Add-On MethylDetox Profile

MTHFR catalyses the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the primary methyl donor for homocysteine remethylation to methionine. The C677T polymorphism (rs1801133) results in an alanine-to-valine substitution that reduces enzyme thermostability; homozygous TT individuals retain roughly 30 per cent of wild-type activity under conditions of riboflavin sufficiency, and enzyme activity falls further when riboflavin (the FAD cofactor) is low.

The C677T variant is associated with elevated homocysteine, particularly when folate or riboflavin status is suboptimal. Mild to moderate hyperhomocysteinaemia has been epidemiologically linked to cardiovascular and neurodegenerative risk, though causality remains contested and supplementation trials have not consistently demonstrated outcome benefit. Genotype alone does not diagnose disease; it informs the interpretation of homocysteine and folate status and may guide targeted B-vitamin repletion in patients with elevated homocysteine.

The A1298C polymorphism (rs1801131) produces a glutamate-to-alanine change in a different domain of the MTHFR protein. Homozygous CC individuals show a more modest reduction in enzyme activity than TT at C677T, and compound heterozygosity (C677T/A1298C) results in intermediate enzyme compromise.

A1298C is generally associated with milder biochemical effects than C677T. It is tested alongside C677T to identify compound heterozygotes and to refine risk stratification in patients with hyperhomocysteinaemia or recurrent pregnancy loss, though clinical utility remains debated.

COMT catalyses the O-methylation of catecholamines (dopamine, noradrenaline, adrenaline) and catechol oestrogens, using S-adenosylmethionine as the methyl donor. The Val158Met polymorphism (rs4680) affects the membrane-bound enzyme in the brain and peripheral tissues; the Met allele reduces enzyme activity roughly threefold at physiological temperature, slowing catecholamine clearance in the prefrontal cortex and altering dopamine tone.

Met/Met individuals exhibit higher synaptic dopamine and may show enhanced cognitive performance under baseline conditions but reduced stress resilience. Val/Val is associated with faster catecholamine clearance and has been linked to lower pain sensitivity and higher stress tolerance. The variant also influences oestrogen metabolism, with slower COMT activity theoretically favouring accumulation of catechol oestrogens, though clinical significance for breast or endometrial disease is unproven. Genotype is explored in functional psychiatry and pain medicine but is not a standalone diagnostic or treatment determinant.

GSTM1 is a phase-II detoxification enzyme that conjugates glutathione to electrophilic xenobiotics and products of oxidative stress, facilitating their excretion. A homozygous deletion polymorphism results in complete absence of GSTM1 enzyme; the null genotype is present in roughly half of many populations.

The GSTM1-null genotype has been associated in epidemiological studies with modestly increased risk of certain cancers (bladder, lung) and adverse responses to environmental toxins, smoking, and some chemotherapeutic agents. It does not cause disease in isolation and is best viewed as a susceptibility modifier. In functional and integrative medicine it informs discussions of detoxification capacity and may guide environmental-exposure counselling, though evidence for genotype-directed interventions is limited.

GSTT1 catalyses glutathione conjugation of smaller hydrophobic electrophiles, including certain industrial solvents and halogenated compounds. Like GSTM1, a homozygous deletion leads to complete absence of enzyme; roughly 10–20 per cent of individuals carry the null genotype, with ethnic variation.

GSTT1-null has been linked to increased susceptibility to certain chemical exposures and modest cancer risk in gene-environment interaction studies. Combined GSTM1/GSTT1-null status may amplify susceptibility. Clinical application remains exploratory, with genotype informing risk stratification and environmental counselling rather than guiding specific therapies.

SOD2 is the mitochondrial manganese superoxide dismutase that converts superoxide radicals to hydrogen peroxide, the first line of defence against mitochondrial oxidative stress. The Ala16Val polymorphism (rs4880) affects the mitochondrial targeting sequence; the Val allele alters enzyme import efficiency and possibly intramitochondrial localisation, with conflicting data on whether it increases or decreases effective activity under different conditions.

The functional consequences of SOD2 A16V remain contested. Some studies associate the Val allele with increased oxidative damage and risk of cardiometabolic or neurodegenerative disease, others find no effect or paradoxical protection. In the context of a methylation and detoxification panel, the genotype is interpreted as a marker of mitochondrial oxidative-stress handling, though its predictive value is uncertain. It does not alter clinical management in isolation.