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Genetic variants in folate metabolism-related genes, serum folate and hepatocellular carcinoma survival: the Guangdong Liver Cancer Cohort study

Published online by Cambridge University Press:  07 November 2024

Yunshan Li ,
Jing Shu ,
Peishan Tan ,
Xiaocong Dong ,
Mingjie Zhang ,
Tongtong He ,
Zhijun Yang ,
Xuehong Zhang ,
Edward L. Giovannucci  and
Zhaoyan Liu
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Yunshan Li
Affiliation:
Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, People’s Republic of China
Jing Shu
Affiliation:
Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, People’s Republic of China
Peishan Tan
Affiliation:
Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, People’s Republic of China
Xiaocong Dong
Affiliation:
Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, People’s Republic of China
Mingjie Zhang
Affiliation:
Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, People’s Republic of China
Tongtong He
Affiliation:
Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, People’s Republic of China
Zhijun Yang
Affiliation:
Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, People’s Republic of China
Xuehong Zhang
Affiliation:
Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA Yale University School of Nursing, Orange, CT, USA
Edward L. Giovannucci
Affiliation:
Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
Zhaoyan Liu
Affiliation:
Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, People’s Republic of China
Zhongguo Zhou
Affiliation:
Department of Hepatobiliary Surgery, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China
Qijiong Li
Affiliation:
Department of Hepatobiliary Surgery, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China
Yanjun Xu
Affiliation:
Department of Chronic Noncommunicable Disease Prevention and Control, Guangdong Provincial Center for Disease Control and Prevention, Guangzhou, People’s Republic of China
Xiaojun Xu
Affiliation:
Department of Chronic Noncommunicable Disease Prevention and Control, Guangdong Provincial Center for Disease Control and Prevention, Guangzhou, People’s Republic of China
Tianyou Peng
Affiliation:
Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, People’s Republic of China
Jialin Lu
Affiliation:
Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, People’s Republic of China
Yaojun Zhang*
Affiliation:
Department of Hepatobiliary Surgery, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China
Huilian Zhu*
Affiliation:
Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, People’s Republic of China
Aiping Fang*
Affiliation:
Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, People’s Republic of China
*
*Corresponding authors: Dr Yaojun Zhang, email zhangyuj@sysucc.org.cn; Dr Huilian Zhu, email zhuhl@mail.sysu.edu.cn; Dr Aiping Fang, email s.r.sarbini@gmail.com
*Corresponding authors: Dr Yaojun Zhang, email zhangyuj@sysucc.org.cn; Dr Huilian Zhu, email zhuhl@mail.sysu.edu.cn; Dr Aiping Fang, email s.r.sarbini@gmail.com
*Corresponding authors: Dr Yaojun Zhang, email zhangyuj@sysucc.org.cn; Dr Huilian Zhu, email zhuhl@mail.sysu.edu.cn; Dr Aiping Fang, email s.r.sarbini@gmail.com
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Abstract

Folate metabolism is involved in the development and progression of various cancers. We investigated the association of single nucleotide polymorphisms (SNP) in folate-metabolising genes and their interactions with serum folate concentrations with overall survival (OS) and liver cancer-specific survival (LCSS) of newly diagnosed hepatocellular carcinoma (HCC) patients. We detected the genotypes of six SNP in three genes related to folate metabolism: methylenetetrahydrofolate reductase (MTHFR), 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) and 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR). Cox proportional hazard models were used to calculate multivariable-adjusted hazard ratios (HR) and 95 % CI. This analysis included 970 HCC patients with genotypes of six SNP, and 864 of them had serum folate measurements. During a median follow-up of 722 d, 393 deaths occurred, with 360 attributed to HCC. In the fully-adjusted models, the MTRR rs1801394 polymorphism was significantly associated with OS in additive (per G allele: HR = 0·84, 95 % CI: 0·71, 0·99), co-dominant (AG v. AA: HR = 0·77; 95 % CI: 0·62, 0·96) and dominant (AG + GG v. AA: HR = 0·78; 95 % CI: 0·63, 0·96) models. Carrying increasing numbers of protective alleles was linked to better LCSS (HR10–12 v. 2–6 = 0·70; 95 % CI: 0·49, 1·00) and OS (HR10–12 v. 2–6 = 0·67; 95 % CI: 0·47, 0·95). Furthermore, we observed significant interactions on both multiplicative and additive scales between serum folate levels and MTRR rs1801394 polymorphism. Carrying the variant G allele of the MTRR rs1801394 is associated with better HCC prognosis and may enhance the favourable association between higher serum folate levels and improved survival among HCC patients.

Keywords

Gene polymorphismmethylenetetrahydrofolate reductase5-methyltetrahydrofolate-homocysteine methyltransferase5-methyltetrahydrofolate-homocysteine methyltransferase reductaseSerum folateHepatocellular carcinomaSurvival
Type
Research Article
Information
British Journal of Nutrition , Volume 132 , Issue 11 , 14 December 2024 , pp. 1411 - 1422
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Copyright
© The Author(s), 2024. Published by Cambridge University Press on behalf of The Nutrition Society

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