N34S Mutation Research Articles

Hereditary Pancreatitis Related to SPINK-1 Mutation. Is There an Increased Risk of Developing Pancreatic Cancer?

It is thought that many of the idiopathic pancreatitis could have a genetic base.Approximately 50% of them correspond to CFTR (cystic fibrosis transmembrane conductance regulator gene) and SPINK-1 (serine protease inhibitor Kazal type 1) mutations.A recent study compares patients with acute pancreatitis andSPINK-1 mutation withpatients with idiopathic acute pancreatitis. The study highlights a12-fold increased risk of developing pancreatic cancer with SPINK-1 mutation versus the control group.Nonetheless, authors conclude that only specificpN34s mutation is related to pancreatic cancer. This relation is controversial, and international consensus guidelines for the follow-up in chronic pancreatitis with pancreatic cancer still do not recommend follow-up in SPINK-1 p. N34S mutation. We believe that developing prospective studies in which subgroups of patients with SPINK-1 mutation benefit from closer follow-ups would be necessary.

PREVALENCE OF SPINK 1 AND CASR GENE MUTATIONS IN ACUTE AND RECURRENT ACUTE PANCREATITIS : A STUDY FROM CENTRAL INDIA

Background: Genetic factors may play an important role in the pathogenesis of acute pancreatitis. It has been observed in various studies that the presence of risk factors alone like alcohol abuse or gall bladder stones does not lead to attacks of pancreatitis in all the patients. This leads to assumption that genetic factors may decrease the threshold for the development of pancreatitis in presence of one or more risk factors. We observed that there is a paucity of data regarding the role of genetics in acute pancreatitis (AP) and recurrent acute pancreatitis (RAP) in our part of the world and we aimed at studying the prevalence of genetic mutations in such patients. Methods: Our study intended to nd the prevalence of SPINK1 N34S (Serine protease inhibitor kazal type 1) and CaSR (Calcium sensing receptor) gene mutations in patients of AP and RAP. A total of 50 patients and 25 age and gender matched controls entered our study. Blood samples were obtained from all the cases and controls for routine investigations and genetic analysis. SPINK 1 N34S and CaSR gene mutation studies were done in all the patients and controls. Results: Alcohol (64%) followed by gallbladder stone disease (20%) was the most common aetiology of pancreatitis. SPINK 1 N34S mutation was present in 21 patients and 2 controls whereas CaSR gene mutation was present in 13 patients and 2 controls. Patients with SPINK 1 N34S and CaSR gene mutations were younger than the patients without these mutations. Prevalence of both SPINK1 N34S and CaSR gene mutations was higher in patients of RAP than AP. These mutations were not associated with aetiology or severity of pancreatitis. Conclusion: The prevalence SPINK 1 N34S and CaSR gene mutations was higher in patients of AP and RAP. Identication of these mutations in patients of AP can help in the identication of patients who are at increased risk of recurrent attacks of AP

A Hypothesized Mechanism for Chronic Pancreatitis Caused by the N34S Mutation of Serine Protease Inhibitor Kazal-Type 1 Based on Conformational Studies.

PurposeAlthough strongly related, the pathophysiological effect of the N34S mutation in the serine protease inhibitor Kazal type 1 (SPINK1) in chronic pancreatitis is still unknown. In this study, we investigate the conformational space of the human cationic trypsin-serine protease inhibitor complex.MethodsSimulations with molecular dynamics, replica exchange, and transition pathway methods are used.ResultsTwo main binding states of the inhibitor to the complex were found, which explicitly relate the influence of the mutation site to conformational changes in the active site of trypsin.ConclusionBased on our result, a hypothesis is formulated that explains the development of chronic pancreatitis through accelerated digestion of the mutant by trypsin.

SPINK1 Mutation in Idiopathic Chronic Pancreatitis: How Pertinent Is It in Coastal Eastern India?

Background and aimIdiopathic chronic pancreatitis (ICP) is said to be present when no identifiable etiology can be identified. Robust evidence suggested that the serine protease inhibitor nucleus Kazol type 1 (SPINK1) N34S mutation was frequently associated with ICP. As there is a paucity of data on genetic studies in ICP cases from the coastal eastern region of India, we performed this study with an aim to evaluate the SPINK1 genetic mutations and other associated clinical correlates in ICP cases.Material and methodsConsecutive ICP cases attending the department of gastroenterology, Institute of Medical Sciences (IMS) and SUM Hospital, were enrolled and evaluated for the pertinent clinical history and undergone detailed biochemical and radiological evaluations. Two ml of venous blood in ethylenediaminetetraacetic acid (EDTA) vials were collected from each case and subjected to a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) test for genetic analysis.ResultIn this study, the mean age of the cases at the time of the first consultation with us and the age of the first clinical presentation were 34.52±6.44 and 28.73±5.52 years, respectively. Males outnumbered females (Male:Female - 2.12:1). Out of the total of 200 cases, 50% had no SPINK1 mutation, whereas 40% and 10% cases had SPINK1 N34S heterozygous and homozygous mutations, respectively. The mean age of clinical presentation, severe abdominal pain, exocrine and endocrine insufficiency, and parenchymal atrophy were significantly more common in mutants as compared to non-mutants (p-value <0.05).ConclusionIn our region, 50% of ICP cases had the SPINK1 N34S mutation. The SPINK1 mutants had a relatively more severe variety of pancreatitis as compared to non-mutants.

PHENOTYPIC AND GENOTYPIC ANALYSIS OF HEREDITARY PANCREATITIS IN PATIENTS AND POTENTIAL CANDIDATES FOR TOTAL PANCREATECTOMY WITH ISLET AUTOTRANSPLANTATION (TP-IAT)

Introduction: Hereditary Pancreatitis (HP) is caused by inheritance of genetic mutations in PRSS1/2, SPINK1, CFTR and CTRC gene regions. HP frequently results in inflammation of the pancreas from a young age, chronic abdominal pain, dependency upon opioids, and elevated risk of pancreatic ductal adenocarcinoma (PDAC) at later stages of life. Total Pancreatectomy with Islet Autotransplantation (TP-IAT) effectively treats patients of HP and prevents diabetes and risk of pancreatic cancer later in life. This project aims to identify HP cases and assess the correlation between phenotypic disease outcome and genotypic mutation variant. Methods: Patients with HP were identified from hospital records and interviewed for phenotype. Criteria include: personal and family medical history, pain management, medical prescriptions, previous surgery, smoking and alcohol history, and quality of life. Salivary biosamples were obtained to be whole-exome-sequenced (WES). WES data was filtered using the VariantGrid pipeline with gnomAD pancreas-related disease frequency >1%. Results: 4 families of 42 individuals, plus 33 additional familial probands of HP had been identified thus far. All 4 families possess the mutation PRSS1, albeit different allelic variants (3 with R122H, 1 with A86T). One PRSS1 R122H mutation variant family also possessed SPINK1 N34S mutation, a known HP disease modifier mutation. In these well-phenotyped families, 23 PRSS1 and 5 SPINK1 genetic mutation carriers were identified from our study cohort. 13 of whom suffered from phenotypic symptoms of HP. Interestingly, 12 of the 33 probands have been genotyped and showed no known HP-associated mutation. Conclusion: Phenotypic disparity in mutation carriers suggests possible existence of unknown modifier genes for HP. Disease phenotype in probands with no known mutation also suggest possible existence of novel HP-associated mutations. Bioinformatics analysis studies of acquired WES data are currently underway for further investigation.

A high prevalence of genetic polymorphisms in idiopathic and alcohol-associated chronic pancreatitis patients in Ireland

Background: Rare pathogenic variants in serine protease inhibitor Kazal type-1 (SPINK1), cationic trypsinogen (PRSS1), cystic fibrosis transmembrane conductance regulator (CFTR) genes are strongly associated with the development and progression of chronic pancreatitis (CP), but are not routinely tested. For a considerable number of CP patients, the cause of disease is unknown or ambiguous despite sophisticated imaging and biochemical investigations. We hypothesised that some patients diagnosed with idiopathic or alcohol-induced CP may carry CP-related mutations. Therefore, we investigated the presence of CP-related gene mutations in idiopathic and alcohol-associated CP patients, compared to controls. Methods: 126 patients with idiopathic and alcohol-induced CP and 167 controls were enrolled following ethical approval. Mutations were assessed by Taqman© genotyping assay. The study was further reinforced by post hoc analysis of SPINK1 N34S with additional controls (total n=508). Results: Mutations were detected in 25 patients (19.8%) and 10 controls (6%)(P<0.001). The presence of a gene mutation increased disease risk three-fold (odds ratio (OR) 3.4). The majority of mutations were found in SPINK1 N34S (12.7%), which increased disease risk six-fold (OR 5.9). CFTR severe mutation (F508del) was present equally in patients and controls (P=0.746). CFTR mild variant (R117H) was not significantly represented amongst patients (P=0.169). PRSS1 variants were not detected in either group. SPINK1 N34S mutations were more common in patients (12.7%) than in controls (2.4% of n=508)(P=5*10-7). Conclusion: 20% of CP patients carried disease-associated / disease-modifying gene mutations, with SPINK1 N34S disease-altering mutation being unexpectedly high. We therefore suggest that the presence of a SPINK1 mutation should be considered in patients with idiopathic or alcohol-induced CP, particularly where diagnosis is uncertain. Early identification of the presence of variants will allow for modification of risk factors and improve CP management. Furthermore, identifying underlying heritable risk factors may contribute to improved options for disease prevention and treatment.

The impact of physiological stress conditions on protein structure and trypsin inhibition of serine protease inhibitor Kazal type 1 (SPINK1) and its N34S variant

One of the most common mutations in the serine protease inhibitor Kazal type 1 (SPINK1) gene is the N34S variant which is strongly associated with chronic pancreatitis. Although it is assumed that N34S mutation constitutes a high-risk factor, the underlying pathologic mechanism is still unknown. In the present study, we investigated the impact of physiological stress factors on SPINK1 protein structure and trypsin inhibitor function using biophysical methods. Our circular dichroism spectroscopy data revealed differences in the secondary structure of SPINK1 and N34S mutant suggesting protein structural changes induced by the mutation as an impairment that could be disease-relevant. We further confirmed that both SPINK1 (KD of 0.15 ± 0.06 nM) and its N34S variant (KD of 0.08 ± 0.02 nM) have similar binding affinity and inhibitory effect towards trypsin as shown by surface plasmon resonance and trypsin inhibition assay studies, respectively. We found that stress conditions such as altered ion concentrations (i.e. potassium, calcium), temperature shifts, as well as environmental pH lead to insignificant differences in trypsin inhibition between SPINK1 and N34S mutant. However, we have shown that the environmental pH induces structural changes in both SPINK1 constructs in a different manner. Our findings suggest protein structural changes in the N34S variant as an impairment of SPINK1 and environmental pH shift as a trigger that could play a role in disease progression of pancreatitis.

Natural history of pancreatitis associated with SPINK1 mutations

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 (~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.GASTROENTEROLOGY 2000;119:615-623

Frequency of Tabagism and N34S and P55S Mutations of Serine Peptidase Inhibitor, Kazal Type 1 (SPINK1) and R254W Mutation of Chymotrypsin C (CTRC) in Patients With Chronic Pancreatitis and Controls.

This study aimed to investigate the association between chronic pancreatitis and smoking or genetic mutations. The study sample comprised 148 patients with chronic pancreatitis, 110 chronic alcoholic subjects without pancreatic disease, and 297 volunteer blood donors. Of the patients with chronic pancreatitis, 74% had alcoholic etiology and 26% had idiopathic pancreatitis. The frequency of smoking was 91.4% in patients with alcoholic pancreatitis, higher than 73.3% in alcoholic subjects without pancreatitis (P < 0.01). The difference in smoking frequency was not significant between the patients with idiopathic pancreatitis and blood donors. The N34S mutation of serine peptidase inhibitor, Kazal type 1 (SPINK1) was found in 2.7% of patients with chronic alcoholic pancreatitis, in 5.3% of patients with idiopathic pancreatitis, and in 0.4% of blood donors (P = 0.02). The P55S mutation of SPINK1 was found in 2.7% of patients with alcoholic pancreatitis and in 0.7% of blood donors (P = 0.12). The R254W mutation of chymotrypsin C was found in 0.9% of patients with alcoholic pancreatitis, in 0.9% of chronic alcoholic subjects without pancreatitis, and in 0.4% of blood donors (P = 0.75). In all cases, the mutations were heterozygous. Smoking and the N34S mutation of SPINK1 were positively correlated with chronic pancreatitis.

Metastatic pancreatic adenocarcinoma associated with chronic calcific pancreatitis and a heterozygous SPINK1 N34S mutation

Contrary to patients with a cationic trypsinogen gene (PRSS1) mutations, Serine protease inhibitor Kazal-type 1 (SPINK1) heterozygote gene mutation carriers have a very low penetrance for acute, acute recurrent and/or chronic pancreatitis. Despite this, heterozygote SPINK 1 gene mutation patients have a similar age of onset of pancreatitis as PRSS 1 gene mutation patients. While the substantially elevated risk of pancreatic cancer in patients with PRSS1 gene mutations with chronic pancreatitis has been well established, little is known about the risk of pancreatic cancer in SPINK 1 gene mutation carriers with pancreatitis. We describe a case of malignant pancreatic cancer diagnosed in a young patient with chronic pancreatitis who is a SPINK 1 heterozygote gene mutation carrier. The risk of pancreatic cancer in gene mutation patients with chronic pancreatitis, in addition to screening options and management options for these patients is discussed.

Genetic predisposition and its impact on natural history of idiopathic acute and acute recurrent pancreatitis in children

BackgroundGenetic predisposition in paediatric idiopathic acute, acute recurrent pancreatitis and its consequences are unknown. We studied frequency of genetic markers in acute, acute recurrent, chronic pancreatitis and their impact on natural history. MethodsOver a period of 2 years 68 consecutive children with pancreatitis (35.3% acute, 32.3% acute recurrent, 32.3% chronic) and 25 controls were recruited in a single centre. Common mutations for serine-protease-inhibitor (SPINK1 N34S), protease-inhibitor (PRSS1 R122H) and cystic fibrosis transmembrane conductance regulator (CFTR DeltaF508, 5T) were analysed. ResultsMean age was 13.4±2.5 years. Overall, 30 cases (SPINK1 N34S n=26, CFTR 5T n=4) and 1 control (SPINK1 N34S) had mutations (p=0.0001). The prevalence of SPINK1 N34S mutation was similar in chronic and acute recurrent pancreatitis (45%). Six children with severe acute pancreatitis had SPINK1 N34S mutations (25%, p<0.05), and 4 were homozygous. On follow-up 5 acute pancreatitis patients with mutations and 1 without mutations developed chronic pancreatitis (p=0.004); 8 cases of acute recurrent pancreatitis progressed to chronic pancreatitis (38%); of these 66.7% had mutations vs. 16.7% who did not (p=0.03). ConclusionsAlmost 50% of idiopathic chronic, acute recurrent and 33% of acute pancreatitis in children are genetically predisposed. Presence of genetic mutations in acute and recurrent acute pancreatitis increases the risk of developing chronic pancreatitis.

The relationship between N34S mutation of serine protease inhibitor Kazal type 1 gene and chronic pancreatitis of different types

Objective To analyze the N34S mutation of serine protease inhibitor Kazal type 1 (SPINK1) gene among patients with chronic pancreatitis of different types,and explore the molecular mechanism of occurrence and development of chronic pancreatitis.Methods Genomic DNA was extracted from 79 patients with chronic pancreatitis and 60 healthy controls.Polymerase chain reaction (PCR) was done first to amplify part of SPINK1 gene and then restriction fragment length polymorphism (RFLP) by using TspR1 to distinguish the N34S mutation.DNA sequencing analysis was also performed to confirm the mutation status.Results N34S mutation of SPINK1 was detected in 6 patients (four cases of idiopatic pancreatitis,one case of biliary pancreatitis,and one case of alcoholic pancreatitis).No N34S mutation was found in patients with autoimmune pancreatitis and healthy controls.Conclusion The occurrence of N34S mutation of SPINK1 was statistically higher in patient with idiopathic pancreatitis,while the frequence of the SPINK1 gene mutation was less significant in patients with biliary,alcoholic and autoimmune pancreatitis.This study provides evidence for the role of N34S mutation of SPINK1 in the pathogenesis of pancreatitis. Key words: Chronic pancreatitis; Serine protease inhibitor Kazal type 1 ; Gene mutation

Tu1817 Frequency of SPINK1 N34S Mutation in Acute and Recurrent Acute Pancreatitis

Tu1817 Frequency of SPINK1 N34S Mutation in Acute and Recurrent Acute Pancreatitis

Modified Puestow procedure for the management of chronic pancreatitis in children

PurposeTo present our experience with the modified Puestow procedure in the management of children with chronic pancreatitis. MethodsRetrospective chart review of patients treated between 2003 and 2012. ResultsSix patients underwent a modified Puestow procedure (lateral pancreaticojejunostomy) for the management of chronic pancreatitis, three females and three males. Four patients had hereditary pancreatitis (three with confirmed N34S mutation in the SPINK1 gene), one patient had chronic pancreatitis of unknown etiology, and one patient with annular pancreas developed obstructive chronic pancreatitis. The pancreatic duct was dilated in all cases, with a maximum diameter of 5 to 10mm. Median time between onset of pain and surgery was 4years (range: 1–9). Median age at surgery was 7.5years (range: 5–15). Median hospital stay was 12days (range: 9–28). Median follow up was 4.5years (range: 5months to 9years). All patients had temporary postoperative improvement of their abdominal pain. In two patients the pain recurred at 6months and 2years postoperatively and eventually required total pancreatectomy to treat intractable pain, 3 and 8years after surgery. Two patients were pain free for two years and subsequently developed occasional episodes of pain. The two most recent patients are pain free at 1year (obstructive chronic pancreatitis) and 5months (hereditary pancreatitis) follow-up. Two patients developed type I diabetes mellitus 10 and 12months postoperatively (one with hereditary and one with idiopathic chronic pancreatitis). ConclusionWe conclude that the modified Puestow procedure in children is feasible and safe. It seems to provide definitive pain control and prevent further damage to the pancreas in patients with obstructive chronic pancreatitis. However, in patients with hereditary pancreatitis, pain control outcomes are variable and the operation may not abrogate the progression of disease to pancreatic insufficiency.

Screening of R122H and N29I Mutations in the PRSS1 Gene and N34S Mutation in the SPINK1 Gene in Mexican Pediatric Patients With Acute and Recurrent Pancreatitis

The study's objective was to assess the association between the PRSS1 R122H and N29I and the SPINK1 N34S mutations and acute pancreatitis (AP) and recurrent pancreatitis in Mexican pediatric patients. The N34S and R122H mutations were detected using polymerase chain reaction-restriction fragment length polymorphism, and the N29I mutation was detected using allele-specific polymerase chain reaction in 92 pancreatitis patients (58 AP and 34 recurrent pancreatitis patients) and 144 controls. We found 1 mutated allele in 4 (4.3%) of 92 pancreatitis patients and none in the controls. All 4 patients bearing mutations had AP, with a frequency of 6.8% (4/58). Three (5.2%) of 58 patients were heterozygous for the N34S mutation, and 1 (1.7%) of 58 patients was heterozygous for the N29I mutation. The comparison between the AP and control groups revealed both a significant number of patients carrying any mutations in the screened genes (P = 0.008) and bearing the N34S mutation (P = 0.023). Moreover, we found that the N34S G allele increased the risk of developing AP (odds ratio, 10.3; confidence interval, 1.1-248.8). Patients bearing the N34S G allele exhibited a 10-fold increased risk of developing AP compared with controls, suggesting that the SPINK1 N34S mutation represents an etiologic risk factor for AP in our Mexican pediatric patients.

The N34S mutation of the SPINK1 gene and alcoholic chronic pancreatitis

Recent studies have shown the key role of genetic factors in the development of chronic pancreatitis. The aim of the study was to establish whether the frequency of the N34S mutation of serine protease inhibitor Kazal type 1 (SPINK1) gene differs between patients with alcoholic chronic pancreatitis, patients with nonalcoholic chronic pancreatitis, alcoholics without any digestive organ damage, and controls. We also sought to investigate whether the frequency of this mutation differs between women and men, and whether the mutation is associated with the age of patients at first diagnosis of chronic pancreatitis. The study included 207 patients: 67 with alcoholic chronic pancreatitis, 35 with nonalcoholic chronic pancreatitis, 43 alcoholics with no damage to digestive organs, and 62 healthy volunteers who served as controls. The N34S mutation of the SPINK1 gene was detected with the polymerase chain reaction. The N34S mutation of the SPINK1 gene occurred in 15 of 207 patients (7.25%). The mutation was most frequent in patients with alcoholic chronic pancreatitis (10 patients, 16.39%) and was more frequent compared with the control group (2 patients, 3.23%) (P = 0.047). There were no statistically significant differences between the other groups: patients with nonalcoholic chronic pancreatitis (2 patients, 5.71%), alcoholics without digestive organ damage (1 patient, 2.33%), and controls. The mutation was more frequent in men than in women (P = 0.043). There were no differences between patients with and without the mutation in terms of the age at first diagnosis of chronic pancreatitis (P >0.05). The N34S mutation of the SPINK1 gene seems to be significantly correlated with alcoholic chronic pancreatitis.

Is Post-ERCP Pancreatitis a Genetically Predisposed Complication?

Background/Objectives. Pancreatitis remains the most common complication of ERCP. History of post-ERCP pancreatitis is an independent risk factor for a new episode, suggesting a genetic background. The N34S mutation in serine protease inhibitor Kazal type 1 (SPINK 1) gene may downregulate the threshold for the development of pancreatitis. The aim of the present study is to evaluate the presence of this mutation among patients with post-ERCP pancreatitis. Methods. During a period of four years, thirty patients with post-ERCP pancreatitis entered the study. Patients and procedural data were collected, focusing on risk factors for pancreatitis. Blood samples were taken for genetic testing for the presence of N34S mutation in SPINK 1 gene. After DNA extraction, we used an allele-specific polymerase chain reaction as an initial screening method for the N34S mutation, and in order to confirm the results and to determine the hetero- and homozygosity genotype status, we used a restriction fragment length polymorphism (RFLP) method. Results. None of the thirty patients was found to carry the N34S mutation, with both of the applied methods. Patients had an average of two of the known risk factors. Conclusion. SPINK1 N34S mutation does not seem to play a role in post-ERCP pancreatitis, but larger studies needed to confirm our results.

Presence of SPINK‐1 variant alters the course of chronic pancreatitis

There is growing evidence that genetic mutations/variants increase susceptibility to the development and progression of chronic pancreatitis (CP). Several mutations have been identified that have a direct and indirect role in events leading to CP. Mutations in the serine protease inhibitor, Kazal type-1 (SPINK-1) gene have been reported to lower the threshold for pancreatitis in the presence of other genetic or environmental factors. The prevalence and impact of SPINK-1 mutations on the clinical course and outcomes of CP remains unclear. This study was conducted to assess the prevalence of the SPINK-1/N34S variant in patients with CP, and to understand the impact of the SPINK-1 mutation on the natural history of CP. A retrospective-prospective analysis of 239 patients with CP was performed. A detailed history, including duration of symptoms, type of pain (intermittent flares or chronic continuous pain), number of flares requiring hospital admission, alcohol and smoking history, and family history was obtained. The baseline morphological stage of CP was categorized by Cambridge classification. Clinical outcome variables included frequency and severity of pain episodes, presence of exocrine failure (defined by presence of steatorrhea and/or fecal elastase < 200 ug/g), and diabetes. The genetic tests included the cationic trypsinogen gene-1 mutation, cystic fibrosis gene mutations (Genzyme assay), and the SPINK-1/N34S mutation. Of the 239 patients with CP, 13 (5.4%) were positive for the SPINK-1/N34S mutation. There were 35 (14.6%) patients with idiopathic pancreatitis (IP) in this cohort. Most of the patients who were positive for the SPINK-1/N34S mutation had IP and were Caucasian (69.2%). The patients with the SPINK-1/N34S mutation had a younger age of onset (32.9 ± 10.2 vs 40.1 ± 13.6 years; P = 0.108) than those with IP and no mutation. Over a median follow up of 9.6 years, the patients with the SPINK-1/N34S mutation had a significantly greater number of acute flares each year, as compared to those without the mutation (11.8 ± 1.5 vs 4 ± 0.98; P = 0.0001). The prevalence of the SPINK-1/N34S mutation in patients with CP is 5.4%, and is approximately 37.1% in patients with IP. These mutations are more prevalent in Caucasian patients with CP. The SPINK-1/N34S mutation predisposes to early onset IP and more frequent acute flares of pancreatitis that might ultimately lead to pancreatic insufficiency. The patients with IP and borderline alcohol history should be considered for testing for genetic analysis, including SPINK-1 mutations, initially restricted to clinical trials.

The Prevalence of Cationic Trypsinogen (PRSS1) and Serine Protease Inhibitor, Kazal Type 1 (SPINK1) Gene Mutations in Polish Patients with Alcoholic and Idiopathic Chronic Pancreatitis

BackgroundThe main cause of chronic pancreatitis (CP) is excessive alcohol consumption. On the other hand, only 5–10% of heavy drinkers develop chronic pancreatitis. We have only limited information regarding the pathogenic mechanism by which alcohol leads to the disease. Mutations of the PRSS1 and SPINK 1 have been mostly implicated in hereditary and idiopathic CP, but their presence in other types of this disease have also been reported.AimsThe aim of the study was to determine the frequency of PRSS1 and SPINK1 mutations in patients with chronic alcoholic (ACP) and idiopathic pancreatitis (ICP) as well as to investigate their relation to the clinical course of the disease.MethodsThe study included 33 ACP and 14 ICP patients as well 46 healthy subjects. The diagnosis of CP was based on clinical data, ultrasound, and computed tomography. After isolation of DNA from peripheral blood two trypsinogen mutations were detected N29I and R122H by allelo-specific amplification polymerase chain reaction (ASA-PCR) and by the PCR-restriction fragment length polymorphism (RFLP). Beside this N34S mutation of SPINK1 was analyzed by PCR restriction fragment length polymorphism (PCR-RFLP).ResultsPRSS1 mutations have been detected in 11 (33%) patients with ACP. The frequency of the PRSS1 mutations was higher in patients with ACP than in controls (4.3%) (p < 0.001). The frequency of PRSS1 mutation was present in 21.4% of ICP patients, which was significantly higher (p < 0.05) than in controls. Overall, six (18%) SPINK1 mutations in ACP group have been detected. Among 14 patients with ICP, in four (28.6%) of them SPINK1 has been detected. The same mutations have also been found in three (6.5%) control subjects. The frequency of the N34S mutation was higher in patients with ICP than in the controls (p < 0.05), but the frequency of N34S mutation did not differ between ACP and the control group. No relations have been detected between PRSS1 and SPINK1 mutations presence and clinical course and complications of CP.ConclusionsThose preliminary data suggest the high prevalence of SPINK1 and PRSS1 mutations in the Polish population, generally, as well as in CP patients. It may be speculated that those mutations contribute to the development of chronic pancreatitis, especially in patients with alcohol overindulgence.

Idiopathic chronic pancreatitis in India: phenotypic characterisation and strong genetic susceptibility due to SPINK1 and CFTR gene mutations

ObjectiveTo study the genetic predisposition, phenotype and prognosis of idiopathic chronic pancreatitis (CP).DesignProspective observational and case–control study.SettingTertiary care academic centre.PatientsConsecutive patients with CP.InterventionsDetailed mutational analysis was done for the cationic...