rs326124 — MTRR
Intronic MTRR variant associated with colorectal cancer survival in interaction with alcohol consumption
Details
- Gene
- MTRR
- Chromosome
- 5
- Risk allele
- A
- Clinical
- Risk Factor
- Evidence
- Emerging
Population Frequency
Category
Methylation & DetoxSee your personal result for MTRR
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MTRR rs326124 — Alcohol Modulates a Methylation Survival Signal in Colorectal Cancer
Methionine synthase reductase (MTRR) keeps the one-carbon methylation cycle
running by reactivating methionine synthase (MTR) after oxidative inactivation.
When MTRR function is reduced — whether by the well-studied coding variant
rs1801394 A66G11 rs1801394 A66G
p.Ile22Met — a missense variant that reduces MTRR's ability to
reactivate B12 or by regulatory effects from intronic variants — the
recycling of vitamin B12 from an inactive form back to active methylcobalamin
is impaired. rs326124 is an intronic variant at position 7,877,065 on chromosome 5
within the MTRR gene. The GRCh38 reference allele at this position is A, but A
is also the minor allele globally (~17%): most people carry G (~83%), meaning
the A-allele carriers are the minority variant group.
The Mechanism
As an intronic variant, rs326124 does not alter the MTRR amino acid sequence.
Its biological effect, if any, is likely regulatory — influencing MTRR transcript
levels, alternative splicing, or intronic regulatory element binding.
Intronic regulatory elements22 Intronic regulatory elements
Including branch points, splicing enhancers, and
non-coding RNA binding sites can influence gene expression without changing the
protein sequence. Reduced MTRR expression would impair the reactivation
of methionine synthase, leading to a functional B12 deficiency in the remethylation
pathway, elevated homocysteine, and downstream effects on global DNA methylation
and epigenetic gene regulation. The precise molecular mechanism of rs326124
has not been characterized experimentally.
The Evidence
The primary evidence comes from the Newfoundland Familial Colorectal Cancer Study33 Newfoundland Familial Colorectal Cancer Study
Wang Y et al. The Roles of MTRR and MTHFR Gene Polymorphisms in Colorectal Cancer
Survival. Nutrients, 2022, which followed 532 colorectal cancer
patients (diagnosed 1999–2003, median follow-up 6.4 years). The study assessed
MTRR haplotype variants — rs326124, rs3776467, rs162040, rs3776455, and the
coding variant rs1801394 — in relation to overall survival (OS) and
disease-free survival (DFS).
For rs326124, along with the other MTRR intronic variants, a significant interaction with pre-diagnostic alcohol consumption was observed: carriers of the protective G allele showed superior overall survival, but only among patients consuming alcohol below the median (2.17 g/day). Among higher alcohol consumers, the allele-associated benefit was not seen. This interaction pattern suggests that alcohol's known disruption of folate absorption and one-carbon methyl-donor homeostasis amplifies the functional consequences of reduced MTRR activity.
The evidence base for rs326124 specifically is limited: one study, a survival cohort of CRC patients, with the variant analyzed as part of an MTRR haplotype block rather than in isolation. No homocysteine association data, no methylation phenotype data, and no prospective general-population data exist for this specific rsid. The SNPedia magnitude of 2.5 reflects the plausible biological context rather than robust independent replication.
Practical Actions
For A-allele carriers (AG or AA genotypes), the actionable insight centers on two exposures that interact with MTRR-dependent methylation: alcohol and B12/folate status. Alcohol reduces intestinal folate absorption and depletes methyl donors; in the context of reduced MTRR regulatory capacity, this may translate to meaningfully compromised methylation. Using active B12 forms (methylcobalamin or hydroxocobalamin rather than cyanocobalamin) and preferring methylfolate over synthetic folic acid supports the one-carbon cycle at both the MTRR step and the downstream methionine synthase reaction.
Monitoring homocysteine provides the most direct readout of functional methylation capacity — elevated homocysteine signals inadequate remethylation and is itself a colorectal cancer risk biomarker. A level above 10 µmol/L warrants targeted nutritional support.
Interactions
rs326124 is in the same MTRR haplotype block as rs3776467, rs162040, and rs3776455, all of which showed parallel survival interactions with alcohol in the Wang 2022 study. The coding variant rs1801394 (MTRR A66G, p.Ile22Met) operates on MTRR catalytic activity and was also studied in the same cohort; combined impairment through both regulatory (rs326124) and catalytic (rs1801394) mechanisms could reduce MTRR function more substantially than either variant alone. Upstream methylfolate supply through MTHFR (rs1801133 C677T) and MTR activity (rs1805087) also modulate the severity of any MTRR impairment.
Nutrient Interactions
Genotype Interpretations
What each possible genotype means for this variant:
Common genotype; standard MTRR expression and methylation capacity
The GG genotype means you do not carry the minor A allele at rs326124. Because rs326124 is an intronic variant, its effects are regulatory rather than structural. The G allele appears to represent the ancestral regulatory state that preserves normal MTRR expression under alcohol and dietary stress. Without independent functional studies of rs326124, the main clinical relevance is the absence of the A-allele interaction with alcohol-driven methylation disruption. Standard dietary folate and B12 intake is appropriate.
One copy of the minor A allele — moderate alcohol-methylation interaction
The heterozygous AG genotype carries one copy of the intronic A allele, which may modulate MTRR transcript levels or splicing efficiency. The survival interaction with alcohol observed in the Wang 2022 cohort suggests that alcohol-induced disruption of the folate/methyl-donor pool amplifies the functional consequence of reduced MTRR regulatory efficiency. The evidence base is limited to one study in CRC patients and cannot yet be generalized to healthy population methylation outcomes; however, optimizing methylation nutrition is low-risk and supported by the broader MTRR biology.
Two copies of the minor A allele — highest alcohol-methylation interaction burden
The AA genotype represents homozygosity for the minor allele at rs326124. Since the GRCh38 reference allele at this locus is A — but A is the population minority — this genotype is effectively the homozygous variant state. The functional consequence is uncertain: intronic variant effects on gene expression are typically smaller than missense changes, and rs326124 has not been directly studied in in vitro or methylation phenotyping studies. However, the convergence of this variant with other MTRR impairments (such as the coding A66G variant rs1801394) in the same haplotype region, and the consistent alcohol-interaction pattern across five MTRR variants in the Wang 2022 data, makes the AA state a reasonable target for proactive methylation support. Homocysteine testing provides the most actionable readout of actual methylation deficit.