ABSTRACT
BACKGROUND: PRSS1 and PRSS2 constitute the only functional copies of a tandemly-arranged five-trypsinogen-gene cluster (i.e., PRSS1, PRSS3P1, PRSS3P2, TRY7 and PRSS2) on chromosome 7q35. Variants in PRSS1 and PRSS2, including missense and copy number variants (CNVs), have been reported to predispose to or protect against chronic pancreatitis (CP). We wondered whether a common trypsinogen pseudogene deletion CNV (that removes two of the three trypsinogen pseudogenes, PRSS3P2 and TRY7) might be associated with CP causation/predisposition. METHODS: We analyzed the common PRSS3P2 and TRY7 deletion CNV in a total of 1536 CP patients and 3506 controls from France, Germany, India and Japan by means of quantitative fluorescent multiplex polymerase chain reaction. RESULTS: We demonstrated that the deletion CNV variant was associated with a protective effect against CP in the French, German and Japanese cohorts whilst a trend toward the same association was noted in the Indian cohort. Meta-analysis under a dominant model yielded a pooled odds ratio (OR) of 0.68 (95% confidence interval (CI) 0.52-0.89; p = 0.005) whereas an allele-based meta-analysis yielded a pooled OR of 0.84 (95% CI 0.77-0.92; p = 0.0001). This protective effect is explicable by reference to the recent finding that the still functional PRSS3P2/TRY7 pseudogene enhancers upregulate pancreatic PRSS2 expression. CONCLUSIONS: The common PRSS3P2 and TRY7 deletion CNV was associated with a reduced risk for CP. This finding provides additional support for the emerging view that dysregulated PRSS2 expression represents a discrete mechanism underlying CP predisposition or protection.
Subject(s)
Pancreatitis, Chronic , Trypsinogen , Humans , Alleles , DNA Copy Number Variations/genetics , Genetic Predisposition to Disease , Genotype , Mutation , Pancreatitis, Chronic/genetics , Trypsin/genetics , Trypsinogen/geneticsABSTRACT
Recently, our resequencing of the promoter region of PRSS1 in French Caucasian individuals led to the identification of a functional variant (c.-204C > A) that is in perfect linkage disequilibrium with the "chronic pancreatitis (CP)-protective" PRSS1 c.-408C > T variant. Here, we extended the resequencing to 626 French Caucasians (242 idiopathic CP patients and 384 controls). We discovered three additional variants (c.-184G > A, c.-173C > T, and c.-147C > T), each being found only once in either patients or controls. We analyzed these three variants, together with a known PRSS1 promoter variant (c.-30_-28delTCC) long considered to be causative for CP, by luciferase promoter reporter assay in AR42J cells treated with dexamethasone. This analysis revealed that c.-30_-28delTCC resulted in reduced rather than increased PRSS1 gene expression, suggesting that it is not a CP risk factor as originally claimed. We provide evidence that c.-147C > T probably confers protection against CP by reducing the affinity of an ATF4 transcription factor binding site.
