rs1532268 — MTRR MTRR S175L

Missense variant in methionine synthase reductase that raises homocysteine when vitamin B12 is low, affecting B12-dependent methylation efficiency

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MTRR S175L — When B12 Supply Determines Methylation Capacity

The MTRR gene (methionine synthase reductase) runs a critical maintenance reaction in the methylation cycle. Methionine synthase (MTR) converts homocysteine back to methionine using vitamin B12 as a cofactor, but in doing so it oxidizes its own cobalamin 11 Cobalamin: the cobalt-containing form of vitamin B12 that acts as the cofactor for MTR cofactor to an inactive form. MTRR's sole job is to reactivate this oxidized B12, keeping MTR running. If MTRR works less efficiently, MTR stalls and homocysteine accumulates — but only when B12 supply is tight.

The Mechanism

The S175L missense variant (c.524C>T) substitutes a serine for leucine at position 175 of the MTRR protein. Serine and leucine differ significantly in polarity: serine is hydrophilic, leucine is hydrophobic. Position 175 lies in a functional domain of MTRR, and the amino acid swap is thought to reduce the enzyme's efficiency at reactivating the cobalamin cofactor. Critically, this effect is only unmasked when intracellular B12 is in short supply — when B12 is adequate, the pathway appears to compensate. Riboflavin (vitamin B2) is also a cofactor for MTRR via its FMN 22 Flavin mononucleotide — the active form of riboflavin used as an electron carrier in MTRR domain, so riboflavin status modulates the variant's downstream impact.

The Evidence

The clearest data on rs1532268 comes from a Spanish population study of 771 adults33 Spanish population study of 771 adults
García-Minguillán CJ et al. Riboflavin status modifies the effects of MTHFR and MTRR polymorphisms on homocysteine. Genes Nutr, 2014. T-allele carriers had 13.7% higher plasma homocysteine when cobalamin was low (≤273 pmol/L, lowest quartile) compared to CC individuals (p < 0.01). When cobalamin was in the upper quartiles, no difference was observed. This gene–environment interaction identifies the key lever: B12 status.

For cancer risk, a meta-analysis of five studies pooling 2800 gastric cancer cases and 2679 controls44 meta-analysis of five studies pooling 2800 gastric cancer cases and 2679 controls
Zhong G et al. MTRR rs1532268 polymorphism and gastric cancer risk. J Int Med Res, 2022 found the T allele increases gastric cancer risk by approximately 14% (OR 1.14, 95% CI 1.01–1.29). A separate Korean case-control study55 Korean case-control study
Lu YT et al. Riboflavin intake, MTRR genetic polymorphism rs1532268 and gastric cancer risk. Br J Nutr, 2022 (377 cases, 756 controls) showed that T-allele carriers with low riboflavin intake had 93% higher gastric cancer risk (OR 1.93, 95% CI 1.09–3.42), while adequate riboflavin appeared protective.

For drug interactions, pediatric ALL patients with the CT or TT genotype showed significantly higher methotrexate serum concentrations66 significantly higher methotrexate serum concentrations
PMID 35434830 at 24 hours than CC patients (p = 0.04), suggesting altered folate pathway pharmacokinetics that may affect toxicity monitoring.

Practical Actions

The actionable insight from this variant is B12-centric: maintaining adequate cobalamin removes the functional penalty of the T allele. Methylcobalamin — the active form that directly participates in the MTR-MTRR cycle — is the preferred supplemental form. Riboflavin status also matters; T-allele carriers on low riboflavin diets face compounded gastric cancer risk, and riboflavin is a cheap, safe supplement. Periodic monitoring of plasma homocysteine provides a functional readout of whether the methylation cycle is running smoothly.

Interactions

MTRR S175L sits directly upstream of MTR (rs1805087, A2756G), which it reactivates. If both MTR and MTRR are running suboptimally, the homocysteine-to-methionine conversion is compromised from two directions simultaneously. MTHFR (rs1801133, C677T) is an upstream pathway partner supplying the methyl-THF substrate for MTR; compound impairment across MTHFR + MTRR + MTR (the "methylation triple") represents the strongest case for targeted B-vitamin supplementation in this pathway. MTRR A66G (rs1801394) is the most studied MTRR variant and is well-established as a functional variant; rs1532268 likely acts independently given its location in a different exon.

Drug Interactions

methotrexate increased_toxicity literature

Nutrient Interactions

vitamin B12 increased_need
riboflavin increased_need

Genotype Interpretations

What each possible genotype means for this variant.

CC Normal Reactivation Normal

Normal MTRR S175L — efficient B12 reactivation

You carry two copies of the common C allele at MTRR rs1532268. Your MTRR enzyme reactivates vitamin B12 efficiently, supporting steady methionine synthase activity. Homocysteine is not elevated through this mechanism. About 40% of Europeans share this genotype.

CT Mildly Reduced Reactivation Intermediate

One MTRR S175L copy — mildly reduced B12 reactivation when B12 is low

The S175L substitution reduces the efficiency with which MTRR reactivates the oxidized cobalamin cofactor that methionine synthase (MTR) produces during normal operation. With one functional copy and one S175L copy, reactivation capacity is intermediate. The key modifier is intracellular B12 availability: at high B12, the substrate is abundant enough to compensate; at low B12, the bottleneck is unmasked and homocysteine rises by roughly 14% (PMID 25322900).

Riboflavin is an independent cofactor for MTRR. Heterozygous carriers with habitually low riboflavin intake face disproportionately elevated gastric cancer risk in observational data (PMID 34078503).

TT Reduced Reactivation Reduced

Two MTRR S175L copies — B12-dependent methylation is vulnerable

Homozygous TT individuals have both copies of MTRR running at reduced B12- reactivation efficiency. The 13.7% homocysteine elevation seen in T-allele carriers as a whole (PMID 25322900) is expected to be more pronounced in TT homozygotes. Gastric cancer risk is elevated in T-allele carriers overall (OR 1.14), and the gene–riboflavin interaction is especially relevant: in T+ carriers with low riboflavin, gastric cancer risk nearly doubles (OR 1.93) compared to CC carriers with adequate riboflavin (PMID 34078503).

Methotrexate disposition is also affected — TT genotype carriers show higher methotrexate serum concentrations, which has implications for toxicity monitoring in oncology settings (PMID 35434830).