Does BHMT rs3733890 (G742A) reduce BHMT function and raise homocysteine?

Betaine-homocysteine methyltransferase (BHMT) is a crucial hepatic enzyme that maintains homocysteine homeostasis through an alternative metabolic pathway. The rs3733890 (G742A) polymorphism is a key genetic variant implicated in this system.

Functional impact of the rs3733890 variant

• Biochemical ambiguity: The precise functional consequence of the BHMT rs3733890 (G742A/R239Q) polymorphism remains biochemically unresolved. While some clinical association studies link this variant to reduced enzymatic efficiency, other functional and nutrigenetic resources characterize it as an "increased-activity" variant that enhances betaine affinity. Direct in vitro kinetic data are currently lacking.
• Folate therapy resistance: Despite this biochemical ambiguity, the variant has clear clinical relevance. Carriers of rs3733890 face a significantly higher risk of oral folate treatment failure, meaning their circulating homocysteine levels frequently remain elevated despite standard folate supplementation.

The folate-independent remethylation buffer

• Pathway mechanics: BHMT catalyzes the conversion of homocysteine to methionine in the liver using betaine as a direct methyl donor. Because this reaction bypasses the classic folate- and vitamin B12-dependent methionine synthase pathway, BHMT activity directly dictates the capacity of the body's folate-independent remethylation buffer.
• Homocysteine regulation: Impaired or reduced BHMT enzymatic activity directly lowers this alternative remethylation capacity, which leads to elevated levels of circulating plasma homocysteine (hyperhomocysteinemia).
• Nutritional modulation: This pathway is highly sensitive to dietary inputs. Betaine serves as the direct substrate for the enzyme; increased dietary betaine availability upregulates BHMT expression and activity, enhancing the clearance of homocysteine.

Bottom line

• While BHMT activity is scientifically established as the determinant of the folate-independent remethylation buffer, the claim that the rs3733890 polymorphism specifically reduces BHMT function is currently classified as plausible due to conflicting literature reporting both increased and decreased enzymatic activity. Nonetheless, the variant remains highly relevant as a clinical marker for folate treatment resistance, where betaine support may offer key therapeutic value.