rs3776455 — MTRR

Intronic MTRR variant associated with altered folate-pathway cancer risk and B12-dependent homocysteine metabolism

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MTRR rs3776455 — An Intronic Depth Variant in the B12 Recycling Gene

Methionine synthase reductase (MTRR) is the enzyme that keeps the methylation cycle running by reactivating its partner enzyme, methionine synthase (MTR). MTR uses methylcobalamin (active vitamin B12) to convert homocysteine to methionine — a reaction central to both cardiovascular health and one-carbon metabolism. During this process, the B12 cofactor is periodically oxidized to an inactive form, and MTRR's job is to reduce it back. Without effective MTRR function, homocysteine accumulates, methylation capacity declines, and the downstream supply of SAM — the universal methyl donor — tightens.

rs3776455 sits deep in an intron of MTRR (c.1677-466 from dbSNP), 466 bases from the nearest exon boundary. It does not change the MTRR protein sequence directly. Its biological significance, like many intronic variants, likely operates through its membership in a functional haplotype or through cis-regulatory effects on MTRR expression — analogous to the well-characterized rs326119 11 rs326119 (MTRR c.56+781 A>C): an intronic variant shown to reduce MTRR transcription via decreased C/EBPα binding, elevating plasma homocysteine in CC homozygotes (PMID 22179537) in the same gene, which reduces transcription via impaired transcription factor binding.

The Mechanism

As an intronic variant, rs3776455 has no direct protein-coding consequence. Functional studies specific to this site have not been published, so its mechanism is inferred from its genomic context. The C allele is the GRCh38 reference but the minor allele in most populations, which is consistent with either neutral drift or subtle selection pressure. Its position within MTRR intron 12 places it in a region that may influence mRNA splicing efficiency or serve as a tag for regulatory elements in linkage disequilibrium.

The strongest mechanistic framework is haplotype-mediated expression change: the C allele may co-segregate with MTRR regulatory variants that reduce enzyme production, paralleling what has been shown experimentally for rs162049 and rs326119 in the same gene. Under this model, C-allele carriers produce less MTRR protein, slowing B12 reactivation for MTR and reducing homocysteine clearance — particularly when B12 or folate intake is marginal.

The Evidence

The most direct evidence comes from a Bayesian network analysis22 Bayesian network analysis
Lautner-Csorba O et al. Roles of genetic polymorphisms in the folate pathway in childhood acute lymphoblastic leukemia. PLoS One, 2013 of folate-pathway polymorphisms in 543 Hungarian children with acute lymphoblastic leukemia (ALL) and 529 controls. The homozygous T genotype at rs3776455 was associated with significantly reduced ALL risk (OR 0.55, p = 1.21×10⁻³ by Bayesian relevance scoring). The protective effect was most pronounced for B-cell ALL and hyperdiploid-ALL subtypes — both of which are sensitive to folate availability, since rapidly proliferating lymphoblasts have high one-carbon demand for nucleotide synthesis. A T-allele-associated improvement in MTRR function would increase methylfolate cycling and reduce hypomethylation-driven genomic instability.

A Canadian prospective study33 Canadian prospective study
Wang Y et al. The Roles of MTRR and MTHFR Gene Polymorphisms in Colorectal Cancer Survival. Nutrients, 2022 of 532 colorectal cancer patients (Newfoundland Familial CRC Study, follow-up 1999–2010) found that protective MTRR variant alleles at rs3776455 were associated with superior overall survival, but only in patients whose pre-diagnostic alcohol consumption was below the median (2.17 g/day). Alcohol antagonizes one-carbon metabolism by depleting folate and inhibiting folate- dependent enzymes; low alcohol consumption preserves the folate pathway context in which MTRR variation has room to influence outcomes.

Both studies are consistent with a model where the T allele confers a modest functional advantage in the MTRR–MTR–homocysteine axis — protective in settings of high folate demand (childhood leukemia) and in the context of preserved folate availability (low alcohol CRC survival). The evidence overall is emerging: two independent cancer-context associations, no large homocysteine quantification studies, and no mechanistic data specific to this variant.

Practical Implications

For C-allele carriers, the interpretation is the same as for other MTRR variants with reduced function: supporting the B12 reactivation pathway with active B12 forms (hydroxocobalamin or methylcobalamin rather than cyanocobalamin) and ensuring adequate methylfolate supply addresses the upstream and downstream consequences of MTRR impairment. Monitoring plasma homocysteine provides an objective readout of whether the cycle is under strain. Minimizing alcohol intake preserves the folate-pathway context in which this variant's effect is most clinically relevant.

Interactions

rs3776455 adds depth to the MTRR locus alongside the better-characterized A66G missense variant (rs1801394) and the intronic expression variant rs162049. Carrying C alleles at rs3776455 alongside the G allele at rs1801394 (which reduces MTRR enzyme efficiency) or the G allele at rs162049 (which reduces MTRR expression) compounds B12 reactivation impairment at the same enzyme by different mechanisms. Combined with MTHFR C677T (rs1801133), which limits methylfolate production upstream, or MTR A2756G (rs1805087), which reduces methionine synthase activity directly, the cumulative effect on homocysteine clearance and DNA methylation capacity may be substantially amplified.

Nutrient Interactions

vitamin B12 increased_need
folate increased_need

Genotype Interpretations

What each possible genotype means for this variant.

TT Normal Function Normal

Normal MTRR haplotype — no elevated risk from this variant

You carry two copies of the T allele at rs3776455, the common protective genotype. This is the most frequent outcome in European populations (about 43%) and is associated with normal MTRR function at this locus. This variant does not add risk to your B12-dependent methylation cycle.

CT One C Allele Intermediate

One C allele — modestly elevated risk at this MTRR locus

The C allele at rs3776455 is the minor allele at this position — carried at 34% frequency in Europeans and 42% globally. As a heterozygote, you have one copy of the C-allele haplotype and one copy of the T-allele protective haplotype. The leukemia study showing OR 0.55 protection for TT homozygotes suggests that CT heterozygotes have intermediate risk — not as protected as TT homozygotes, but not at the elevated risk of CC homozygotes. The practical consequence of carrying one C allele is subtle: mild reduction in MTRR pathway efficiency, most relevant when B12 or folate intake is borderline or when combined with other MTRR/MTR/MTHFR variants.

CC Homozygous C Reduced

Two C alleles — greatest risk at this MTRR locus; support the B12 recycling pathway

The CC genotype at rs3776455 represents homozygosity for the C allele, which appears to reduce MTRR pathway function — likely through a haplotype-mediated mechanism involving expression regulation or splicing efficiency, as the variant itself is intronic and does not alter the protein sequence. The protective effect of the TT genotype observed in the childhood ALL study (OR 0.55) implies that CC homozygotes face elevated risk in high-folate-demand settings. The CRC survival study adds that this risk is modulated by alcohol intake, with protective variant alleles conferring survival benefit only in low-alcohol drinkers — consistent with alcohol's known depletion of folate and inhibition of folate-pathway enzymes.

Functionally, reduced MTRR pathway efficiency at this locus means slower B12 reactivation for methionine synthase (MTR), reduced homocysteine remethylation to methionine, and tighter supply of SAM — the universal methyl donor. The practical consequence is a methylation cycle that runs at reduced capacity, particularly when B12 or folate intake is marginal, alcohol intake is elevated, or when combined with other MTRR, MTR, or MTHFR variants. The evidence for this variant is emerging: two independent cancer-context associations but no large mechanistic or intervention studies specific to rs3776455.