rs4072037 — MUC1

MUC1 Variant — Gastric Mucus Protection and H. Pylori Susceptibility

The MUC1 gene encodes mucin-1, a membrane-bound glycoprotein¹¹ membrane-bound glycoprotein
MUC1 is a large transmembrane mucin that forms a protective barrier on the surface of gastric epithelial cells that plays a crucial role in protecting the gastric lining from environmental insults, particularly the bacterium Helicobacter pylori (H. pylori)²² Helicobacter pylori (H. pylori)
H. pylori is the primary bacterial cause of gastric ulcers and gastric cancer, infecting about half the world's population. The rs4072037 variant, though synonymous³³ synonymous
A synonymous variant doesn't change the amino acid sequence but can affect mRNA splicing and gene expression, significantly affects how effectively this protective barrier functions by influencing alternative splicing of the MUC1 gene.

The Mechanism

The rs4072037 variant (G>A) is located in exon 2 of the MUC1 gene at chromosome 1q22. Though it doesn't change the encoded amino acid (making it synonymous), the A variant disrupts normal splicing patterns, leading to production of a 27-nucleotide shorter transcript⁴⁴ 27-nucleotide shorter transcript
The A allele introduces an alternative splice site that removes 27 nucleotides from the mature mRNA. This altered MUC1 protein has reduced ability to block H. pylori adhesion to gastric mucosa. The protective G allele maintains normal MUC1 structure, which more effectively blocks H. pylori adhesin binding⁵⁵ blocks H. pylori adhesin binding
MUC1 blocks both BabA (blood group antigen-binding adhesin) and SabA (sialic acid-binding adhesin) of H. pylori, limiting bacterial colonization.

The Evidence

Multiple meta-analyses⁶⁶ Multiple meta-analyses
Liu et al. Meta-analysis of 9 studies with 10,410 cases and 11,437 controls have established that the G allele provides significant protection against gastric cancer, with an odds ratio of 0.70 (95% CI: 0.64-0.76). This protective effect is particularly strong in Asian populations, where the association reaches genome-wide significance. A recent Iranian study⁷⁷ recent Iranian study
Shekarriz et al. Case-control study of 99 gastric cancer patients and 98 controls found that individuals with GA or GG genotypes who are H. pylori-positive show significantly increased gastric cancer susceptibility (OR=0.251), demonstrating a critical gene-environment interaction.

The AA genotype is associated with 2.2-fold increased gastric cancer risk⁸⁸ 2.2-fold increased gastric cancer risk
Jia et al. Polish gastric cancer study compared to GG, and the effect is most pronounced for diffuse-type gastric cancer⁹⁹ diffuse-type gastric cancer
Diffuse gastric cancer is a more aggressive subtype with worse prognosis. Studies across multiple ethnic groups consistently show this pattern, though the effect size is larger in Asian populations (where gastric cancer and H. pylori rates are higher) than in Caucasians.

Practical Implications

If you carry one or two copies of the A allele, your gastric mucus barrier may be less effective at preventing H. pylori colonization. This doesn't mean you'll definitely develop problems, but it suggests increased vigilance around gastric health, particularly if you're in a region with high H. pylori prevalence. Consider testing for H. pylori infection if you experience persistent digestive symptoms, as early treatment can prevent progression to more serious conditions.

The protective G allele is relatively common globally (37-40% frequency), meaning that a substantial portion of the population benefits from enhanced natural defense against H. pylori. Those with GG genotype have the strongest protective effect, but even GA carriers show intermediate protection compared to AA individuals.

Interactions

The rs4072037 variant's effect is most pronounced in the presence of H. pylori infection, demonstrating a critical gene-environment interaction. The variant also exists in linkage disequilibrium¹⁰¹⁰ linkage disequilibrium
Linkage disequilibrium means these variants are often inherited together as a block with other MUC1 variants including rs2070803 and rs2075570, which also affect gastric cancer risk. The combined effect of multiple MUC1 variants may further modulate gastric mucosal protection, though individual risk from rs4072037 is well-established independent of other variants.