The Missing Detoxifier — GSTT1 Gene Deletion

In roughly one in five people of European descent — and nearly half of East Asians — the GSTT1 gene is completely absent¹¹ the GSTT1 gene is completely absent
GSTT1 was absent from 38% of the global population, with higher frequencies in Asian populations. Not mutated. Not damaged. Simply deleted from the genome entirely. This isn't a typo in your genetic code; it's a common polymorphism that eliminates an entire phase II detoxification enzyme²² eliminates an entire phase II detoxification enzyme
Homozygous deletion results in complete absence of enzyme activity.

GSTT1³³ GSTT1
glutathione S-transferase theta-1 belongs to a family of enzymes that conjugate glutathione to toxic compounds, making them water-soluble for elimination. While its relatives GSTM1 and GSTP1 handle a broad spectrum of toxins, GSTT1 has a narrower but critical substrate preference: industrial halogenated solvents⁴⁴ industrial halogenated solvents
dichloromethane, ethylene oxide, methyl bromide, and methyl chloride, certain environmental carcinogens, and reactive metabolites from alcohol and tobacco smoke.

Without functional GSTT1, you can't efficiently detoxify these compounds. They linger longer in tissues, increasing oxidative DNA damage⁵⁵ increasing oxidative DNA damage
GSTT1-null subjects showed 1.6-fold increase in genotoxicity from industrial exposures and creating a documented cancer risk that varies by exposure and ethnicity.

The Mechanism

GSTT1 is a phase II metabolizing enzyme⁶⁶ phase II metabolizing enzyme
constitutively expressed in liver, kidney, lung, and gastrointestinal tract that catalyzes the conjugation of reduced glutathione (GSH) to electrophilic substrates. The gene is located at 22q11.23⁷⁷ 22q11.23
chromosome 22, cytogenetic band 11.23, in a gene cluster with its paralogues GSTT2 and GSTT2B.

The null variant results from a complete deletion of the entire gene⁸⁸ complete deletion of the entire gene
deletion spans all five exons. Individuals inherit two copies (chromosomes), creating three possible states: both copies present (GSTT1-positive), one copy present (heterozygous), or both copies deleted (GSTT1-null). The deletion follows Mendelian intermediary inheritance⁹⁹ Mendelian intermediary inheritance
gene-dosage effect with doubled expression in two functional alleles, where heterozygotes have roughly 50% enzyme activity compared to homozygous wild-type.

In GSTT1-null individuals, substrates cannot be efficiently conjugated and eliminated¹⁰¹⁰ substrates cannot be efficiently conjugated and eliminated
unable to perform biotransformation of toxic products via glutathione conjugation, leading to accumulation in tissues and increased oxidative stress.

Important limitation: This SNP (rs71748309) is a tag SNP used to infer GSTT1 deletion status, not a direct measurement of gene copy number. 23andMe does not reliably detect gene deletions¹¹¹¹ 23andMe does not reliably detect gene deletions
SNPs used to assess GSTT1 variants were not available on v5 chip; detection accuracy is uncertain. Results should be interpreted with caution and confirmed with specialized testing if clinically important.

The Evidence

GSTT1 null status has been extensively studied across dozens of cancer types and populations. The most consistent associations emerge from large meta-analyses¹²¹² large meta-analyses
combined evidence from 117+ studies totaling over 60,000 subjects:

Urinary system cancers: A meta-analysis of 117 studies¹³¹³ meta-analysis of 117 studies
26,666 cases, 37,210 controls found GSTT1 null genotype significantly increases risk (OR=1.13, 95% CI=1.05-1.22), with stronger effects for bladder cancer (OR=1.13) and prostate cancer (OR=1.14), particularly in Caucasians (OR=1.16) and Indians (OR=2.05).

Lung cancer: Among Asian populations, a meta-analysis of 23 studies¹⁴¹⁴ Asian populations, a meta-analysis of 23 studies
4,065 cases, 5,390 controls showed OR=1.28 (95% CI=1.10-1.49) for overall lung cancer risk. The effect was dramatically amplified in smokers: OR=1.94 (95% CI=1.27-2.96) for ever-smokers with GSTT1 null. Gene-environment interaction¹⁵¹⁵ Gene-environment interaction
heavy smokers (>60 pack-years) with GSTT1 null had OR=158.49.

Colorectal cancer: Pooled analysis of 46 case-control studies¹⁶¹⁶ Pooled analysis of 46 case-control studies
overall OR=1.21, 95% CI=1.10-1.33 showed increased risk in both Asians and Caucasians, with stronger association for rectal cancer (OR=1.13).

Breast cancer: Results vary by population. Chinese population meta-analysis¹⁷¹⁷ Chinese population meta-analysis
OR=1.31, 95% CI=1.02-1.67, though other studies show weaker or null associations. Asian-focused meta-analysis¹⁸¹⁸ Asian-focused meta-analysis
OR=1.19, 95% CI=1.01-1.41.

Alcohol metabolism: GSTT1 null genotype increases oxidative stress from alcohol¹⁹¹⁹ increases oxidative stress from alcohol
reactive oxygen species accumulate when GSTT1 is absent, contributing to liver disease risk in chronic drinkers. The enzyme helps detoxify acetaldehyde-derived reactive metabolites.

Chemotherapy toxicity: GSTT1 null individuals show higher risk of severe gastrointestinal toxicity²⁰²⁰ higher risk of severe gastrointestinal toxicity
from chemoradiation therapy in cervical cancer and increased drug-induced liver injury risk²¹²¹ increased drug-induced liver injury risk
PharmGKB very important pharmacogene designation.

Evidence level is strong for urinary and lung cancers, moderate for colorectal and breast cancers. The gene-environment interactions with smoking, occupational solvent exposure, and alcohol are well-established.

Practical Actions

If you carry the GSTT1 null genotype, you lack a specialized detoxification pathway. Compensation requires reducing substrate exposure²²²² reducing substrate exposure
minimize halogenated solvents, smoking, and heavy alcohol and supporting alternative glutathione-dependent pathways.

Avoidance strategies: Minimize exposure to GSTT1-specific substrates²³²³ GSTT1-specific substrates
dichloromethane in paint strippers, ethylene oxide in sterilization, halomethanes in chlorinated water. If you smoke, quitting is especially critical — the interaction between tobacco and GSTT1 null multiplies cancer risk²⁴²⁴ the interaction between tobacco and GSTT1 null multiplies cancer risk
OR increases from 1.28 baseline to 1.94 in smokers. Limit alcohol intake to reduce acetaldehyde burden.

Glutathione support: Cruciferous vegetables²⁵²⁵ Cruciferous vegetables
broccoli, Brussels sprouts, cabbage, kale are rich in glutathione precursors and upregulate remaining GST enzymes²⁶²⁶ upregulate remaining GST enzymes
isothiocyanates induce compensatory GST activity. However, effectiveness varies by genotype²⁷²⁷ varies by genotype
GSTT1 null individuals may have blunted response to cruciferous induction.

Antioxidant support: Alpha-lipoic acid regenerates oxidized glutathione²⁸²⁸ Alpha-lipoic acid regenerates oxidized glutathione
enhances intracellular and extracellular glutathione concentrations. Selenium supports glutathione recycling²⁹²⁹ Selenium supports glutathione recycling
key cofactor for glutathione peroxidase. N-acetylcysteine (NAC) provides cysteine³⁰³⁰ N-acetylcysteine (NAC) provides cysteine
rate-limiting precursor for glutathione synthesis.

Medical monitoring: Consider more frequent cancer screening³¹³¹ cancer screening
especially for urinary tract and lung if you have additional risk factors (smoking history, occupational exposures). Discuss GSTT1 status with your oncologist if undergoing chemotherapy — certain regimens carry higher toxicity risk³²³² certain regimens carry higher toxicity risk
drug-induced liver injury.

Interactions

GSTT1 doesn't operate alone. The glutathione S-transferase superfamily includes GSTM1 (rs1138272) and GSTP1 (rs1695), all working in concert to detoxify environmental toxins. Combined null genotypes amplify risk³³³³ Combined null genotypes amplify risk
dual GSTM1/GSTT1 null increases prostate cancer OR.

Oxidative stress defense: GSTT1 interacts with other antioxidant genes including SOD2 (rs4880) and GPX1 (rs1050450)³⁴³⁴ SOD2 (rs4880) and GPX1 (rs1050450)
combined polymorphisms increase oxidative damage. Genetic risk scores combining these variants³⁵³⁵ Genetic risk scores combining these variants
five-risk-genotype combinations increased metabolic syndrome risk.

Methylation pathway: Glutathione synthesis requires homocysteine-to-cysteine conversion³⁶³⁶ homocysteine-to-cysteine conversion
via the transsulfuration pathway. MTHFR variants (rs1801133, rs1801131) that elevate homocysteine may reduce glutathione availability³⁷³⁷ elevate homocysteine may reduce glutathione availability
MTHFR and GST polymorphisms studied together in oxidative stress conditions.

Smoking interaction: The multiplicative effect of smoking with GSTT1 null³⁸³⁸ multiplicative effect of smoking with GSTT1 null
lung cancer OR=158.49 for heavy smokers represents one of the strongest gene-environment interactions in cancer epidemiology. Similarly, occupational solvent exposure in GSTT1 null individuals³⁹³⁹ occupational solvent exposure in GSTT1 null individuals
increased risk of chronic toxic encephalopathy.

Cruciferous vegetable response: Effectiveness of dietary detox support varies by GST genotype⁴⁰⁴⁰ varies by GST genotype
GSTT1-null individuals may have altered response to isothiocyanates, though cruciferous intake still provides glutathione precursors⁴¹⁴¹ cruciferous intake still provides glutathione precursors
even without enzyme induction.

Proposed compound actions for supervisor review:

1. GSTT1 null + GSTM1 null (dual null genotype)

• Genotypes: rs71748309 DD + rs1138272 DD (or equivalent GSTM1 deletion marker)
• Combined effect: Complete loss of both theta and mu GST classes, severely compromising phase II detoxification
• Evidence: OR for lung cancer increases to 8.25 with dual deletion (PMID: 18463401)
• Recommendation: Strict avoidance of industrial solvents, smoking cessation mandatory, high-dose glutathione support (NAC 600mg twice daily, liposomal glutathione 500mg, alpha-lipoic acid 600mg), quarterly liver function monitoring
• Evidence level: strong
• Action type: lifestyle + supplement + monitoring

2. GSTT1 null + GSTP1 Ile105Val (rs1695 AG/GG)

• Genotypes: rs71748309 DD + rs1695 AG or GG
• Combined effect: Loss of GSTT1 plus reduced GSTP1 activity creates broad detoxification impairment
• Evidence: Elevated risk for prostate cancer and chemotherapy toxicity (PMID: 17707637)
• Recommendation: Enhanced cruciferous vegetable intake (3+ servings daily) to upregulate remaining GSTP1, avoid pesticides and herbicides, comprehensive antioxidant support
• Evidence level: moderate
• Action type: diet + avoidance

3. GSTT1 null + heavy smoking exposure

• Genotypes: rs71748309 DD + current or former smoker (>10 pack-years)
• Combined effect: Multiplicative cancer risk — lung cancer OR increases from 1.28 to 158.49 for heavy smokers
• Evidence: Multiple meta-analyses (PMID: 23637998, 15105047)
• Recommendation: Smoking cessation is non-negotiable, annual low-dose CT lung cancer screening starting age 50, NAC 1200mg daily for ex-smokers
• Evidence level: established
• Action type: avoidance + monitoring

4. GSTT1 null + MTHFR C677T homozygous (rs1801133 AA)

• Genotypes: rs71748309 DD + rs1801133 AA
• Combined effect: Impaired methylation reduces glutathione synthesis (homocysteine can't efficiently convert to cysteine)
• Evidence: GST and MTHFR polymorphisms studied together in oxidative stress (PMID: 24339523)
• Recommendation: Methylated B-vitamin complex (methylfolate 800mcg, methylB12 1000mcg, B6 50mg), NAC 600mg twice daily to bypass transsulfuration bottleneck
• Evidence level: moderate
• Action type: supplement

5. GSTT1 null + SOD2 Ala16Val (rs4880 GG)

• Genotypes: rs71748309 DD + rs4880 GG
• Combined effect: Reduced mitochondrial superoxide dismutase plus absent GSTT1 increases oxidative damage
• Evidence: Combined polymorphisms increase metabolic syndrome risk (PMID: 31396447)
• Recommendation: Mitochondrial antioxidant stack (CoQ10 200mg ubiquinol, alpha-lipoic acid 600mg, selenium 200mcg), reduce environmental oxidant exposure
• Evidence level: moderate
• Action type: supplement + lifestyle