rs10505806 — MGST1

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.