SPINK1/PSTI mutations are associated with tropical pancreatitis in Bangladesh. A preliminary report.

BACKGROUND/AIMS: Tropical pancreatitis (TP) refers to a severe type of idiopathic chronic pancreatitis that develops in children in tropical regions of Africa and southern Asia. Phenotypically TP is subdivided into fibrocalculous pancreatic diabetes (FCPD) and tropical calcific pancreatitis without diabetes mellitus (TCP). Recently an association was identified between idiopathic pancreatitis in the USA and Europe and mutations in the serine protease inhibitor, Kazal type 1 (SPINK1) gene (previously termed pancreatic secretory trypsin inhibitor, PSTI). Our aim was to determine if either form of TP has a genetic basis. METHODS: We studied 8 well-characterized patients from Bangladesh with FCPD, 4 with TCP and 4 controls without pancreatic disease. The entire SPINK1 gene was sequenced in these patients. RESULTS: We detected two disease-associated SPINK1 mutations (N34S/IVS1 - 37T > C and IVS3 + 2T > C) in 6 of 8 patients from Bangladesh with FCPD but not in 4 patients with TCP (p < 0.03) or 4 controls (p < 0.03). CONCLUSIONS: We conclude that SPINK1 mutations are associated with FCPD in Bangladesh. Since SPINK1 mutations in Europeans and North Americans are associated with idiopathic chronic pancreatitis that is phenotypically different from FCPD, we further conclude that mutated SPINK1 markedly increases the risk of developing a variety of pancreatic diseases possibly through a chronic elevation of active trypsin within the pancreas.

Hereditary pancreatitis in North America: the Pittsburgh-Midwest Multi-Center Pancreatic Study Group Study.

BACKGROUND: Hereditary pancreatitis (HP) was defined on a clinical basis alone until the first cationic trypsinogen gene (PRSS1) mutation was discovered through the initial phase of the current Pittsburgh Midwest Multi-Center Pancreatic Study Group (MMPSG) HP study in 1996, making genetic testing available. AIM: To evaluate the regional distribution of HP in the United States, and to compare the study's gene mutation database with the pedigree databases to determine whether family history alone predicts the likelihood of detecting mutations in the cationic trypsinogen gene. METHODS: Probands of families with HP, familial pancreatitis and idiopathic chronic pancreatitis were recruited through referrals from MMPSG collaborating centers, other physicians and self-referral of patients who had learned of the study through the World Wide Web (www.pancreas.org). Pedigrees were constructed, detailed questionnaires were completed and a blood sample was drawn for each proband and participating family members. The birthplace and current location of each patient was recorded, DNA was analyzed for known mutations and the pattern of phenotype inheritance was determined from analysis of each pedigree. RESULTS: A total of 717 individuals were ascertained; 368 (51%) had clinical pancreatitis confirmed and the rest were primarily unaffected family members used for linkage studies. Forty-six clinically unaffected individuals were silent mutation carriers (11% of mutation-positive individuals). HP was most common in Minnesota, New York and the central mid-Atlantic states plus Kentucky and Ohio. One hundred and fifteen of 150 kindreds fulfilled the strict definition of an HP family, and 60 (52%) had PRSS1 mutations. Of the families with a detected mutation, 11% did not fulfill the clinical definition of an HP kindred. CONCLUSIONS: The distribution of HP within the United States shows major regional differences. The etiology of HP can be identified in a small majority of HP families through genetic testing. However, family history alone is not a good predictor of finding a mutation in the cationic trypsinogen (PRSS1) gene.

SPINK1 mutations are associated with multiple phenotypes.

Mutations in the gene encoding for the pancreatic secretory trypsin inhibitor or serine protease inhibitor, Kazal type I (SPINK1) have been associated with different entities of chronic pancreatitis. While there is no doubt about the involvement of SPINK1 mutations in pancreatic inflammatory disease, much controversy has arisen regarding which alterations are associated with disease and what type of disease model should be applied when the SPINK1 gene is examined. This article presents the existing data on SPINK1 mutations in idiopathic chronic pancreatitis, familial pancreatitis, hereditary pancreatitis and tropical pancreatitis. The possible role of SPINK1 mutations and polymorphisms in pancreatic disease is discussed.

SPINK1/PSTI polymorphisms act as disease modifiers in familial and idiopathic chronic pancreatitis.

BACKGROUND & AIMS: 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.

Acute pancreatitis.

Acute pancreatitis is a process that continues to interest physicians and research scientists. Understanding potential factors initiating acute pancreatitis, mechanisms regulating the local and distant inflammatory response, methods for accurately predicting outcome, and possible therapeutic interventions continue to be investigated. Current interest in inflammatory response of the acute injury focuses on proinflammatory and anti-inflammatory cytokines as markers for disease severity and predictors of outcome. Recent studies confirm the utility of physical examination and existing markers such as C-reactive protein and interleukin-6 in predicting the severity of acute pancreatitis. Understanding the molecular mechanism of lung injury remains a major focus for future therapeutic targets, since pancreatitis-associated pulmonary injury results in significant morbidity and is a major indication for intensive care unit admissions.