ORIGINAL RESEARCH article
Front. Nutr.
Sec. Clinical Nutrition
Volume 12 - 2025 | doi: 10.3389/fnut.2025.1644302
Association between MTHFR polymorphisms and vitamin D status in infertile women: a mediation analysis
Provisionally accepted
Ruiqiong Zhou1,2
Zhenghong Zhu3
Zhaoyi Wang1
Mei Dong1,2
Li Huang1,2Songlu Wang1,2Xiqian Zhang1,2*
Fenghua Liu1,2*- 1Guangdong women and children hospital, Guangzhou, China
- 2Southern University of Science and Technology, Shenzhen, China
- 3Sun Yat-Sen University, Guangzhou, China
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Background: Methylenetetrahydrofolate reductase (MTHFR) regulates folate metabolism and homocysteine (Hcy) methylation. Impaired folate metabolism and vitamin D deficiency are both closely associated with female reproductive disorders, but their specific roles and relationship remain largely unknown. This study aimed to investigate the relationship between MTHFR polymorphisms and vitamin D status and to examine the mediating effect of Hcy.Methods: A total of 6344 infertile patients were included in this retrospective study.Multivariable logistic regression and multiple linear regression models, and stratified analyses were used to investigate the relationship between MTHFR polymorphisms (C677T and A1298C) and vitamin D status. Smooth curve fitting model and spearman correlation analysis were used to explore the correlation between Hcy levels and vitamin D status. Mediation analyses were performed to examine the direct and indirect effects of MTHFR polymorphisms on vitamin D status.The risk of vitamin D deficiency and serum Hcy levels were significantly higher in patients with MTHFR677CT and TT compared with CC (P < 0.001 for both). In multivariate regression models, MTHFR677CT and TT were positively associated with vitamin D deficiency compared with CC. No significant differences were found for A1298C polymorphism. Smooth curve fitting models showed that serum Hcy was linearly correlated with both 25(OH)D levels (p-nonlinear = 0.063) and prevalence of vitamin D deficiency (p-nonlinear=0.261). In mediation analyses using logistic regression models, Hcy mediated 15.8% and 41.6% of the associations between 677CT and TT (versus CC) and vitamin D deficiency, respectively.The effect of C677T polymorphism on vitamin D status can be explained jointly by a direct association between C677T polymorphism and vitamin D, and an indirect association mediated by Hcy.
Keywords: MTHFR polymorphism, Vitamin D, Homocysteine, Infertility, Mediation analysis
Received: 10 Jun 2025; Accepted: 28 Aug 2025.
Copyright: © 2025 Zhou, Zhu, Wang, Dong, Huang, Wang, Zhang and Liu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Xiqian Zhang, Guangdong women and children hospital, Guangzhou, China
Fenghua Liu, Guangdong women and children hospital, Guangzhou, China
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