title: Discovery and Functional Annotation of PRSS1 Promoter Variants in Chronic Pancreatitis.
abstract: 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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U1078, Brest, France.|Faculté de Médecine et des Sciences de la Santé, Université de Bretagne Occidentale (UBO), Brest, France.|Etablissement Français du sang (EFS) - Bretagne, Brest, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Boulling
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U1078, Brest, France.|Faculté de Médecine et des Sciences de la Santé, Université de Bretagne Occidentale (UBO), Brest, France.|Laboratoire de Génétique Moléculaire et d'Histocompatibilité, Centre Hospitalier Régional Universitaire (CHRU) Brest, Hôpital Morvan, Brest, France.|Service de Gastro-Entérologie, Centre Hospitalier Régional Universitaire (CHRU) Brest, Hôpital Cavale Blanche, Brest, France.
authors.forename: Amandine
authors.initials: A
authors.lastname: Abrantes
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U1078, Brest, France.|Laboratoire de Génétique Moléculaire et d'Histocompatibilité, Centre Hospitalier Régional Universitaire (CHRU) Brest, Hôpital Morvan, Brest, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Masson
authors.affiliation: Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors.forename: David N
authors.initials: DN
authors.lastname: Cooper
authors.affiliation: Service de Gastro-Entérologie, Centre Hospitalier Régional Universitaire (CHRU) Brest, Hôpital Cavale Blanche, Brest, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Robaszkiewicz
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U1078, Brest, France. Jian-Min.Chen@univ-brest.fr.|Faculté de Médecine et des Sciences de la Santé, Université de Bretagne Occidentale (UBO), Brest, France. Jian-Min.Chen@univ-brest.fr.|Etablissement Français du sang (EFS) - Bretagne, Brest, France. Jian-Min.Chen@univ-brest.fr.
authors.forename: Jian-Min
authors.initials: JM
authors.lastname: Chen
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U1078, Brest, France.|Faculté de Médecine et des Sciences de la Santé, Université de Bretagne Occidentale (UBO), Brest, France.|Etablissement Français du sang (EFS) - Bretagne, Brest, France.|Laboratoire de Génétique Moléculaire et d'Histocompatibilité, Centre Hospitalier Régional Universitaire (CHRU) Brest, Hôpital Morvan, Brest, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Férec
mesh_terms: D002460:Cell Line; D005260:Female; D005602:France; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D050500:Pancreatitis, Chronic / Q000208:ethnology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D017422:Sequence Analysis, DNA / Q000379:methods*; D017384:Sequence Deletion; D014357:Trypsin / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: C489303:PRSS1 protein, human; D014357:Trypsin
keywords: chronic pancreatitis; electrophoretic mobility shift assay; precision medicine; promoter reporter gene assay; supershift