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Clinical nutrition

Association between gene promoter methylation of the one-carbon metabolism pathway and serum folate among patients with hyperhomocysteinemia

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Abstract

Aim

Age and lower folate concentrations are well-known risk factors for cardiovascular disease (CVD), but the potential roles of age and folate deficiency in hyperhomocysteinemia (HHcy), especially in HHcy patients with abnormal methylation levels of key enzyme genes promoter in homocysteinemia (Hcy) pathway, have not been thoroughly evaluated. The purpose of this study was to evaluate the relationship between the promoter methylation levels of six key enzyme genes and age and serum folate level to better understand the pathogenesis of HHcy.

Methods

In 299 HHcy patients, six key enzyme genes promoter methylation was analyzed by PCR amplification and MethylTargetTM methods.

Results

The betaine homocysteine methyltransferase (BHMT), Cystathionine β-synthase (CBS), and Methionine synthasegene (MTR) promoter methylation levels were positively associated with age and a negative correlation was found between CBS promoter methylation level and folate levels. However, these associations were not significant after Bonferroni correction. The stratified analysis showed that the methylation level of CBS gene promoter was positively correlated with age in males, and a positive correlation was also found between BHMT gene promoter methylation level and age in HHcy patients with a history of diabetes or hypertension. Moreover, stratified analysis according to sex revealed that the methylation levels of three CpG regions of BHMT_2, CBS_2, and CBS_3 were positively correlated with age in males after Bonferroni correction.

Conclusions

Our data suggested that age and folate deficiency may increase the risk of HHcy by mediating methylation of the promoter regions of key enzyme genes in the one-carbon metabolism pathway.

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Fig. 1: A simplified illustration of the homocysteine metabolism pathway.
Fig. 2: The correlation between the methylation levels of BHMT or CBS promoters and age or folate levels was analyzed by gender stratification.

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Acknowledgements

This project was funded by the Department of Science and Technology of Henan Province (no. 132102310431). The funder did not participate in the design, analysis or writing, or approval of the paper. All authors thank the staff from the Department of Neurology, the Fifth Affiliated Hospital of Zhengzhou University, for their assistance and support.

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Authors and Affiliations

  1. Department of Epidemiology, School of Public Health, Zhengzhou University, Zhengzhou, 450001, Henan, China

    Xiaowen Huang, Qinglin Zhao, Dankang Li, Bingnan Ren, Limin Yue, Fengxian Shi, Xiliang Wang, Caifang Zheng, Xiaorui Chen & Weidong Zhang

  2. Department of Biostatistics and Bioinformatics, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA, 70112, USA

    Chengda Zhang

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  1. Xiaowen Huang
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Contributions

All authors’ responsibilities were as follows: XH contributed to the writing of this paper. QZ and DL were involved in the study concept and design. BR, LY, FS, and XW acquired data of this study. CZ, XC and CZ carried out data analysis and interpretation. WZ was in charge of study supervision.

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Correspondence to Weidong Zhang.

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Huang, X., Zhao, Q., Li, D. et al. Association between gene promoter methylation of the one-carbon metabolism pathway and serum folate among patients with hyperhomocysteinemia. Eur J Clin Nutr 74, 1677–1684 (2020). https://doi.org/10.1038/s41430-020-0657-9

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