SPINK1 Promoter Variants in Chronic Pancreatitis.
OBJECTIVE
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.
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.
Eszter
E
Hegyi
Andrea
A
Geisz
Miklós
M
Sahin-Tóth
Monique H M
MH
Derikx
Balázs Csaba
BC
Németh
Anita
A
Balázs
István
I
Hritz
Ferenc
F
Izbéki
Adrienn
A
Halász
Andrea
A
Párniczky
Tamás
T
Takács
Dezső
D
Kelemen
Patrícia
P
Sarlós
Péter
P
Hegyi
László
L
Czakó
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D002460:Cell Line; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D017930:Genes, Reporter; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D006814:Hungary; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D050500:Pancreatitis, Chronic / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D051381:Rats; D012042:Registries; D012307:Risk Factors; D014162:Transfection; D014359:Trypsin Inhibitor, Kazal Pancreatic
D002352:Carrier Proteins; C486642:SPINK1 protein, human; D014359:Trypsin Inhibitor, Kazal Pancreatic