MTHFR Gene Polymorphisms: A Single Gene with Wide-Ranging Clinical Implications-A Review

Abstract

The enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a process essential for the methylation of homocysteine to methionine. Polymorphisms in the MTHFR gene can reduce enzyme activity, disrupting the folate cycle and leading to hyperhomocysteinemia. The two most common polymorphisms associated with this gene are 667C>T (rs1801133) and 1298A>C (rs1801131). Background: This review provides a comprehensive summary of the current knowledge regarding MTHFR polymorphisms, with a particular focus on their potential impact on disease susceptibility. We hope this review will serve as a valuable resource for understanding the significance of MTHFR polymorphisms and their complex relationships with various diseases. Methods: For this review, we prioritized recent evidence, focusing on reviews and meta-analyses published between 2015 and 2025, sourced from PubMed and Google Scholar. Results: We explore the connection between these polymorphisms and a broad spectrum of medical conditions, including cardiovascular diseases and oxidative stress pathology; neurological and psychiatric disorders, such as Autism Spectrum Disorder, Alzheimer's disease, Schizophrenia, and Major Depressive Disorder; fertility, pregnancy, and neonatal complications, including recurrent pregnancy loss, pre-eclampsia, preterm birth, low birth weight, and neural tube defects; metabolic disorders, such as diabetes mellitus, inflammatory bowel disease, and non-alcoholic fatty liver disease; and oncological conditions, including breast, prostate, and ovarian cancers; as well as leukemia, and autoimmune diseases, particularly rheumatoid arthritis. Conclusions: While some diseases have a well-established association with MTHFR polymorphisms, others require further investigation. Our analysis highlights the crucial role of environmental factors, such as ethnic background and dietary folate intake, in influencing study outcomes.

Keywords: Alzheimer’s disease; MTHFR; NTDs; atherosclerosis; cancerogenesis; diabetes; folate; homocysteine; mutations; polymorphisms.

Figure 1

Graphic representation of the reactions of the folate cycle with information specified in the introduction, the destination of the indicated products is shown.

Figure 2

The figure depicts the effects of hyperhomocysteinemia/elevated homocysteine levels on the cardiovascular and the nervous system, focusing on the endothelium and neurons, based on the information provided in the introduction [13,14].

Figure 3

The figure shows the discussed pathomechanism of epithelial damage and its contribution to atherosclerotic plaque formation in hyperhomocysteinemia.

Figure 4

Selection of diseases with a possible connection to MTHFR 677C>T and 1298A>C polymorphisms. Here are some of the most important articles on the subject of MTHFR and the following associated issues: oxidative stress—Kaplan et al. [18]; atherosclerosis—Yuan et al. [16], and Raghubeer and Matsha [24]; ischemic stroke—Ahmed et al. [28], Qin et al. [30], Zhao et al. [31], and Song et al. [32]; schizophrenia—Meng et al. [79], Yoo et al. [89], and Zhang et al. [90]; bipolar disorder—Khan et al. [78], Meng et al. [79], and Zhang et al. [90]; major depressive disorder—Zhang et al. [90], and Asif et al. [93]; autism spectrum disorder—Qiu et al. [81], Li et al. [82], and Razi et al. [83]; leukemia—Raoufi et al. [73], and Lien et al. [74]; breast cancer—Petrone et al. [58], and Kumar et al. [63]; prostate cancer—You et al. [64]; metabolic syndrome—Wang et al. [121]; obesity—Fu et al. [123]; inflammatory bowel disease—Varzari et al. [137], and Karban et al. [138]; non-alcoholic fatty liver disease—Sun et al. [129]; male infertility—Gong et al. [145]; preterm birth—Huang et al. [158], and Wu et al. [161]; recurrent pregnancy loss—Mehta et al. [149]; neural tube defects—Almekkawi et al. [166], and Li et al. [167]; gestational diabetes mellitus—Tan and Chen [116]; type 2 diabetes mellitus—Meng et al. [103], and Yan et al. [107].