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Discovery and Functional Annotation of PRSS1 Promoter Variants in Chronic Pancreatitis
Author(s) -
Boulling Arnaud,
Abrantes Amandine,
Masson Emmanuelle,
Cooper David N.,
Robaszkiewicz Michel,
Chen JianMin,
Férec Claude
Publication year - 2016
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23053
Subject(s) - biology , pancreatitis , promoter , transcription factor , linkage disequilibrium , genetics , gene , microbiology and biotechnology , cancer research , gene expression , genotype , single nucleotide polymorphism , medicine
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.