Do PRSS1 rs10273639 CT and CLDN2 rs7057398 TT increase chronic pancreatitis risk?

Genetic research into chronic pancreatitis (CP) has identified specific variants in the PRSS1 and CLDN2 loci that significantly influence disease susceptibility. However, the influence of these variants is divergent: one acts as a risk factor while the other serves a protective role.

Genetic and clinical evidence

Evidence from large-scale genome-wide association studies (GWAS) and meta-analyses confirms a significant association between these loci and chronic pancreatitis risk, particularly in the context of alcohol consumption.

• CLDN2 rs7057398 (Risk Variant): The rs7057398 variant is a well-replicated risk factor for CP. Because the CLDN2 gene is located on the X chromosome, the risk is particularly pronounced in males (who are hemizygous) and in females with the TT genotype. The risk allele is associated with an odds ratio (OR) of approximately 1.3 to 1.7 for alcohol-related CP across multiple European cohorts (e.g., North American Pancreatitis Study 2 and European Pancreatic Disease GWAS).
• PRSS1 rs10273639 (Protective Variant): Contrary to the claim, the T allele at rs10273639 is established as a protective factor. Research involving thousands of cases and controls shows that individuals with the CT or TT genotype have a ~30% reduction in CP risk (OR ≈ 0.7). The risk is actually associated with the C allele (the ancestral allele), which is more prevalent in patients with CP compared to healthy controls.

Mechanistic insights

The interaction between these two loci reflects the balance between trypsin production and ductal defense mechanisms.

• Trypsinogen Regulation: The PRSS1 rs10273639 T allele is in strong linkage disequilibrium with a promoter variant (rs4726576) that significantly decreases the mRNA expression of PRSS1 (cationic trypsinogen). By lowering the amount of trypsinogen available in the pancreas, the variant reduces the likelihood of premature intrapancreatic activation and subsequent autodigestion.
• Ductal Barrier Integrity: CLDN2 encodes claudin-2, a protein forming tight junction pores that regulate paracellular permeability. The rs7057398 risk variant is associated with the ectopic or increased expression of claudin-2 in the pancreatic ductal epithelium during inflammation. This "leakiness" may impair the duct’s ability to flush out activated enzymes or maintain appropriate bicarbonate levels, facilitating a proinflammatory environment.

Bottom line

The claim is only partially accurate: while the CLDN2 rs7057398 TT genotype significantly increases the risk of chronic pancreatitis, the PRSS1 rs10273639 CT genotype is actually a protective marker that lowers risk by reducing trypsinogen levels. For a 41-year-old female, the presence of the CLDN2 risk variant may elevate susceptibility, particularly if combined with environmental triggers like alcohol, but this effect is mitigated if the PRSS1 protective variant is also present.