Role of the Common PRSS1-PRSS2 Haplotype in Alcoholic and Non-Alcoholic Chronic Pancreatitis: Meta- and Re-Analyses.

Anthony F Herzig,Emmanuelle Génin,Emmanuelle Masson,David N Cooper,Claude Férec,Jian-Min Chen

doi:10.3390/genes11111349

Abstract

The association between a common PRSS1-PRSS2 haplotype and alcoholic chronic pancreatitis (ACP), which was revealed by the first genome-wide association study of chronic pancreatitis (CP), has been consistently replicated. However, the association with non-ACP (NACP) has been controversial. Herein, we sought to clarify this basic issue by means of an allele-based meta-analysis of currently available studies. We then used studies informative for genotype distribution to explore the biological mechanisms underlying the association data and to test for gene-environment interaction between the risk haplotype and alcohol consumption by means of a re-analysis. A literature search was conducted to identify eligible studies. A meta-analysis was performed using the Review Manager software. The association between the risk genotypes and NACP or ACP was tested for the best-fitting genetic model. Gene-environment interaction was estimated by both case-only and multinomial approaches. Five and eight studies were employed for the meta-analysis of ACP and NACP findings, respectively. The risk allele was significantly associated with both ACP (pooled odds ratio (OR) 1.67, 95% confidence interval (CI) 1.56–1.78; p < 0.00001) and NACP (pooled OR 1.28, 95% CI 1.17–1.40; p < 0.00001). Consistent with a dosage effect of the risk allele on PRSS1/PRSS2 mRNA expression in human pancreatic tissue, both ACP and NACP association data were best explained by an additive genetic model. Finally, the risk haplotype was found to interact synergistically with alcohol consumption.

Highlights

Chronic pancreatitis (CP) is a chronic inflammatory process of the pancreas that leads to irreversible morphological changes and progressive impairment of both exocrine and endocrine functions [1,2].chronic pancreatitis (CP) can be caused by genetic and/or environmental factors [3]
Studies that satisfied the following criteria were included for meta-analysis: (i) published in a peer-reviewed journal; (ii) the common PRSS1-PRSS2 haplotype was analysed in both alcoholic CP (ACP) and/or NACP patients and controls; and (iii) the tagging single nucleotide polymorphism (SNP) of interest was in Hardy–Weinberg equilibrium in the controls
The remaining eight studies were included in our meta-analysis; five of these reported data on both ACP and NACP [6,9,10,32,33], whereas the other three reported data only for NACP [34,35,36]

Summary

Introduction

CP can be caused by genetic and/or environmental factors [3]. Rare gain-of-function missense or copy number variants in the PRSS1 gene (encoding cationic trypsinogen; MIM# 276000). Can cause autosomal dominant hereditary pancreatitis [4,5]. Alcohol abuse is the most frequent environmental factor causing CP worldwide [2,3]. PRSS1-PRSS2 haplotype was reported to be associated with both alcoholic CP (ACP) and non-ACP. PRSS2 encodes anionic trypsinogen (MIM# 601564), the second major trypsinogen isoform after cationic trypsinogen. This association has a strong biological basis: the risk (C) allele of the lead single nucleotide polymorphism (SNP), rs10273639C/T, appeared to be associated with increased PRSS1

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Conclusion