Serum Folate and Plasma Homocysteine According to MTHFR C677T Genotype and Folic Acid Supplementation in Japanese Women Preparing for Pregnancy: A Cross-Sectional Study
- 1Koga Fumitoshi Women’s Clinic, Fukuoka 810-0001, Japan
- 2Himawari Ladies Clinic Kokura, Fukuoka 802-0001, Japan
Abstract
Background: Periconceptional folic acid supplementation reduces the risk of neural tube defects. Serum folate primarily reflects recent folate exposure, whereas plasma homocysteine may provide complementary, although non-specific, information on folate-related one-carbon metabolism. We investigated the relationships among serum folate, plasma homocysteine, methylenetetrahydrofolate reductase (MTHFR) C677T genotype, and folic acid supplementation in Japanese women preparing for pregnancy. Methods: This cross-sectional observational study included 359 Japanese women attending a fertility clinic who underwent MTHFR C677T genotyping and measurement of serum folate and plasma homocysteine. Participants were categorized according to reported supplemental folic acid intake (none, 400 µg/day, or 800 µg/day). Serum folate and plasma homocysteine concentrations were compared across supplementation categories within each genotype. Multivariable logistic regression was used to identify factors associated with plasma homocysteine concentrations ≥ 8.62 µmol/L, which was treated as an exploratory threshold rather than an established clinical cutoff. Results: Serum folate concentrations were significantly higher among women reporting folic acid supplementation across all three genotype groups. Plasma homocysteine concentrations differed across supplementation categories in the CT and TT genotype groups, but not in the CC genotype group. Among women with the TT genotype, the proportions with plasma homocysteine concentrations ≥ 8.62 µmol/L were 64.3% without supplementation, 25.0% with 400 µg/day, and 12.5% with 800 µg/day. In multivariable analysis, the TT genotype was associated with higher odds of plasma homocysteine ≥ 8.62 µmol/L compared with the CC genotype (adjusted OR, 2.65; 95% CI, 1.25–5.56), whereas reported supplementation with 400 µg/day and 800 µg/day was associated with lower odds compared with no supplementation (adjusted OR, 0.36; 95% CI, 0.19–0.67 and adjusted OR, 0.33; 95% CI, 0.16–0.65, respectively). Conclusions: Serum folate and plasma homocysteine provided complementary information across MTHFR C677T genotypes in this cohort. Plasma homocysteine should be interpreted in the context of multiple nutritional and genetic determinants and should not be regarded as a specific marker of folate status alone. Combined assessment of serum folate, plasma homocysteine, and MTHFR genotype may provide additional information for preconception nutritional evaluation. Further prospective studies are needed to determine the clinical utility of this approach.
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BibTeX
@article{koga2026serum,
title = {{Serum Folate and Plasma Homocysteine According to MTHFR C677T Genotype and Folic Acid Supplementation in Japanese Women Preparing for Pregnancy: A Cross-Sectional Study}},
author = {Fumitoshi Koga and Shogo Nakayama and Shigeki Kitagami and Masayo Matsunaga and Naoko Yokoyama and Tomoyuki Fujita},
journal = {Nutrients},
year = {2026},
month = oct,
doi = {10.3390/nu18213594},
url = {https://www.mdpi.com/2072-6643/18/21/3594},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Serum Folate and Plasma Homocysteine According to MTHFR C677T Genotype and Folic Acid Supplementation in Japanese Women Preparing for Pregnancy: A Cross-Sectional Study
AU - Fumitoshi Koga
AU - Shogo Nakayama
AU - Shigeki Kitagami
AU - Masayo Matsunaga
AU - Naoko Yokoyama
AU - Tomoyuki Fujita
PY - 2026
DA - 2026/10/29
JO - Nutrients
DO - 10.3390/nu18213594
UR - https://www.mdpi.com/2072-6643/18/21/3594
AB - Background: Periconceptional folic acid supplementation reduces the risk of neural tube defects. Serum folate primarily reflects recent folate exposure, whereas plasma homocysteine may provide complementary, although non-specific, information on folate-related one-carbon metabolism. We investigated the relationships among serum folate, plasma homocysteine, methylenetetrahydrofolate reductase (MTHFR) C677T genotype, and folic acid supplementation in Japanese women preparing for pregnancy. Methods: This cross-sectional observational study included 359 Japanese women attending a fertility clinic who underwent MTHFR C677T genotyping and measurement of serum folate and plasma homocysteine. Participants were categorized according to reported supplemental folic acid intake (none, 400 µg/day, or 800 µg/day). Serum folate and plasma homocysteine concentrations were compared across supplementation categories within each genotype. Multivariable logistic regression was used to identify factors associated with plasma homocysteine concentrations ≥ 8.62 µmol/L, which was treated as an exploratory threshold rather than an established clinical cutoff. Results: Serum folate concentrations were significantly higher among women reporting folic acid supplementation across all three genotype groups. Plasma homocysteine concentrations differed across supplementation categories in the CT and TT genotype groups, but not in the CC genotype group. Among women with the TT genotype, the proportions with plasma homocysteine concentrations ≥ 8.62 µmol/L were 64.3% without supplementation, 25.0% with 400 µg/day, and 12.5% with 800 µg/day. In multivariable analysis, the TT genotype was associated with higher odds of plasma homocysteine ≥ 8.62 µmol/L compared with the CC genotype (adjusted OR, 2.65; 95% CI, 1.25–5.56), whereas reported supplementation with 400 µg/day and 800 µg/day was associated with lower odds compared with no supplementation (adjusted OR, 0.36; 95% CI, 0.19–0.67 and adjusted OR, 0.33; 95% CI, 0.16–0.65, respectively). Conclusions: Serum folate and plasma homocysteine provided complementary information across MTHFR C677T genotypes in this cohort. Plasma homocysteine should be interpreted in the context of multiple nutritional and genetic determinants and should not be regarded as a specific marker of folate status alone. Combined assessment of serum folate, plasma homocysteine, and MTHFR genotype may provide additional information for preconception nutritional evaluation. Further prospective studies are needed to determine the clinical utility of this approach.
SN - 2072-6643
ER -