Eszter Hegyi1, Andrea Geisz, Miklós Sahin-Tóth, Monique H M Derikx, Balázs Csaba Németh, Anita Balázs, István Hritz, Ferenc Izbéki, Adrienn Halász, Andrea Párniczky, Tamás Takács, Dezső Kelemen, Patrícia Sarlós, Péter Hegyi, László Czakó. 1. From the *First Department of Medicine, University of Szeged, Szeged, Hungary; †Second Department of Pediatrics, Comenius University Medical School, University Children's Hospital, Bratislava, Slovakia; ‡Department of Molecular and Cell Biology, Boston University Henry M. Goldman School of Dental Medicine, Boston, MA; §First Department of Medicine, Szent György Teaching Hospital of County Fejér, Székesfehérvár; ∥Heim Pál Children's Hospital, Budapest; ¶Department of Surgery and #First Department of Internal Medicine, University of Pécs, Pécs; and **MTA-SZTE Translational Gastroenterology Research Group, Szeged, Hungary.
Abstract
OBJECTIVES: Serine protease inhibitor Kazal type 1 (SPINK1) provides an important line of defense against premature trypsinogen activation within the pancreas. Our aim was to identify pathogenic SPINK1 promoter variants associated with chronic pancreatitis (CP). METHODS: One hundred CP patients (cases) and 100 controls with no pancreatic disease from the Hungarian National Pancreas Registry were enrolled. Direct sequencing of SPINK1 promoter region was performed. Functional characterization of variants was carried out using luciferase reporter gene assay. RESULTS: Two common polymorphisms (c.-253T>C and c.-807C>T) were found in both cases and controls. Variant c.253T>C was enriched in cases relative to controls (odds ratio, 2.1; 95% confidence interval, 1.2-3.8; P = 0.015). Variant c.-215G>A was detected in 3 of 100 cases; always linked with the pathogenic variant c.194+2T>C. Novel promoter variants c.-14G>A, c.-108G>T, and c.-246A>G were identified in 1 case each. Functional analysis showed decreased promoter activity for variants c.-14G>A (80%), c.-108G>T (31%), and c.-246A>G (47%) whereas activity of variant c.-215G>A was increased (201%) and variant c.-253T>C was unchanged compared with wild type. CONCLUSIONS: The common promoter variant c.-253T>C was associated with CP in this cohort. Two of 3 newly identified SPINK1 promoter variants seem to exhibit significant functional defects and should be considered potential risk factors for CP.
OBJECTIVES:Serine protease inhibitor Kazal type 1 (SPINK1) provides an important line of defense against premature trypsinogen activation within the pancreas. Our aim was to identify pathogenic SPINK1 promoter variants associated with chronic pancreatitis (CP). METHODS: One hundred CP patients (cases) and 100 controls with no pancreatic disease from the Hungarian National Pancreas Registry were enrolled. Direct sequencing of SPINK1 promoter region was performed. Functional characterization of variants was carried out using luciferase reporter gene assay. RESULTS: Two common polymorphisms (c.-253T>C and c.-807C>T) were found in both cases and controls. Variant c.253T>C was enriched in cases relative to controls (odds ratio, 2.1; 95% confidence interval, 1.2-3.8; P = 0.015). Variant c.-215G>A was detected in 3 of 100 cases; always linked with the pathogenic variant c.194+2T>C. Novel promoter variants c.-14G>A, c.-108G>T, and c.-246A>G were identified in 1 case each. Functional analysis showed decreased promoter activity for variants c.-14G>A (80%), c.-108G>T (31%), and c.-246A>G (47%) whereas activity of variant c.-215G>A was increased (201%) and variant c.-253T>C was unchanged compared with wild type. CONCLUSIONS: The common promoter variant c.-253T>C was associated with CP in this cohort. Two of 3 newly identified SPINK1 promoter variants seem to exhibit significant functional defects and should be considered potential risk factors for CP.
Authors: Monique H M Derikx; Andrea Geisz; Éva Kereszturi; Miklós Sahin-Tóth Journal: Am J Physiol Gastrointest Liver Physiol Date: 2015-03-19 Impact factor: 4.052
Authors: Amanda Takáts; Gergő Berke; Andrea Szentesi; Gyula Farkas; Ferenc Izbéki; Bálint Erőss; László Czakó; Áron Vincze; Péter Hegyi; Miklós Sahin-Tóth; Eszter Hegyi Journal: Pancreatology Date: 2021-08-26 Impact factor: 3.977
Authors: Andrea Párniczky; Eszter Hegyi; Anna Zsófia Tóth; Ákos Szücs; Andrea Szentesi; Áron Vincze; Ferenc Izbéki; Balázs Csaba Németh; Péter Hegyi; Miklós Sahin-Tóth Journal: Int J Mol Sci Date: 2016-12-20 Impact factor: 5.923