Polymorphisms at PRSS1-PRSS2 and CLDN2-MORC4 loci associate with alcoholic and non-alcoholic chronic pancreatitis in a European replication study

Gut. 2015 Sep;64(9):1426-33. doi: 10.1136/gutjnl-2014-307453. Epub 2014 Sep 24.

Abstract

Objective: Several genetic risk factors have been identified for non-alcoholic chronic pancreatitis (NACP). A genome-wide association study reported an association of chronic pancreatitis (CP) with variants in PRSS1-PRSS2 (rs10273639; near the gene encoding cationic trypsinogen) and CLDN2-MORC4 loci (rs7057398 in RIPPLY1 and rs12688220 in MORC4). We aimed to refine these findings in a large European cohort.

Design: We studied 3062 patients with alcohol-related CP (ACP) or NACP and 5107 controls. Also, 1559 German patients with alcohol-associated cirrhosis or alcohol dependence were included for comparison. We performed several meta-analyses to examine genotype-phenotype relationships.

Results: Association with ACP was found for rs10273639 (OR, 0.63; 95% CI 0.55 to 0.72). ACP was also associated with variants rs7057398 and rs12688220 in men (OR, 2.26; 95% CI 1.94 to 2.63 and OR, 2.66; 95% CI 2.21 to 3.21, respectively) and in women (OR, 1.57; 95% CI 1.14 to 2.18 and OR 1.71; 95% CI 1.41 to 2.07, respectively). Similar results were obtained when German patients with ACP were compared with those with alcohol-associated cirrhosis or alcohol dependence. In the overall population of patients with NACP, association with rs10273639 was absent (OR, 0.93; 95% CI 0.79 to 1.01), whereas rs7057398 of the X chromosomal single nucleotide polymorphisms was associated with NACP in women only (OR, 1.32; 95% CI 1.15 to 1.51).

Conclusions: The single-nucleotide polymorphisms rs10273639 at the PRSS1-PRSS2 locus and rs7057398 and rs12688220 at the CLDN2-MORC4 locus are associated with CP and strongly associate with ACP, but only rs7057398 with NACP in female patients.

Keywords: CHRONIC PANCREATITIS; GENETIC POLYMORPHISMS; PANCREATITIS; TRYPSINOGEN.

Publication types

  • Comparative Study

MeSH terms

  • Case-Control Studies
  • Claudins / genetics*
  • Confidence Intervals
  • Europe
  • Female
  • Genetic Loci
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Nuclear Proteins / genetics*
  • Odds Ratio
  • Pancreatitis, Alcoholic / genetics*
  • Pancreatitis, Alcoholic / mortality
  • Pancreatitis, Alcoholic / physiopathology
  • Pancreatitis, Chronic / genetics
  • Pancreatitis, Chronic / mortality
  • Pancreatitis, Chronic / physiopathology
  • Polymorphism, Genetic
  • Polymorphism, Single Nucleotide*
  • Reference Values
  • Sex Factors
  • Survival Analysis
  • Trypsin / genetics*
  • Trypsinogen / genetics*

Substances

  • CLDN2 protein, human
  • Claudins
  • MORC4 protein, human
  • Nuclear Proteins
  • PRSS2 protein, human
  • Trypsinogen
  • PRSS1 protein, human
  • Trypsin