SPINK1 Promoter Variants in Chronic Pancreatitis

Eszter Hegyi, Andrea Geisz, Miklós Sahin-Tóth, Monique H.M. Derikx, Balázs Csaba Németh, Anita Balázs, I. Hritz, F. Izbéki, Adrienn Halász, Andrea Párniczky, T. Takács, Dezs Kelemen, Patrícia Sarlós, P. Hegyi, L. Czakó

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish
JournalPancreas.
DOIs
Publication statusAccepted/In press - Sep 4 2015

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Serine Proteinase Inhibitors
Chronic Pancreatitis
Pancreas
Trypsinogen
Pancreatic Diseases
Luciferases
Reporter Genes
Genetic Promoter Regions
Registries
Odds Ratio
Confidence Intervals

ASJC Scopus subject areas

  • Hepatology
  • Internal Medicine
  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

Hegyi, E., Geisz, A., Sahin-Tóth, M., Derikx, M. H. M., Németh, B. C., Balázs, A., ... Czakó, L. (Accepted/In press). SPINK1 Promoter Variants in Chronic Pancreatitis. Pancreas.. https://doi.org/10.1097/MPA.0000000000000412

SPINK1 Promoter Variants in Chronic Pancreatitis. / Hegyi, Eszter; Geisz, Andrea; Sahin-Tóth, Miklós; Derikx, Monique H.M.; Németh, Balázs Csaba; Balázs, Anita; Hritz, I.; Izbéki, F.; Halász, Adrienn; Párniczky, Andrea; Takács, T.; Kelemen, Dezs; Sarlós, Patrícia; Hegyi, P.; Czakó, L.

In: Pancreas., 04.09.2015.

Research output: Contribution to journalArticle

Hegyi, E, Geisz, A, Sahin-Tóth, M, Derikx, MHM, Németh, BC, Balázs, A, Hritz, I, Izbéki, F, Halász, A, Párniczky, A, Takács, T, Kelemen, D, Sarlós, P, Hegyi, P & Czakó, L 2015, 'SPINK1 Promoter Variants in Chronic Pancreatitis', Pancreas.. https://doi.org/10.1097/MPA.0000000000000412
Hegyi E, Geisz A, Sahin-Tóth M, Derikx MHM, Németh BC, Balázs A et al. SPINK1 Promoter Variants in Chronic Pancreatitis. Pancreas. 2015 Sep 4. https://doi.org/10.1097/MPA.0000000000000412
Hegyi, Eszter ; Geisz, Andrea ; Sahin-Tóth, Miklós ; Derikx, Monique H.M. ; Németh, Balázs Csaba ; Balázs, Anita ; Hritz, I. ; Izbéki, F. ; Halász, Adrienn ; Párniczky, Andrea ; Takács, T. ; Kelemen, Dezs ; Sarlós, Patrícia ; Hegyi, P. ; Czakó, L. / SPINK1 Promoter Variants in Chronic Pancreatitis. In: Pancreas. 2015.
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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.",
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AU - Hegyi, Eszter

AU - Geisz, Andrea

AU - Sahin-Tóth, Miklós

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AU - Németh, Balázs Csaba

AU - Balázs, Anita

AU - Hritz, I.

AU - Izbéki, F.

AU - Halász, Adrienn

AU - Párniczky, Andrea

AU - Takács, T.

AU - Kelemen, Dezs

AU - Sarlós, Patrícia

AU - Hegyi, P.

AU - Czakó, L.

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N2 - 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.

AB - 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.

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