rs10380 — MTRR His595Tyr

MTRR His595Tyr — When the B12 Reactivation Engine Misfires

Methionine synthase reductase (MTRR) is an enzyme whose sole job is to keep another enzyme — methionine synthase (MTR) — running. MTR converts homocysteine to methionine using methylcobalamin¹¹ methylcobalamin
The methyl-carrying, active form of vitamin B12 (active B12) as a cofactor, but during each catalytic cycle the B12 becomes oxidized to an inactive form. MTRR reduces it back to active methylcobalamin so MTR can continue. Without efficient MTRR, the methylation cycle slows, homocysteine accumulates, and the production of SAM — the universal methyl donor for DNA, RNA, and protein methylation — declines.

The His595Tyr missense variant (rs10380, c.1783C>T) swaps histidine for tyrosine at position 595 of the MTRR protein. This amino acid change sits in a functionally important region and was co-identified with the intronic variant rs162049 in the same pancreatic cancer risk haplotype — a haplotype shown in functional cell-line studies to produce less MTRR protein, elevated homocysteine in culture medium, and reduced LINE-1 methylation²² LINE-1 methylation
LINE-1 (long interspersed element-1): repetitive DNA sequences whose methylation status is a proxy for genome-wide DNA methylation. The T allele is the minor allele globally, occurring in about 11% of chromosomes in gnomAD exomes, with substantial variation by ancestry (approximately 33–34% in African and Latino populations, versus ~9–10% in Europeans).

The Mechanism

His595 is a conserved residue in MTRR's methyltransferase domain. The histidine-to-tyrosine substitution is predicted to alter the local protein fold, reducing the enzyme's ability to perform the reductive methylation of cob(II)alamin³³ reductive methylation of cob(II)alamin
The chemical step by which MTRR converts oxidized, inactive cobalamin back to methylcobalamin for MTR back to active methylcobalamin. Functional data from risk-haplotype transfectants (containing both rs10380 and rs162049) confirmed that cells carrying the risk haplotype produced less MTRR protein, higher extracellular homocysteine, and lower LINE-1 methylation compared to wild-type cells — consistent with impaired B12 cycling and downstream methylation deficit.

The Evidence

The discovery study by Ohnami et al.⁴⁴ Ohnami et al.
Ohnami S et al. His595Tyr polymorphism in the methionine synthase reductase gene is associated with pancreatic cancer risk. Gastroenterology, 2008 found rs10380 associated with pancreatic cancer risk (OR 1.45, 95% CI 1.11–1.88; P=0.0063) in a multicenter Japanese case-control study of 317 cases and 1,232 controls, surviving permutation testing for multiple comparisons (P=0.023 recessive model). The association was attributed to impaired methylation-dependent regulation of tumor-suppressor genes.

A California population-based study by Shaw et al.⁵⁵ Shaw et al.
Shaw GM et al. 118 SNPs in folate-related genes and spina bifida risk. BMC Med Genet, 2009 found heterozygous or homozygous rs10380 carriers had OR 3.4 (95% CI 1.6–7.1) for spina bifida risk among 259 cases and 359 controls — a striking result that implicates impaired MTRR function in neural tube closure, where adequate methylation is essential for proper gene regulation during embryogenesis. No association was found with conotruncal heart defects in the same study.

A more recent Han Chinese case-control study of 595 children with congenital heart disease⁶⁶ congenital heart disease
CHD: structural heart abnormalities present from birth, often linked to disrupted epigenetic regulation during cardiac development and 605 controls found the TT genotype associated with CHD risk (OR 2.27, 95% CI 1.20–4.31). Critically, maternal folic acid supplementation during pregnancy reduced CHD risk (OR 0.55), suggesting that adequate one-carbon supply during cardiac development can partially compensate for impaired MTRR function.

Other studies examining rs10380 in colorectal cancer, gastric cancer, and DNA methylation have reported null or inconsistent results — consistent with a variant whose effect is tissue-context-dependent and modified by folate/B12 nutritional status.

Practical Implications

The His595Tyr substitution impairs MTRR's ability to recycle B12 for MTR. The primary intervention strategy is to maintain high active-B12 supply to compensate for reduced recycling efficiency: more incoming methylcobalamin means MTR is less dependent on MTRR-mediated recycling to stay active. Hydroxocobalamin is an especially useful form because it enters both methylcobalamin and adenosylcobalamin pathways. Methylfolate (5-MTHF) upstream of MTR keeps the methyl-donor pool full. Homocysteine measurement is a direct functional readout — elevated homocysteine (above 10 µmol/L) signals that the remethylation pathway is running below capacity. The CHD data further suggest that periconceptional folic acid use is especially important for T allele carriers planning a pregnancy.

Interactions

rs10380 and rs162049 (intronic MTRR) were co-identified in the same functional haplotype; individuals carrying both likely have a compounded impairment of MTRR expression and enzymatic efficiency. Combined with MTRR A66G (rs1801394), which reduces enzyme efficiency at the protein level via p.Ile22Met, or with MTR A2756G (rs1805087), which reduces MTR activity directly, the overall B12 cycling capacity is further curtailed. The most clinically significant interaction is with MTHFR C677T (rs1801133): reduced methylfolate supply from MTHFR combined with impaired B12 recycling from MTRR creates dual pressure on homocysteine remethylation that neither variant produces alone.