與肝癌超聲篩查的乙型肝炎表面抗原攜帶者的病例對照研究進行了縱向診斷前血漿樣品的代謝物分析，其中一項在政府僱員隊列中進行（其中109例HCC病例和107例對照中有870例）醫院為基礎的隊列（來自63例HCC病例和114例對照的266個樣本）。在34種測定的代謝產物中，酪氨酸，異亮氨酸和谷氨酰胺始終與HCC相關。在結合縱向數據進行的分析中，即使針對臨床因素進行了調整或進行了評估，基於這三種氨基酸的高代謝風險評分也與肝癌風險的增加密切相關（OR = 3.71，95％置信區間：2.53-5.42）。在診斷之前≥8年的不同時間。在一項獨立的前瞻性分析中，觀察到相似的關聯，該分析由633名政府僱員組成的團隊隨機選擇。更重要的是，這種代謝物特徵在縱向上受到HBV感染期的影響，並逐漸發展為肝纖維化和肝硬化。此外，調解分析表明，該得分介導了關鍵比例的關鍵病毒因素，胰島素抵抗和糖尿病狀態與HCC風險之間的關聯。我們的結果表明，氨基酸失調代謝型可能在HBV相關HCC發生中起作用，也可能與介導HCC風險增加的常見途徑有關。