Metabolic & Cardiometabolic
MTHFR C677T increases homocysteine
Strong support Metabolic & Cardiometabolic 💰 Industry COI noted
Part of: • MTHFR C677T
RefutedContestedStrong support
consensus score 1.00
📅 Last reviewed: 2026-07-15 ⓘ
Evidence ladder
How far up the ladder this claim has climbed. A high consensus on a low rung means "consistent so far," not "proven in people."
Top evidence so far: Population patterns (Observational)
MechanismIn-vitroAnimalObservationalRCTMeta-analysis
How the studies fall
11 support 0 contradict 0 tested null 0 mixed · 11 sources, 11 independent groups
What the evidence shows
The MTHFR C677T TT genotype is associated with higher serum homocysteine in women with PCOS (reduced enzyme activity → impaired homocysteine remethylation). Mechanistic basis for the vascular/stroke-risk thread.
The evidence (11)
| Source | Grade | Stance | Quality | Finding |
|---|---|---|---|---|
| Song J, Zhang J, Guo Q, Zhao Q 2026 · Frontiers in Endocrinology | observational | supports | moderate # was invalid enum "medium" (silently read as 1.0 anyway); normalized 2026-08-18 | N. China diabetic-nephropathy cohort (n=397): Hcy 17.29±8.95 (TT) vs 13.08±6.20 (CT) vs 12.65±4.35 µmol/L (CC), p<0.001; TT genotype 12.7x risk of nephropathy vs CC. |
| Zhao J, Li X, Chen Q 2024 · Gene | observational | supports | low | Abstract-grade only (no OA full text; the prior '[FT-verified]' tag and 'tierB-fulltext' locus are unsupported by the source note's own provenance). Retrospective case-control, 104 PCOS vs 104 controls: within PCOS, TT homocysteine 'was significantly greater than that in the CT (P = 0.003) and CC' '(P = 0.002) groups'. Supports the PCOS-scoped claim, but CC/CT/TT subgroup sizes, assay methods and covariates are unseen and the authors themselves note the 'limitations of this investigation, large-sample, high-quality prospective' studies are needed -> quality low. |
| Zhou R et al 2025 · Front Nutr | observational | supports | moderate | Large infertility cohort (n=6344): serum Hcy significantly higher in MTHFR 677CT and TT vs CC (p<0.001 for both); Hcy mediated 15.8% (CT) and 41.6% (TT) of the genotype–vitamin-D-deficiency association. |
| Shareef ZA et al 2025 · Ann Med Surg (Lond) | observational | supports | moderate | Iraqi Kurdish cross-sectional study (140 T2DM patients, 140 controls; Duhok). Within T2DM patients, homocysteine rose monotonically with T-allele dose: CC 9.67 +/- 4.31, CT 16.78 +/- 4.21, TT 22.08 +/- 5.74 umol/L (P < 0.001) -- 'homocysteine (Hcy) levels were markedly higher in the TT genotype (22.08 +/- 5.74 umol/L) compared with the CC (9.67 +/- 4.31 umol/L) and CT (16.78 +/- 4.21 umol/L) genotypes' (Table 5; the comparator values the earlier abstract-level extract lacked). Serum folate fell across the same genotypes (7.41 -> 6.48 -> 5.82 ng/mL, P < 0.001), consistent with the enzymatic mechanism. Limits: genotype-stratified homocysteine is reported for T2DM patients only (no control breakdown), the comparison is unadjusted, TT n = 28, and no HWE test statistic is reported. |
| Oliveira IO, Silva LP, Borges MC, Cruz OM, Tessmann JW, Motta JVS, Seixas FK, Horta BL, Gigante DP 2017 · Eur J Clin Nutr | observational | supports | high | 1982 Pelotas Birth Cohort, whole-city general population, n=3803 young adults aged 22-23 y: 'The MTHFR 677TT genotype increased serum Hcy concentrations by 60% in men and 20% in women compared with the CC genotype (P < 0.001)'. Table 1 means: men TT 14.2 (13.6, 14.7) vs CC 8.8 (8.6, 9.1) micromol/l; women TT 8.6 (8.3, 9.0) vs CC 7.1 (7.0, 7.3). Overall ~3.45 micromol/l higher in 677TT vs 677CC (5.4 in men, 1.5 in women). Effect is folate- and lifestyle-modified in men only: 677TT smokers with low folate reached 20.9 (19.1, 22.8) micromol/l, while 'high blood folate concentrations attenuated the effects of MTHFR C677T on blood Hcy concentrations (P-value for the interaction < 0.001)'. In women no strong evidence of SNP x lifestyle interaction. Genotype frequencies 48% CC / 43% CT / 9% TT, both SNPs in Hardy-Weinberg equilibrium (P=0.64, P=0.41), >99.9% genotyping concordance on a 5% re-run, analyses adjusted for self-reported skin color as a population-structure control. No conflict of interest; Wellcome Trust / FAPERGS / CNPq funded. |
| Oliveira APG, de Matos GCB, Vieira MCDS, Corvelo TCO 2024 · Diagn Microbiol Infect Dis | observational | supports | low | Oliveira 2024, retrospective cohort of 168 H. pylori-infected patients (UFPA, Belem, Brazil), MTHFR genotyped by PCR-RFLP from gastric biopsies: 'The averages of the total homocysteine concentrations were associated with the TT genotype, advanced age and the male sex, but no dependence relationship was found with Helicobacter pylori infection.' Direction only - the abstract reports no group means, effect size, CI or adjusted model, and the sample is selected entirely on H. pylori infection. |
| Jin M et al 2022 · Medicine (Baltimore) | observational | supports | low | Han Chinese case-control, Heilongjiang (1810 LAAIS patients, 1765 controls). Among the PATIENTS (Table 4 — not the full sample), plasma homocysteine was genotype-dependent by ANOVA: TT 22.13 ± 7.76, CT 19.26 ± 9.65, CC 11.96 ± 4.13 μmol/L (P < .001 vs CC; CT vs TT P = .15). Direction confirmed on full text, but the TT cell is only 30 patients, folate and B12 were not measured ('we did not determine folate and vitamin B levels, neither in patients nor in controls'), and the reported control T-allele frequency (12.7%, TT 0.8%) is far below the established Northern-Han value — a genotyping-validity concern the authors acknowledge but do not resolve. Counts as a directional vote only; the magnitude should not be quoted. |
| Oh S et al 2026 · Eur Heart J Case Rep | observational | supports | low | Single-patient case report (n=1): homozygous MTHFR C677T confirmed by genetic screening, with plasma homocysteine >50 µmol/L (normal 5.08–15.39) and a concurrent marked folate deficiency (5.31 nmol/L, normal >12.19; B12 normal at 264 pmol/L). Other thrombophilias excluded (Factor V Leiden negative; protein C 90%, protein S 120%, antithrombin III 96.9%, antiphospholipid panel negative). The genotype's contribution cannot be separated from the folate deficiency, and no post-treatment homocysteine value is reported — the only 6-month outcome given is imaging: 'After 6 months of outpatient follow-up, the PTE completely resolved and the AT partially improved'. Authors: 'although this remains hypothesis-generating and cannot establish causality.' |
| Akácsos-Szász OZ et al 2026 · Biomedicines | observational | supports | low | Critical-PAD subgroup (n=31; 13 G/G, 12 G/A, 6 A/A): 'Significantly higher (p = 0.0334) serum homocysteine levels were measured in patients with homozygous mutation (29.61 ± 14.44 (SD) μmol/L) compared to patients without gene mutations (16.23 ± 7.73 (SD) μmol/L), but there was no significant difference (p > 0.05) when compared to heterozygous MTHFR mutation homocysteine values (12.54 ± 5.52 (SD) μmol/L).' Vitamin B12 and folate were not measured, and undetermined genotype calls were assigned to the A/A group. |
| Li Y, Diao R, Ou Y, Li D, Yu S, Ye X, Guo Y, Xu X, Tan Q, Wang L 2025 · J Reprod Immunol | observational | supports | low | Li 2025, retrospective single-centre cross-sectional study of a spontaneous-abortion cohort (474 women, 235 men; Shenzhen Second People's Hospital, Lingnan, China, Jul 2019-Nov 2022), participants split CC/CT/TT: 'In women with SA, TT carriers exhibited significantly higher TPO-Ab (P = 0.005), Tg-Ab (P < 0.001), and HCY (P = 0.002) levels than CC and CT.' Direction only - no mean, SD, effect size or CI is reported for homocysteine. Homocysteine is incidental to this paper: the modelled outcome is thyroid autoantibodies and HCY enters the regression as a covariate ('adjusted for age, BMI, and HCY'). Male homocysteine by genotype is NOT reported; the paper's only male null is for autoantibodies ('Thyroid autoantibodies levels did not differ across MTHFR genotypes in male participants'), so no sex difference in the HCY effect can be read from this source. Abstract-grade: not open access, no full text obtainable. |
| Daghlas I et al 2026 · J Neuroimmunol | observational | supports | low | [Abstract-grade; homocysteine data are secondhand] Daghlas 2026 (J Neuroimmunol 410:578784), two-sample Mendelian randomization + colocalization run on GWAS summary statistics. The paper's own outcome is multiple sclerosis, not homocysteine: 'We obtained genetic associations of C677T with homocysteine levels (n = 1210), MS risk (meta-analysis of three datasets: 43,069 cases), and MS severity (12,584 cases).' The C677T-homocysteine association is therefore an externally obtained instrument, not measured here, and no genotype-specific homocysteine mean, per-allele beta or CI appears anywhere in the readable text. What the paper contributes to this claim is (a) the direction encoded in its own scaling - effects reported 'per homocysteine-raising allele' and 'scaled to an SD increase in genetically determined homocysteine levels due to MTHFR perturbation' - and (b) its own colocalization result, 'Colocalization analyses supported C677T as a shared causal variant for MS and homocysteine levels at the MTHFR locus.' Directional support only, from the smallest and only secondhand homocysteine sample in this ledger. Reader caution: this paper's headline runs the OTHER way on disease - the homocysteine-raising allele was protective against MS (OR 0.91, 95 % CI 0.89-0.93 per allele; OR 0.73, 95 % CI 0.66-0.79 per SD genetically raised homocysteine), and that 0.73 - previously quoted in this extract beside a homocysteine statement - is an MS odds ratio, not an effect on homocysteine. |
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