Connections between genetics and clinical data: Role of MCP-1, CFTR, and SPINK-1 in the setting of acute, acute recurrent, and chronic pancreatitis.
OBJECTIVE
Acute, acute recurrent, and chronic pancreatitis are inflammatory diseases with multifactorial pathogenic mechanisms. Genetic mutations and polymorphisms have been correlated with pancreatitis. The aim of this study was to investigate the association of cystic fibrosis transmembrane conductance regulator (CFTR) and serine protease inhibitor Kazal type 1 (SPINK-1) gene mutations and monocyte chemoattractant protein 1 (MCP-1) -2518A/G polymorphism with acute pancreatitis (AP), acute recurrent pancreatitis (ARP), and chronic pancreatitis (CP), and to associate genetic backgrounds with clinical phenotype in these three conditions.


METHODS
One hundred eighteen AP, 64 ARP, 142 CP patients, and 88 normal controls were enrolled consecutively. We analyzed MCP-1 serum levels using enzyme-linked immunosorbent assay. Polymorphism -2518 of MCP-1 and SPINK-1 N34S gene mutations were determined by PCR-restriction-fragment length polymorphism. Sequence analysis was performed when necessary. Thirty-three CFTR mutations were analyzed in CP and ARP patients using multiplex DNA testing.


RESULTS
Serum MCP-1 levels were significantly higher in all patients affected by pancreatic inflammatory diseases. Moreover, we found a significant over-representation of the MCP-1G allele in ARP patients. We found a statistically significant association of CFTR gene mutations with ARP, but not with CP. We did not find a statistically significant association of ARP or CP with the N34S SPINK-1 gene mutation. Interestingly, 39 of 64 ARP patients (61%) carried at least one genetic mutation and/or polymorphism. Five of 64 ARP patients had pancreas divisum and four of these five also carried the G allele.


CONCLUSIONS
Analysis of a comprehensive range of potential susceptibility variants is needed to support modeling of the effects of genes and environment in pancreatitis. As such, beyond gene mutations, the context within which those mutations exist must be considered. In pancreatitis the context includes the inflammatory response, clinical features, and exogenous factors.
Department of Clinical Science, University of Parma, Italy. giuliamartina.cavestro@unipr.it
Giulia Martina
GM
Cavestro
Raffaella Alessia
RA
Zuppardo
Simone
S
Bertolini
Giuliana
G
Sereni
Luca
L
Frulloni
Stefano
S
Okolicsanyi
Cristina
C
Calzolari
Satish K
SK
Singh
Mario
M
Sianesi
Paolo
P
Del Rio
Gioacchino
G
Leandro
Angelo
A
Franzè
Francesco
F
Di Mario
D000208:Acute Disease; D048868:Adaptor Proteins, Signal Transducing; D000368:Aged; D000483:Alleles; D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D018932:Chemokine CCL2 / Q000235:genetics*; D016009:Chi-Square Distribution; D002908:Chronic Disease; D016001:Confidence Intervals; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D000077614:Golgi Matrix Proteins; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D026901:Membrane Transport Proteins; D008875:Middle Aged; D009154:Mutation; D016017:Odds Ratio; D010195:Pancreatitis / Q000000981:diagnostic imaging / Q000235:genetics*; D010641:Phenotype; D011110:Polymorphism, Genetic; D012008:Recurrence; D014057:Tomography, X-Ray Computed; D014359:Trypsin Inhibitor, Kazal Pancreatic; D014463:Ultrasonography
D048868:Adaptor Proteins, Signal Transducing; C111835:CCL2 protein, human; D002352:Carrier Proteins; D018932:Chemokine CCL2; C434484:GOPC protein, human; D000077614:Golgi Matrix Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C486642:SPINK1 protein, human; D014359:Trypsin Inhibitor, Kazal Pancreatic