title: SPINK1/PSTI polymorphisms act as disease modifiers in familial and idiopathic chronic pancreatitis.
abstract: OBJECTIVE
  Gain-of-function trypsin mutations cause acute pancreatitis and chronic pancreatitis. Loss of trypsin inhibitor function may have similar effects. We investigated the prevalence of SPINK1 (PSTI) mutations in familial pancreatitis, idiopathic chronic pancreatitis, and controls.
  
  
  METHODS
  Genetic-linkage studies were performed in 5 familial pancreatitis families. The entire SPINK1 gene was sequenced in 112 affected individuals and 95 control DNA samples, and exon 3 was sequenced in 95 additional controls. X-ray crystallography-based model building and statistical studies were performed.
  
  
  RESULTS
  Significant linkage between pancreatitis and 5q31.1-2 was excluded. Novel SPINK1 mutations, one D50E mutation, one IVS3+125 C>A, and five IVS3+184 T>A intronic polymorphisms were identified. The N34S and P55S mutations were observed in 29 of 112 patients (25%) as N34S/N34S (n = 7), N34S/wt (n = 19), N34S/P55S (n = 2), and N34S/D50E (n = 1). Three hundred eighty control alleles revealed 3 N34S (0.77%), 2 P55S (0.53%), and no D50E mutations. Age of disease onset and severity were similar between homozygous and heterozygous patients. Structural modeling revealed several possible pathophysiologic mechanisms for the N34S mutation.
  
  
  CONCLUSIONS
  SPINK1 mutations are common in the population (approximately 2%), but are clearly associated with pancreatitis. The mutation-associated risk is low. Modeling and familial clustering suggest that SPINK1 mutations are disease modifying, possibly by lowering the threshold for pancreatitis from other genetic or environmental factors, but by themselves do not cause disease.
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: R H
authors.initials: RH
authors.lastname: Pfützer
authors.forename: M M
authors.initials: MM
authors.lastname: Barmada
authors.forename: A P
authors.initials: AP
authors.lastname: Brunskill
authors.forename: R
authors.initials: R
authors.lastname: Finch
authors.forename: P S
authors.initials: PS
authors.lastname: Hart
authors.forename: J
authors.initials: J
authors.lastname: Neoptolemos
authors.forename: W F
authors.initials: WF
authors.lastname: Furey
authors.forename: D C
authors.initials: DC
authors.lastname: Whitcomb
mesh_terms: D000595:Amino Acid Sequence / Q000235:genetics; D002908:Chronic Disease; D004252:DNA Mutational Analysis; D005260:Female; D008040:Genetic Linkage; D005820:Genetic Testing; D006801:Humans; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010195:Pancreatitis / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics / Q000502:physiology*; D014359:Trypsin Inhibitor, Kazal Pancreatic / Q000235:genetics*
chemical_list: D014359:Trypsin Inhibitor, Kazal Pancreatic