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Interventions and public health nutrition

Association of genetic and epigenetic variants in one-carbon metabolism gene with folate treatment response in hyperhomocysteinaemia

Abstract

Background

Folate supplementation treatment is the first-line therapy in hyperhomocysteinaemia (HHcy). Up to 40% of HHcy patients do not benefit from folate therapy. Genetic and epigenetic factors of one-carbon metabolism (1-CM) might be identified as a predictor of folate supplementation treatment response. In the present study, we attempt to identify whether genetic and epigenetic factors might predict folate treatment response.

Methods

A total of 230 patients with HHcy were involved in this prospective cohort study. Differences between baseline concentrations and concentrations obtained at 90 days of treatment were calculated to evaluate the treatment response. General linear models and Pearson correlation was used to explore associations among single-nucleotide polymorphisms (SNPs), DNA methylation, and folate treatment response. Finally, mediation analysis was performed to investigate whether DNA methylation of MTRR mediates the association between SNPs and treatment response.

Results

MTHFD rs1950902 and MTRR rs162036, rs1801394 was associated with the folate treatment response (P = 0.000, 0.048, and 0.043, respectively). CBS and CBS_2 DNA methylation was significantly associated with folate treatment response (P = 0.0009 and < 0.001). DNA methylation of MTHFR, MTR, and MTRR was also significantly associated with folate treatment response (P < 0.001). DNA methylation of MTRR and MTRR_1 mediated 40.71% and 40.47% of the effect of rs1801394 on folate treatment response, respectively.

Conclusions

Our results indicated that the 1-CM gene SNPs and DNA methylation was associated with folate treatment response and can be further evaluated relationship between SNPs and DNA methylation in 1-CM with treatment response in a larger sample.

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Fig. 1: Simplified overview of the one-carbon metabolism pathway.
Fig. 2: Association between one-carbon metabolism gene SNPs and folate treatment response.
Fig. 3: Association between DNA methylation of one-carbon metabolism gene and folate treatment response.
Fig. 4: Association between MTRR SNPs and DNA methylation.
Fig. 5: Mediation analysis and sensitivity analysis of MTRR rs1801394 SNPs (predictor), DNA methylation (mediator), and folate treatment response (outcome).

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Acknowledgements

We appreciated all the members from the Fifth Affiliated Hospital of Zhengzhou University to achieve such results for their truly magnificent efforts. The Department of Science and Technology of Henan Province had no role in the design, analysis, or writing of this article.

Funding

Funding was provided by the Department of Science and Technology of Henan Province (no.132102310431).

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Contributions

All authors reviewed and approved the final paper. DL had full access to the data and write the paper; QZ and XH: experiments conception and design; OG: data acquisition; CZ: data analysis and interpretation; WZ: study supervision.

Corresponding author

Correspondence to Weidong Zhang.

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The authors declare that they have no conflict of interest.

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Li, D., Zhao, Q., Huang, X. et al. Association of genetic and epigenetic variants in one-carbon metabolism gene with folate treatment response in hyperhomocysteinaemia. Eur J Clin Nutr 74, 1073–1083 (2020). https://doi.org/10.1038/s41430-020-0611-x

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