rs6922269 — MTHFD1L

Intronic variant in the mitochondrial folate enzyme MTHFD1L, associated with increased coronary artery disease risk and post-ACS cardiovascular mortality through impaired one-carbon unit supply

See your personal result for MTHFD1L

Upload your DNA data to find out which genotype you carry and what it means for you.

Upload your DNA data

Works with 23andMe, AncestryDNA, and other DNA test exports. Results in under 60 seconds.

The Mitochondrial Folate Link to Heart Disease

Most people associate folate metabolism with the MTHFR enzyme in the cytoplasm. But folate cycling actually begins in the mitochondria, and a second enzyme — MTHFD1L, the mitochondrial C1-tetrahydrofolate synthase11 MTHFD1L, the mitochondrial C1-tetrahydrofolate synthase
it catalyzes the conversion of 10-formyl-THF back to formate plus free THF in mitochondria, releasing one-carbon units for export to the cytoplasm — does much of the critical upstream work. rs6922269 is an intronic variant in MTHFD1L that became one of the first confirmed genetic loci for coronary artery disease (CAD) when it reached genome-wide significance in the landmark 2007 WTCCC study.

The Mechanism

MTHFD1L sits at the interface of mitochondrial and cytoplasmic one-carbon metabolism. Inside the mitochondrion, serine and glycine donate one-carbon units that are progressively oxidized through a series of folate-bound intermediates. MTHFD1L catalyzes the final step, releasing formate from 10-formyl-THF22 MTHFD1L catalyzes the final step, releasing formate from 10-formyl-THF
the resulting free tetrahydrofolate is recycled within the mitochondrion, while formate is exported through the inner mitochondrial membrane to the cytoplasm. In the cytoplasm, this formate is the primary one-carbon donor for purine synthesis, thymidylate synthesis, and — critically — the remethylation of homocysteine to methionine via the methyl cycle.

rs6922269 lies in intron 11 of MTHFD1L. Although the precise functional mechanism by which this intronic variant alters enzyme activity or expression has not been fully characterized, reduced MTHFD1L formate output would restrict cytoplasmic one-carbon availability. This would limit methylation capacity and homocysteine remethylation — a plausible biological link to cardiovascular risk. However, studies to date have not found a statistically significant association between rs6922269 genotype and plasma homocysteine levels, suggesting the cardiovascular mechanism may be more nuanced or may act through folate-dependent purine synthesis pathways rather than homocysteine elevation alone.

A distinctive feature of this variant is its association with lower active vitamin B12 (holotranscobalamin)33 active vitamin B12 (holotranscobalamin)
the biologically available fraction of serum B12 that is bound to transcobalamin II and can enter cells; only about 20-30% of total serum B12 is in this active form. The AA genotype was associated with significantly lower baseline active B12 in ACS patients even after adjustment for age and hypertensive status — pointing to an interplay between MTHFD1L function, mitochondrial one-carbon metabolism, and B12 bioavailability.

The Evidence

The foundational evidence comes from Samani et al. 200744 Samani et al. 2007
a joint analysis of two genome-wide association studies: the Wellcome Trust Case Control Consortium (WTCCC, ~2,000 CAD cases and ~3,000 controls) and the German Myocardial Infarction Family Study (~875 early-onset MI cases and ~1,644 controls). rs6922269 on chromosome 6q25.1 reached genome-wide significance (combined P=2.9×10⁻⁸) with a per-allele odds ratio of 1.23 (95% CI 1.15–1.33) for the A allele. At the time, it was one of only a small number of variants meeting genome-wide significance for CAD beyond the 9p21 locus.

The CAD association was extended to post-event prognosis in a cohort study of 1,940 patients with acute coronary syndromes in the Coronary Disease Cohort Study (CDCS)55 1,940 patients with acute coronary syndromes in the Coronary Disease Cohort Study (CDCS)
with a validation cohort of 842 post-myocardial infarction patients. AA homozygotes had significantly higher all-cause mortality at follow-up (19.6%) compared to GA (12.0%) and GG carriers (11.6%), a difference that remained after Cox adjustment for established ACS risk factors (P=0.03). However, the association was not validated in the independent PMI cohort, limiting the strength of this prognostic finding.

A Czech cohort analysis of 2,117 ACS patients (1,614 men, 503 women) followed for 7 years66 2,117 ACS patients (1,614 men, 503 women) followed for 7 years
compared with 2,559 population-based controls; genotype frequencies were similar between ACS patients and controls, suggesting the variant may influence prognosis more than incidence in this population found a striking sex-specific effect: AA genotype predicted cardiovascular mortality in males (OR 2.52, 95% CI 1.40–4.55, P<0.001) but not in females. This sex-specific finding is preliminary and awaits independent replication in a larger mixed-sex cohort.

Earlier screening of 95 GWAS-identified CAD variants for post-ACS mortality in 811 white ACS patients77 811 white ACS patients
from a prospective Australian cohort found rs6922269 to be the only variant achieving statistical significance, with a 2.6-fold mortality hazard (P=0.007 after adjustment for other ACS risk factors) — consistent with the CDCS findings.

Taken together, the evidence supports rs6922269 as a robust GWAS-identified CAD susceptibility locus with an emerging prognostic role, particularly for post-ACS mortality in males.

Practical Actions

Because the mechanism involves mitochondrial folate metabolism and active B12 handling, ensuring optimal status of folate (as methylfolate rather than synthetic folic acid) and active B12 (measured as holotranscobalamin rather than total serum B12) is the most evidence-aligned response. The AA genotype's association with lower active B12 suggests that tracking holotranscobalamin specifically — not just total B12 — gives a more accurate picture of B12 status in this context.

Plasma homocysteine monitoring is warranted as a functional marker of the methylation/remethylation pathway, even though rs6922269 itself has not shown a direct homocysteine association in studies to date. Any elevation in homocysteine would confirm downstream insufficiency in this pathway and sharpen the intervention.

Interactions

rs6922269 is in a distinct LD block from rs2073067, the MTHFD1L variant associated with Alzheimer's disease and altered plasma homocysteine. These two variants tag different haplotypes within the same gene and their effects may be partially independent. Carriers of risk alleles at both loci may face a compounded reduction in MTHFD1L mitochondrial formate output, warranting attention to both cardiovascular and neurocognitive folate-pathway monitoring.

The common MTHFR C677T (rs1801133)88 MTHFR C677T (rs1801133)
reduces cytoplasmic MTHFR enzyme activity, raising homocysteine and reducing methylation capacity variant compounds the upstream mitochondrial restriction that rs6922269 may impose: if both mitochondrial formate supply (MTHFD1L) and cytoplasmic folate processing (MTHFR) are impaired, the cumulative effect on homocysteine and methylation capacity is likely larger than either variant alone. This combination is a strong candidate for a compound action.

The MTHFD1L splicing variant rs3832406 affects mRNA splicing efficiency and is associated with neural tube defect risk in a separate LD block from rs6922269.

Nutrient Interactions

folate altered_metabolism
vitamin B12 increased_need
formate impaired_conversion

Genotype Interpretations

What each possible genotype means for this variant.

GG Typical Risk Normal

Reference genotype for MTHFD1L rs6922269 — standard cardiovascular risk at this locus

You carry two copies of the G allele at rs6922269, the reference allele in the GRCh38 genome. In the WTCCC genome-wide association study, GG homozygotes served as the low-risk reference group for coronary artery disease at this locus. About 43% of people globally share this genotype; in Europeans the proportion is higher, around 53%. Your MTHFD1L mitochondrial folate metabolism at this specific variant is typical.

AG One Risk Allele Intermediate

One copy of the CAD-risk allele — moderately elevated coronary artery disease risk

The A allele at rs6922269 tags a haplotype in the MTHFD1L gene that may reduce the efficiency of mitochondrial formate production — the key step connecting mitochondrial one-carbon metabolism to the cytoplasmic folate cycle and methyl cycle. Lower formate export from the mitochondrion restricts cytoplasmic one-carbon unit availability, potentially reducing methylation capacity and purine synthesis efficiency, both of which are relevant to vascular biology.

The CDCS cohort study (Mager et al. 2014, PMID 24618918) found that GA carriers had intermediate survival outcomes after acute coronary syndromes (12.0% mortality) compared to GG (11.6%) and AA (19.6%) — though the GA/GG difference was small and non-significant, suggesting most of the excess risk is concentrated in AA homozygotes. Monitoring active vitamin B12 (holotranscobalamin) is valuable regardless of the exact mechanism, as AA carriers showed reduced active B12 levels in the same study.

AA Both Risk Alleles High Risk

Homozygous for the CAD-risk allele — elevated coronary artery disease risk and post-ACS mortality signal

The MTHFD1L gene encodes the mitochondrial enzyme that exports one-carbon units (as formate) from mitochondria to the cytoplasm. These units are indispensable for purine synthesis (required for DNA replication and repair), thymidylate synthesis (for DNA), and remethylation of homocysteine to methionine via the methyl cycle. The A allele at rs6922269 tags a haplotype in this gene that appears to impair these downstream processes, though the precise molecular mechanism of this intronic variant has not been fully characterized.

One consistent finding in the CDCS study (Mager et al. 2014) was that AA carriers had significantly lower active vitamin B12 (holotranscobalamin) after adjustment for confounders — suggesting an interaction between MTHFD1L function and B12 bioavailability. Active B12 is the cofactor for methionine synthase (which remethylates homocysteine) and methylmalonyl-CoA mutase (mitochondrial energy metabolism). Lower active B12 would compound any reduction in one-carbon supply from impaired MTHFD1L function, creating a dual constraint on the methyl cycle.

Notably, the CDCS study found no significant association between rs6922269 genotype and plasma homocysteine levels, suggesting the cardiovascular mechanism is not simply mediated through elevated homocysteine. This is an important distinction from MTHFR variants, where homocysteine elevation is the primary proxy for risk. The MTHFD1L mechanism appears to be more upstream and broader, affecting one-carbon supply for multiple pathways simultaneously.

The sex-specific mortality finding from the Czech study (Hubáček et al. 2015) requires cautious interpretation — it emerged from a planned analysis but has not yet been independently replicated in other cohorts.