rs567754 — BHMT BHMT-02

BHMT-02: A Benign Methylation Gene Variant Linked to Selenium Metabolism

The BHMT gene encodes betaine-homocysteine methyltransferase, a zinc-dependent enzyme that provides an alternative pathway for converting homocysteine back to methionine.

BHMT is involved in regulating homocysteine metabolism by converting betaine and homocysteine to dimethylglycine and methionine . This alternative remethylation pathway operates independently of the folate-dependent methionine synthase pathway, making it particularly important when MTHFR function is impaired.

In the liver, BHMT is responsible for about half of homocysteine metabolism .

The Variant

Rs567754, commonly known as BHMT-02, is an intronic variant located in the BHMT gene on chromosome 5.

Rs567754 is an intronic variant of the BHMT gene, and neither previous data nor published studies revealed an association with congenital heart defects or ventricular septal defects in offspring . Unlike the well-studied functional variant rs3733890 (which causes an amino acid change), rs567754 does not alter the BHMT protein structure or enzyme activity.

The T allele of rs567754 has been associated with decreased selenium levels in both blood and toenail measurements.

A genome-wide association study identified a significant locus at 5q14 near BHMT associated with selenium concentrations .

The T allele is associated with decrease in toenail and blood selenium levels . However, this association with selenium metabolism does not appear to translate into disease risk.

The Evidence

Multiple large studies have examined rs567754 for disease associations and consistently found no significant effects. In a study of 426 mothers of children with ventricular septal defects and 740 controls¹¹ In a study of 426 mothers of children with ventricular septal defects and 740 controls
Feng et al. Maternal BHMT gene polymorphisms and ventricular septal defects. Nutrients, 2022, rs567754 showed no association with congenital heart defects, unlike other BHMT variants in the same study. A comprehensive functional characterization study²² A comprehensive functional characterization study
Kraus et al. Human BHMT and BHMT2 gene sequence variation. Molecular Genetics and Metabolism, 2008 found that intronic variants in BHMT, including rs567754, did not affect enzyme activity or protein levels when tested in cell culture assays.

The main finding for rs567754 comes from genome-wide association studies of selenium metabolism. A meta-analysis of toenail selenium concentrations in 4,162 European descendants³³ A meta-analysis of toenail selenium concentrations in 4,162 European descendants
Cornelis et al. Selenium GWAS. Human Molecular Genetics, 2015 identified the 5q14 region harboring BHMT and neighboring genes as associated with selenium levels, explaining approximately 1% of the variance in selenium concentrations.

Proteins encoded by genes at this locus function in homocysteine metabolism, and the findings show evidence of a genetic link between selenium and homocysteine pathways, both involved in cardiometabolic disease .

Practical Implications

Since rs567754 has not been associated with elevated homocysteine levels, cardiovascular disease risk, or other health conditions in multiple studies, it does not require specific interventions. The modest association with selenium levels is of uncertain clinical significance, as the variant explains only about 1% of selenium variation and selenium deficiency is rare in developed countries with typical Western diets.

The BHMT enzyme does require betaine (trimethylglycine) as a substrate and zinc as a cofactor for its function. Supporting overall methylation cycle health through adequate intake of B vitamins, choline (which converts to betaine), and zinc remains sensible regardless of BHMT genotype, particularly for individuals with other methylation cycle variants like MTHFR C677T.

Interactions

Rs567754 is located in the BHMT gene, which provides an alternative remethylation pathway that can compensate for impaired MTHFR function. Individuals carrying both MTHFR variants (rs1801133 C677T or rs1801131 A1298C) and BHMT variants may have compounded effects on homocysteine metabolism, though rs567754 itself does not appear functionally significant. The more relevant BHMT variant for such interactions is rs3733890 (R239Q), which does affect enzyme function.

Compound effects between MTHFR variants and functional BHMT variants (such as rs3733890) would warrant increased attention to betaine/choline intake and B vitamin status, particularly folate and B12, to support both remethylation pathways. However, since rs567754 has shown no functional impact in studies, specific compound implications for this variant are not warranted.