rs10505806 — MGST1

Intergenic variant near MGST1 that modifies whether aspirin/NSAIDs reduce colorectal cancer risk; T allele carriers may lose the protective benefit

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The MGST1 Locus — When Aspirin's Cancer Protection Depends on Your Genotype

Aspirin and NSAIDs are among the best-studied cancer-prevention agents in medicine. Regular aspirin use is associated with a roughly 30% lower risk of colorectal cancer11 roughly 30% lower risk of colorectal cancer
Meta-analyses consistently show OR ~0.69 for regular vs. non-regular aspirin/NSAID users across large population studies — a finding replicated across dozens of cohort and case-control studies. But this protection is not evenly distributed across people. Your genome contains switches that determine whether aspirin's cancer-fighting effect works for you.

The rs10505806 variant sits in a biologically active intergenic region on chromosome 12p12.3, approximately 726 kilobases downstream of the MGST1 gene. MGST1 encodes microsomal glutathione S-transferase 1, a MAPEG-family enzyme that synthesizes prostaglandin E2 (PGE2)22 microsomal glutathione S-transferase 1, a MAPEG-family enzyme that synthesizes prostaglandin E2 (PGE2)
MAPEG = membrane-associated proteins in eicosanoid and glutathione metabolism; PGE2 is the key prostaglandin that drives colorectal cancer cell proliferation and suppresses anti-tumor immunity. Aspirin inhibits COX-1 and COX-2 to reduce prostaglandin production — but MGST1 provides an alternative, COX-independent PGE2 synthesis route that aspirin does not directly block.

The Mechanism

The chr12p12.3 locus containing rs10505806 and the nearby rs2965667 variant appears to regulate MGST1 expression through long-range enhancer elements. When aspirin suppresses COX-derived prostaglandins, the MGST1 pathway becomes proportionally more important33 When aspirin suppresses COX-derived prostaglandins, the MGST1 pathway becomes proportionally more important
This is a bypass mechanism — if MGST1 expression is higher, the prostaglandin-driven tumor promotion signal is harder to silence with aspirin alone. T allele carriers at rs10505806 are in the same genomic neighborhood as T/A allele carriers at rs2965667, the variant with the strongest genome-wide evidence (P = 4.6 × 10⁻⁹) for modifying aspirin-CRC protection.

PGE2 promotes colorectal cancer through multiple mechanisms: it stimulates cancer cell proliferation, suppresses cytotoxic T-cell activity, and promotes angiogenesis. The MGST1 pathway is therefore not a minor backup — it is a key determinant of whether COX inhibition by aspirin translates into actual tumor suppression.

The Evidence

Nan et al. 2015 in JAMA44 Nan et al. 2015 in JAMA conducted a genome-wide interaction study of aspirin/NSAID use with colorectal cancer risk, combining 5 case-control and 5 cohort studies with 8,634 cancer cases and 8,553 controls. The top hit on chromosome 12 (rs2965667 at chr12:17,291,799, 44 kb from rs10505806) reached genome-wide significance (P = 4.6 × 10⁻⁹) for modifying aspirin/NSAID protection. Individuals with the common TT genotype at rs2965667 gained strong protection from aspirin (OR 0.66), while the rare TA/AA carriers (4% of the population) showed a paradoxical increase in risk with aspirin use (OR 1.89, P = .002). rs10505806 is in this same intergenic locus and likely tags the same regulatory variation.

The overall aspirin benefit is substantial: regular use was associated with OR 0.69 (95% CI 0.64–0.74) for colorectal cancer prevention in the full analysis. Drew & Chan's 2021 review55 Drew & Chan's 2021 review and the 2022 JAMA evidence update66 2022 JAMA evidence update both confirm this protective association while noting that individual variation in response is likely genetic.

Practical Actions

For the ~95% of people with the common AA genotype at rs10505806, aspirin's colorectal cancer protection is expected to be robust — consistent with the overall population benefit. For T allele carriers at this locus (AT or TT), the picture is more complex: based on evidence from the neighboring rs2965667, T-carrying genotypes may not benefit from, or could even be harmed by, aspirin used specifically for colorectal cancer chemoprevention.

This does not automatically mean T carriers should avoid aspirin for cardiovascular indications — those benefits operate through different pathways (platelet TXA2 suppression) and are largely preserved. The uncertainty is specifically about the cancer prevention use case. T carriers considering aspirin for colorectal cancer chemoprevention should discuss this genetic profile with their gastroenterologist.

Interactions

The chr12p12.3 region interacts with the IL16-containing locus on chromosome 15q25.2 (rs16973225) — the second genome-wide significant aspirin-CRC interaction identified in Nan et al. 2015. Separately, aspirin's mechanism depends on COX-2 activity, so genetic variants in PTGS2 (COX-2) are relevant co-regulators. The 2024 Science Advances genome-wide interaction study (rs72833769 near TBC1D7/MTOR, and rs350047 near PTGER4) identified additional aspirin-CRC modifiers through the mTOR and PGE2 receptor pathways — functionally linked to MGST1's role in the same prostaglandin axis.

Drug Interactions

aspirin reduced_efficacy literature
ibuprofen reduced_efficacy literature
naproxen reduced_efficacy literature

Genotype Interpretations

What each possible genotype means for this variant.

AA Standard Aspirin Responder Normal

Standard aspirin protection against colorectal cancer applies

You carry the common AA genotype at rs10505806. The large majority of people in all populations share this genotype — approximately 94.6% globally. Based on the genome-wide evidence from the chr12p12.3 locus, your MGST1 regulatory region is in the configuration associated with the population-average aspirin benefit. Regular aspirin or NSAID use is expected to provide the well-documented ~30% reduction in colorectal cancer risk seen in large epidemiological studies.

AT Reduced NSAID Responder Intermediate

Aspirin's colorectal cancer protection may be reduced or absent

The chromosome 12p12.3 intergenic region containing rs10505806 appears to regulate MGST1, a MAPEG enzyme that synthesizes PGE2 through a COX-independent pathway. When the T allele is present at this locus, the MGST1 regulatory environment may allow continued PGE2 production even when aspirin suppresses COX-1 and COX-2 — effectively bypassing aspirin's anti-cancer mechanism. The clinical implication is not that aspirin is dangerous for AT carriers, but that its specific utility for colorectal cancer chemoprevention is uncertain and may be reduced.

This does not affect aspirin's cardiovascular benefits, which operate through platelet TXA2 inhibition rather than prostaglandin suppression in the colon.

TT Poor NSAID Responder Reduced

Aspirin may not protect against colorectal cancer and could confer risk

The TT genotype at rs10505806 represents the maximal dose of the T-allele regulatory effect at this MGST1-associated locus. The biologically plausible explanation is that this variant configuration leads to sustained MGST1-mediated PGE2 production in colonic tissue that is not suppressed by aspirin's COX inhibition. Paradoxically, the mild anti-platelet and systemic anti-inflammatory effects of aspirin may alter the immune tumor microenvironment in a way that does not benefit, or could slightly harm, individuals with intact MGST1-bypass PGE2 synthesis.

Critically: this genetic effect is specific to colorectal cancer chemoprevention. Aspirin's cardiovascular benefits (stroke and MI prevention through platelet inhibition) are not mediated through this pathway and are not affected by rs10505806 genotype.