rs366631 — GSTM1 Tag SNP for gene deletion

GSTM1 — Your Body's Frontline Defense Against Environmental Toxins

Glutathione S-transferase Mu 1 (GSTM1) is a Phase II detoxification enzyme¹¹ Phase II detoxification enzyme
Phase II enzymes conjugate reactive intermediates produced by Phase I (CYP450) enzymes with water-soluble molecules like glutathione, making toxins easier to excrete that plays a critical role in neutralizing environmental carcinogens, pollutants, and reactive oxygen species. It works by conjugating glutathione²² glutathione
The body's most abundant intracellular antioxidant, a tripeptide of glutamate, cysteine, and glycine to electrophilic compounds — essentially tagging dangerous molecules for safe elimination from the body.

What makes GSTM1 remarkable among genetic variants is the sheer scale of its most common polymorphism: roughly half of all people of European descent carry a complete deletion of the GSTM1 gene on both chromosomes, resulting in zero enzyme production. This is one of the most prevalent pharmacogenomic variants in the human genome.

The Mechanism

Unlike typical SNPs that change a single DNA base, the GSTM1 "null" variant involves a whole-gene deletion³³ whole-gene deletion
A ~20kb segment containing the entire GSTM1 gene is deleted through unequal homologous recombination between flanking GSTM2 and GSTM5 sequences. The rs366631 variant reported here is not the deletion itself but a tag SNP⁴⁴ tag SNP
A SNP in linkage disequilibrium with the true variant of interest, used as a proxy when the actual variant is difficult to genotype directly — a proxy that tracks the deletion status on genotyping arrays like those used by 23andMe. The AA genotype at rs366631 indicates the GSTM1 gene is absent on both chromosomes (GSTM1 null), while AG indicates one functional copy and GG indicates two functional copies.

The study that established this tag SNP relationship⁵⁵ study that established this tag SNP relationship
Girirajan S et al. Population-specific GSTM1 copy number variation. Hum Mol Genet, 2009 showed that rs366631 is technically a non-polymorphic site — the apparent genotype variation arises because the genotyping probe cross-hybridizes with a homologous sequence in the GSTM1 region. When the gene is deleted, the probe cannot bind, producing a different signal that reliably tracks deletion status.

GSTM1 is particularly important for detoxifying polycyclic aromatic hydrocarbons (PAHs)⁶⁶ polycyclic aromatic hydrocarbons (PAHs)
Carcinogenic compounds found in tobacco smoke, charred/grilled foods, diesel exhaust, and air pollution, aflatoxins⁷⁷ aflatoxins
Toxic compounds produced by certain molds that contaminate grains, nuts, and spices — potent liver carcinogens, and reactive oxygen species. Without functional GSTM1, these compounds persist longer in the body and are more likely to form DNA adducts⁸⁸ DNA adducts
Chemical bonds between carcinogens and DNA that can cause mutations and initiate cancer.

The Evidence

The health consequences of GSTM1 null status have been studied extensively, with over 1,900 published studies as cataloged in a 2022 worldwide systematic review⁹⁹ 2022 worldwide systematic review
Correia C et al. Worldwide Systematic Review of GSTM1 and GSTT1 Null Genotypes by Continent, Ethnicity, and Therapeutic Area. OMICS, 2022.

Bladder cancer has the strongest association. A pooled analysis of 17 studies¹⁰¹⁰ pooled analysis of 17 studies
Engel LS et al. Pooled analysis and meta-analysis of glutathione S-transferase M1 and bladder cancer: a HuGE review. Am J Epidemiol, 2002 with 2,149 cases and 3,646 controls found GSTM1 null carriers had a 44% increased risk (OR 1.44, 95% CI 1.23-1.68). An updated meta-analysis¹¹¹¹ updated meta-analysis
Yu C et al. GSTM1 and GSTT1 polymorphisms are associated with increased bladder cancer risk. Oncotarget, 2016 confirmed this (OR 1.36, 95% CI 1.25-1.47) and found that individuals null for both GSTM1 and GSTT1 had an even higher risk (OR 1.84, 95% CI 1.50-2.26).

Lung cancer risk is also elevated, particularly in combination with smoking or air pollution exposure. A meta-analysis of 53 studies¹²¹² meta-analysis of 53 studies
Wang H et al. The association of GSTM1 deletion polymorphism with lung cancer risk in Chinese population. Sci Rep, 2015 found GSTM1 null carriers had 46% higher lung cancer risk (OR 1.46, 95% CI 1.32-1.66). In never-smokers exposed to secondhand smoke for 20+ years, the risk was 2.3-fold higher for GSTM1 null individuals.

Cruciferous vegetables and sulforaphane. The relationship between GSTM1 status and cruciferous vegetable benefit is nuanced. A clinical study by Gasper et al.¹³¹³ clinical study by Gasper et al.
Gasper AV et al. Glutathione S-transferase M1 polymorphism and metabolism of sulforaphane from standard and high-glucosinolate broccoli. Am J Clin Nutr, 2005 found that GSTM1-null individuals metabolize and excrete sulforaphane more rapidly than GSTM1-positive individuals. Paradoxically, some studies suggest GSTM1-null individuals may derive greater cancer protection from cruciferous vegetables because the isothiocyanates remain bioactive rather than being conjugated and excreted. However, this effect varies by cancer type and population, and GSTM1-null individuals still lack the enzyme's broader detoxification functions.

Practical Implications

GSTM1 null status is not a disease — it is a common genetic variation that shifts your baseline detoxification capacity. The practical response focuses on three areas: reducing toxic exposures, supporting alternative detoxification pathways, and increasing dietary protective factors.

Cruciferous vegetables (broccoli, broccoli sprouts, cauliflower, Brussels sprouts, kale, cabbage) are particularly valuable because they contain sulforaphane and other isothiocyanates¹⁴¹⁴ sulforaphane and other isothiocyanates
Compounds that induce Phase II detoxification enzymes through the Nrf2 pathway, partially compensating for the lost GSTM1 activity. Broccoli sprouts contain 20-100 times more sulforaphane precursor than mature broccoli. Supporting glutathione levels through N-acetylcysteine (NAC) provides the conjugation substrate that other GST family members (GSTP1, GSTA1) can use to partially compensate for absent GSTM1 activity.

Interactions

The most important interaction is with GSTT1 (glutathione S-transferase Theta 1), another Phase II enzyme with a common whole-gene deletion. Individuals null for both GSTM1 and GSTT1 ("double null") show significantly higher cancer risk than either deletion alone — the bladder cancer meta-analysis found OR 1.84 for double null versus OR 1.36 for GSTM1 null alone. The double null genotype reduces the overall glutathione conjugation capacity more severely because GSTM1 and GSTT1 have partially overlapping but distinct substrate specificities.

GSTM1 also interacts with NAT2 (N-acetyltransferase 2), another Phase II enzyme. Slow NAT2 acetylators who are also GSTM1 null show compounded risk for bladder cancer from aromatic amine exposure (found in tobacco smoke and certain occupational chemicals).