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Ramsey ML, Heald B, Gokun Y, Baker J, Groce JR, Han S, Hart PA, Krishna SG, Lara LF, Lee PJ, Papachristou GI, Pearlman R, Poll S, Roberts ME, Stanich PP. Germline multigene panel testing in acute and chronic pancreatitis. PLoS One 2024; 19:e0307076. [PMID: 39172977 PMCID: PMC11341018 DOI: 10.1371/journal.pone.0307076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2024] [Accepted: 06/29/2024] [Indexed: 08/24/2024] Open
Abstract
BACKGROUND/OBJECTIVES Germline genetic testing is recommended for younger patients with idiopathic pancreatitis but there has been a lack of consensus in recommendations for those over age 35. We aimed to analyze the results of genetic testing among subjects of varying ages. METHODS Individuals who underwent germline multigene testing for pancreatitis susceptibility genes (CASR, CFTR, CPA1, CTRC, PRSS1, SPINK1) through a large commercial laboratory between 2017 and 2022 were included. Test results and information collected from test requisition forms were evaluated. Multivariable logistic regression models were performed to identify factors associated with a positive pancreatitis panel (pathogenic, likely pathogenic, and/or increased risk variants) in pancreatitis-related genes. RESULTS Overall, 2,468 subjects with primary indication of acute pancreatitis (AP) (n = 401), chronic pancreatitis (CP) (n = 631), pancreatic cancer (n = 128), or other indications (n = 1,308) completed germline testing. Among patients with AP or CP, the prevalence of any positive result for those <35 versus ≥35 years of age was 32.1% and 24.5% (p = 0.007), and the prevalence of a clinically meaningful result was 10.8% and 5.4%, respectively (p = 0.001). Positive family history of pancreatitis was associated with increased odds ratio (OR) of 8.59 (95% confidence interval (CI) 2.92-25.25) for a clinically significant panel result while each 5-year increase in age at test completion had lower odds (OR 0.89, 95% CI 0.83-0.95). CONCLUSIONS The highest prevalence of pathogenic variants is seen in younger individuals with a positive family history of pancreatitis. However, clinically meaningful results are identified in older subjects, suggesting that genetic counseling and testing should be considered for all age groups.
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Affiliation(s)
- Mitchell L. Ramsey
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America
| | - Brandie Heald
- Medical Affairs, Invitae Corporation, San Francisco, California, United States of America
| | - Yevgeniya Gokun
- Department of Biomedical Informatics, Center for Biostatistics, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America
| | - Josie Baker
- Division of Human Genetics, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America
| | - J. Royce Groce
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America
| | - Samuel Han
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America
| | - Phil A. Hart
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America
| | - Somashekar G. Krishna
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America
| | - Luis F. Lara
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America
| | - Peter J. Lee
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America
| | - Georgios I. Papachristou
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America
| | - Rachel Pearlman
- Division of Human Genetics, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America
| | - Sarah Poll
- Medical Affairs, Invitae Corporation, San Francisco, California, United States of America
| | - Maegan E. Roberts
- Division of Human Genetics, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America
| | - Peter P. Stanich
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America
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Girodon E, Rebours V, Chen JM, Pagin A, Levy P, Ferec C, Bienvenu T. WITHDRAWN: Clinical interpretation of PRSS1 gene variants in patients with pancreatitis. Clin Res Hepatol Gastroenterol 2022; 46:101531. [PMID: 36057185 DOI: 10.1016/j.clinre.2020.08.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Accepted: 08/27/2020] [Indexed: 02/04/2023]
Abstract
The Publisher regrets that this article is an accidental duplication of an article that has already been published in Clinics and Research in Hepatology and Gastroenterology, Volume 45, Issue 1, 2021, 101497. https://doi.org/10.1016/j.clinre.2020.07.004. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal
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Affiliation(s)
- Emmanuelle Girodon
- Laboratoire de G..n..tique et Biologie Mol..culaires, H..pital Cochin, APHP.Centre-Universit.. de Paris, France
| | - Vinciane Rebours
- Service de Pancr..atologie-Gastroent..rologie, P..le des Maladies de l'Appareil Digestif, Universit.. Denis Diderot, H..pital Beaujon, APHP, DHU UNITY, Clichy, and Centre de R..f..rence des Maladies Rares du Pancr..as...PAncreaticRaresDISeases (PaRaDis), France
| | - Jian Min Chen
- INSERM UMR1078 "G..n..tique, G..nomique Fonctionnelle et Biotechnologies", EFS - Bretagne, Universit.. de Brest, CHRU Brest, Brest, France
| | - Adrien Pagin
- CHU Lille, Service de Toxicologie et G..nopathies, Lille, France
| | - Philippe Levy
- Service de Pancr..atologie-Gastroent..rologie, P..le des Maladies de l'Appareil Digestif, Universit.. Denis Diderot, H..pital Beaujon, APHP, DHU UNITY, Clichy, and Centre de R..f..rence des Maladies Rares du Pancr..as...PAncreaticRaresDISeases (PaRaDis), France
| | - Claude Ferec
- INSERM UMR1078 "G..n..tique, G..nomique Fonctionnelle et Biotechnologies", EFS - Bretagne, Universit.. de Brest, CHRU Brest, Brest, France
| | - Thierry Bienvenu
- Laboratoire de G..n..tique et Biologie Mol..culaires, H..pital Cochin, APHP.Centre-Universit.. de Paris, France.
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Clinical interpretation of PRSS1 variants in patients with pancreatitis. Clin Res Hepatol Gastroenterol 2021; 45:101497. [PMID: 33257277 DOI: 10.1016/j.clinre.2020.07.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Accepted: 07/01/2020] [Indexed: 02/04/2023]
Abstract
Since the description of the PRSS1 gene encoding the cationic trypsinogen as being involved in dominant hereditary pancreatitis, more than 50 PRSS1 variants have been reported. Among the PRSS1 variants that have been classified as pathogenic, some have a high penetrance and others have a low penetrance. Assessing the clinical relevance of PRSS1 variants is often complicated in the absence of functional evidence and interpretation of rare variants is not very easy in clinical practice. The aim of this study was to review the different variants identified in the PRSS1 gene and to classify them according to their degree of deleterious effect. This classification was based on the results of several in vitro experiments and on population data, in comparing the allelic frequency of each variant in patients with pancreatitis and in unaffected individuals. This review should help geneticists and clinicians in charge of patient's care and genetic counseling to interpret molecular results.
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Girodon E, Rebours V, Chen JM, Pagin A, Levy P, Ferec C, Bienvenu T. Clinical interpretation of SPINK1 and CTRC variants in pancreatitis. Pancreatology 2020; 20:1354-1367. [PMID: 32948427 DOI: 10.1016/j.pan.2020.09.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 08/31/2020] [Accepted: 09/02/2020] [Indexed: 12/11/2022]
Abstract
Since the description of the SPINK1 gene encoding the serine protease inhibitor Kazal type 1 and the CTRC gene encoding the Chymotrypsin C as being involved in chronic pancreatitis, more than 56 SPINK1 and 87 CTRC variants have been reported. Assessing the clinical relevance of SPINK1 and CTRC variants is often complicated in the absence of functional evidence and interpretation of rare variants is not very easy in clinical practice. The aim of this study was to review the different variants identified in these two genes and to classify them according to their degree of damaging effect. This classification was based on the results of in vitro experiments, in silico analysis using different prediction tools, and on population data, in comparing the allelic frequency of each variant in patients with pancreatitis and in unaffected control individuals. This review should help geneticists and clinicians in charge of patient's care and genetic counseling to interpret the results of genetic studies.
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Affiliation(s)
- Emmanuelle Girodon
- Laboratoire de Génétique et Biologie Moléculaires, Hôpital Cochin, APHP. Centre-Université de Paris, France
| | - Vinciane Rebours
- Service de Pancréatologie-Gastroentérologie, Pôle des Maladies de l'Appareil Digestif, Université Denis Diderot, Hôpital Beaujon, APHP, DHU UNITY, Clichy, France; Centre de Référence des Maladies Rares du Pancréas, PAncreaticRaresDISeases (PaRaDis), France
| | - Jian Min Chen
- UMR1078 "Génétique, Génomique Fonctionnelle et Biotechnologies", INSERM, EFS - Bretagne, Université de Brest, CHRU Brest, Brest, France
| | - Adrien Pagin
- CHU Lille, Service de Toxicologie et Génopathies, Lille, France
| | - Philippe Levy
- Service de Pancréatologie-Gastroentérologie, Pôle des Maladies de l'Appareil Digestif, Université Denis Diderot, Hôpital Beaujon, APHP, DHU UNITY, Clichy, France
| | - Claude Ferec
- Centre de Référence des Maladies Rares du Pancréas, PAncreaticRaresDISeases (PaRaDis), France
| | - Thierry Bienvenu
- Laboratoire de Génétique et Biologie Moléculaires, Hôpital Cochin, APHP. Centre-Université de Paris, France.
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Abstract
OBJECTIVES This research was applied to case-control studies of the association between pancreatitis and SPINK1 gene to assess the joint evidence for the association, the influence of individual studies, and evidence for publication bias. METHODS MEDLINE and Embase were searched to identify longitudinal studies evaluating pancreatitis and SPINK1. Odds ratios (ORs) and 95% confidence interval (CI) were pooled using random-effect models and calculated using Carlin method. Publication bias was assessed using Egger et al's approach (A famous statistic method by Egger et al). Sensitivity, heterogeneity, and trim and fill analyses were conducted. RESULTS Based on the results, we found that (1) the results support for the association between pancreatitis and SPINK1, when analyzed totally and by subdivision (total [OR, 7.771; 95% CI, 5.232-11.543; P < 0.000]; European [OR,6.400; 95% CI, 4.346-9.426; P < 0.000]; Asian [OR, 11.823; 95% CI, 4.612-30.310; P < 0.000]; American [OR, 3.777; 95% CI, 1.596-8.939; P = 0.002]; mixed: [OR, 13.566; 95% CI, 2.322-79.252, P = 0.004]); (2) no evidence indicates that this association is accounted for by any one study, and no evidence indicates any publication bias exists. CONCLUSIONS The results indicated that SPINK1 gene, particularly the N34S mutation, has a genetic association with the development of pancreatitis.
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Di Leo M, Bianco M, Zuppardo RA, Guslandi M, Calabrese F, Mannucci A, Neri TM, Testoni PA, Leandro G, Cavestro GM. Meta-analysis of the impact of SPINK1 p.N34S gene variation in Caucasic patients with chronic pancreatitis. An update. Dig Liver Dis 2017; 49:847-853. [PMID: 28546062 DOI: 10.1016/j.dld.2017.04.023] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Revised: 04/24/2017] [Accepted: 04/26/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND SPINK1 p.N34S gene variation is one of the endogenous factors which seem to be associated with chronic pancreatitis (CP). However, in literature there is no clear agreement regarding its contribution in different ethnicity and CP etiologies. AIM To investigate the role of SPINK1 p.N34S gene variation in CP patients with European origin by means of meta-analysis. METHODS Literature search was conducted and case-control studies evaluating Caucasian population, published between May 2007 and May 2015, were included. We also included Caucasian selected studies analyzed in previous meta-analysis. We carried out meta-analysis including all selected studies. After that, we performed two additional meta-analyses considering the incidence of SPINK1 p.N34S gene variation in alcoholic or in idiopathic CP patients vs control group. RESULTS Twenty-five studies were included and the total number of subjects was 8800 (2981 cases and 5819 controls). The presence of p.N34S variation increased nine times the overall CP risk in population of European origin [OR 9.695 (CI 95% 7.931-11.851)]. Also, the contribution of SPINK1 in idiopathic pancreatitis [OR 13.640 (CI 95% 8.858-21.002)] was found to be higher than in alcoholic CP [5.283 (CI 95% 3.449-8.092)]. CONCLUSION The association between SPINK1 p.N34S gene variation and CP is confirmed. Also, we confirmed that the idiopathic etiology needs a better definition by means of genetic analysis.
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Affiliation(s)
- Milena Di Leo
- Gastroenterology and Gastrointestinal Endoscopy Unit, Division of Experimental Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy.
| | - Margherita Bianco
- Gastroenterology Unit 1, Gastroenterological Hospital 'S. De Bellis' IRCCS, Castellana Grotte, BA, Italy
| | - Raffaella Alessia Zuppardo
- Gastroenterology and Gastrointestinal Endoscopy Unit, Division of Experimental Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Mario Guslandi
- Gastroenterology and Gastrointestinal Endoscopy Unit, Division of Experimental Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Federica Calabrese
- Gastroenterology and Gastrointestinal Endoscopy Unit, Division of Experimental Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Alessandro Mannucci
- Gastroenterology and Gastrointestinal Endoscopy Unit, Division of Experimental Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Tauro Maria Neri
- Unit of Medical Genetics, Laboratory of Molecular Genetics, Diagnostic Department, University Hospital of Parma, Parma, Italy
| | - Pier Alberto Testoni
- Gastroenterology and Gastrointestinal Endoscopy Unit, Division of Experimental Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Gioacchino Leandro
- Gastroenterology Unit 1, Gastroenterological Hospital 'S. De Bellis' IRCCS, Castellana Grotte, BA, Italy; Institute for Digestive and Liver Health, University College, London, UK
| | - Giulia Martina Cavestro
- Gastroenterology and Gastrointestinal Endoscopy Unit, Division of Experimental Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy
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7
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Abstract
Genetic investigations have provided unique insight into the mechanism of chronic pancreatitis in humans and firmly established that uncontrolled trypsin activity is a central pathogenic factor. Mutations in the PRSS1, SPINK1, and CTRC genes promote increased activation of trypsinogen to trypsin by stimulation of autoactivation or by impairing protective trypsinogen degradation and/or trypsin inhibition. Here we review key genetic and biochemical features of the trypsin-dependent pathological pathway in chronic pancreatitis.
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Affiliation(s)
- Eszter Hegyi
- Center for Exocrine Disorders, Department of Molecular and Cell Biology, Boston University Henry M. Goldman School of Dental Medicine, 72 East Concord Street, Evans-433, Boston, MA, 02118, USA
| | - Miklós Sahin-Tóth
- Center for Exocrine Disorders, Department of Molecular and Cell Biology, Boston University Henry M. Goldman School of Dental Medicine, 72 East Concord Street, Evans-433, Boston, MA, 02118, USA.
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Singh D, Negi TS, Upadhyay G, Choudhuri G. Polymorphism of Alcohol Metabolizing Gene ADH3 Predisposes to Development of Alcoholic Pancreatitis in North Indian Population. Front Mol Biosci 2015; 2:67. [PMID: 26734614 PMCID: PMC4680944 DOI: 10.3389/fmolb.2015.00067] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Accepted: 11/13/2015] [Indexed: 12/16/2022] Open
Abstract
Background and aim: Genetic factors regulating alcohol metabolism could predispose in developing alcoholic pancreatitis (ACP). Studies revealed that alcohol could be metabolized by both ways, oxidative and non-oxidative. The main oxidative pathway includes alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH), and cytochrome P450 enzyme. We investigated the association of polymorphisms in these enzymes with the alcoholic pancreatitis in the north Indian population. Method: Patients with alcoholic pancreatitis (ACP; n = 72), tropical calcific pancreatitis (TCP; n = 75), alcoholic controls (AC; n = 40), and healthy controls (HC; n = 100) were included in the study. Blood samples were collected from the subjects in EDTA coated vials. DNA was extracted and genotyping for ADH3, ALDH2, and CYP2E1 was done by PCR-RFLP (polymerase chain reaction—restriction fragment length polymorphism). The products were analyzed by gel electrophoresis. Result: The frequency distribution of ADH3*1/*1 genotype was significantly higher in ACP group (59.7%) compared with TCP (38.7%), HC (42%), and AC (37.5%) and was found to be associated with increased risk of alcoholic pancreatitis. There was no statistically significant difference between the frequency distribution of ADH3*1/*1, ADH3*1/*2, and ADH3*2/*2 genotypes between TCP and HC or healthy alcoholics. ALDH2 gene was monomorphic in our population, and the frequencies for CYP2E1 intron 6 Dra I polymorphism were comparable in all the four groups. Conclusion: This study shows that carriers of ADH3*1/*1 individuals consuming alcohol are at higher risk for alcoholic pancreatitis than those with other genotypes such as ADH3*1/*2 and ADH3*2/*2.
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Affiliation(s)
- Divya Singh
- Department of Biology, City College of New YorkNew York, NY, USA; Department of Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical SciencesLucknow, India
| | - Tajwar S Negi
- Department of Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences Lucknow, India
| | | | - Gourdas Choudhuri
- Department of Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical SciencesLucknow, India; Department of Gastroenterology and Hepatobiliary Sciences, Fortis Memorial Research InstituteGurgaon, India
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Kondo S, Fujiki K, Ko SBH, Yamamoto A, Nakakuki M, Ito Y, Shcheynikov N, Kitagawa M, Naruse S, Ishiguro H. Functional characteristics of L1156F-CFTR associated with alcoholic chronic pancreatitis in Japanese. Am J Physiol Gastrointest Liver Physiol 2015; 309:G260-9. [PMID: 26089335 PMCID: PMC4537928 DOI: 10.1152/ajpgi.00015.2014] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2014] [Accepted: 06/09/2015] [Indexed: 01/31/2023]
Abstract
Although cystic fibrosis is rare in Japanese, measurement of sweat Cl(-) has suggested mild dysfunction of cystic fibrosis transmembrane conductance regulator (CFTR) in some patients with chronic pancreatitis. In the present study, we have investigated the association of CFTR variants and chronic pancreatitis in Japanese and the functional characteristics of a Japanese- and pancreatitis-specific CFTR variant, L1156F. Seventy patients with alcoholic chronic pancreatitis, 18 patients with idiopathic chronic pancreatitis, and 180 normal subjects participated. All exons and their boundaries and promoter region of the CFTR gene were sequenced. Human embryonic kidney-293 cells were transfected with three CFTR variants (M470V, L1156F, and M470V+L1156F), and the protein expression was examined. Xenopus laevis oocytes were injected with the CFTR variants, and bicarbonate (HCO3 (-)) transport activity was examined. CFPAC-1 cells were transfected with the CFTR variants and Cl(-)/HCO3 (-) exchange activity was examined. Six variants (E217G, I556V, M470V, L1156F, Q1352H, and R1453W) were identified in the coding region of the CFTR gene. Cystic fibrosis-causing mutations were not found. The allele frequencies of L1156F and Q1352H in alcoholic chronic pancreatitis (5.0 and 7.9%) were significantly (P < 0.01) higher than those in normal subjects (0.6 and 1.9%). L1156F was linked with a worldwide CFTR variant, M470V. Combination of M470V and L1156F significantly reduced CFTR expression to ∼60%, impaired CFTR-mediated HCO3 (-)/Cl(-) transport activity to 50-60%, and impaired CFTR-coupled Cl(-)/HCO3 (-) exchange activity to 20-30%. The data suggest that the Japanese-specific CFTR variant L1156F causes mild dysfunction of CFTR and increases the risk of alcoholic chronic pancreatitis in Japanese.
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Affiliation(s)
- Shiho Kondo
- Department of Human Nutrition, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kotoyo Fujiki
- Department of Nutrition, Nagoya University of Arts and Sciences, Nisshin, Japan
| | - Shigeru B H Ko
- Department of Systems Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Akiko Yamamoto
- Department of Human Nutrition, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Miyuki Nakakuki
- Department of Human Nutrition, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yasutomo Ito
- Division for Medical Research Engineering, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Nikolay Shcheynikov
- Epithelial Signaling and Transport Section, National Institute of Dental and Craniofacial Research, Bethesda, Maryland; and
| | - Motoji Kitagawa
- Department of Nutrition, Nagoya University of Arts and Sciences, Nisshin, Japan
| | | | - Hiroshi Ishiguro
- Department of Human Nutrition, Nagoya University Graduate School of Medicine, Nagoya, Japan;
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Genetic susceptibility factors for alcohol-induced chronic pancreatitis. Pancreatology 2015; 15:S23-31. [PMID: 26149858 DOI: 10.1016/j.pan.2015.05.476] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2014] [Revised: 04/10/2015] [Accepted: 05/27/2015] [Indexed: 12/11/2022]
Abstract
Chronic pancreatitis is a progressive inflammatory disease of the pancreas and frequently associated with immoderate alcohol consumption. Since only a small proportion of alcoholics eventually develop chronic pancreatitis genetic susceptibility factors have long been suspected to contribute to the pathogenesis of the disease. Smaller studies in ethnically defined populations have found that not only polymorphism in proteins involved in the metabolism of ethanol, such as Alcohol Dehydrogenase and Aldehyde Dehydrogenase, can confer a risk for developing chronic pancreatitis but also mutations that had previously been reported in association with idiopathic pancreatitis, such as SPINK1 mutations. In a much broader approach employing genome wide search strategies the NAPS study found that polymorphisms in the Trypsin locus (PRSS1 rs10273639), and the Claudin 2 locus (CLDN2-RIPPLY1-MORC4 locus rs7057398 and rs12688220) confer an increased risk of developing alcohol-induced pancreatitis. These results from North America have now been confirmed by a European consortium. In another genome wide approach polymorphisms in the genes encoding Fucosyltransferase 2 (FUT2) non-secretor status and blood group B were not only found in association with higher serum lipase levels in healthy volunteers but also to more than double the risk for developing alcohol-associated chronic pancreatitis. These novel genetic associations will allow to investigate the pathophysiological and biochemical basis of alcohol-induced chronic pancreatitis on a cellular level and in much more detail than previously possible.
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Madro A, Ciesielka M, Celinski K, Slomka M, Czechowska G, Kurzepa J, Kaszelan-Szczerbinska B, Buszewicz G, Madro R. The genetic predisposition and its impact on the diabetes mellitus development in patients with alcoholic chronic pancreatitis. Gastroenterol Res Pract 2015; 2015:309156. [PMID: 25838820 PMCID: PMC4369946 DOI: 10.1155/2015/309156] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2015] [Accepted: 03/04/2015] [Indexed: 12/24/2022] Open
Abstract
The most common cause of chronic pancreatitis (CP) is alcohol abuse. The aim of the present study was to identify patients with genetic predisposition to CP abusing alcohol. The question posed was whether CP manifests at a younger age and diabetes mellitus develops earlier in individuals with genetic predisposition. The study encompassed 79 patients with alcoholic chronic pancreatitis (ACP) and control group (100 persons). The following mutations were determined: R122H and N29I of PRSS1 and N34S of SPINK1 as well as E366K and E288V of SERPINA 1. No R122H and N291 mutations were observed in the group of ACP patients and in controls. Moreover, there was no E288V mutation. In 79 ACP patients, six SPINK 1 (N34S/wt) mutations were observed. In the control group, one heterozygous SPINK 1N34S gene mutation was found (P = 0.0238). Two PiZ mutations were identified in patients with ACP and one analogical mutation in controls. Amongst patients with ACP as well as SPINK1 and PiZ mutations, the onset of disease was observed earlier and developed earlier. The prevalence of SPINK1 mutation is higher in patients with ACP than in healthy populations. This mutation together with the effects of alcohol accelerates the development of ACP and of diabetes mellitus.
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Affiliation(s)
- Agnieszka Madro
- Department of Gastroenterology with Endoscopic Units, Medical University, Jaczewski Street 8, 20-954 Lublin, Poland
| | - Marzanna Ciesielka
- Department of Forensic Medicine, Medical University, Ceramiczna Street 1, 20-150 Lublin, Poland
| | - Krzysztof Celinski
- Department of Gastroenterology with Endoscopic Units, Medical University, Jaczewski Street 8, 20-954 Lublin, Poland
| | - Maria Slomka
- Department of Gastroenterology with Endoscopic Units, Medical University, Jaczewski Street 8, 20-954 Lublin, Poland
| | - Grazyna Czechowska
- Department of Gastroenterology with Endoscopic Units, Medical University, Jaczewski Street 8, 20-954 Lublin, Poland
| | - Jacek Kurzepa
- Department of Medical Chemistry, Medical University, Chodźki Street 4a, 20-093 Lublin, Poland
| | - Beata Kaszelan-Szczerbinska
- Department of Gastroenterology with Endoscopic Units, Medical University, Jaczewski Street 8, 20-954 Lublin, Poland
| | - Grzegorz Buszewicz
- Department of Forensic Medicine, Medical University, Ceramiczna Street 1, 20-150 Lublin, Poland
| | - Roman Madro
- Department of Forensic Medicine, Medical University, Ceramiczna Street 1, 20-150 Lublin, Poland
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12
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Itkonen O, Stenman UH. TATI as a biomarker. Clin Chim Acta 2014; 431:260-9. [DOI: 10.1016/j.cca.2014.02.014] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2013] [Revised: 02/14/2014] [Accepted: 02/18/2014] [Indexed: 12/22/2022]
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Brock C, Nielsen LM, Lelic D, Drewes AM. Pathophysiology of chronic pancreatitis. World J Gastroenterol 2013; 19:7231-7240. [PMID: 24259953 PMCID: PMC3831204 DOI: 10.3748/wjg.v19.i42.7231] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2013] [Revised: 07/09/2013] [Accepted: 08/29/2013] [Indexed: 02/06/2023] Open
Abstract
Chronic pancreatitis (CP) is an inflammatory disease of the pancreas characterized by progressive fibrotic destruction of the pancreatic secretory parenchyma. Despite the heterogeneity in pathogenesis and involved risk factors, processes such as necrosis/apoptosis, inflammation or duct obstruction are involved. This fibrosing process ultimately leads to progressive loss of the lobular morphology and structure of the pancreas, deformation of the large ducts and severe changes in the arrangement and composition of the islets. These conditions lead to irreversible morphological and structural changes resulting in impairment of both exocrine and endocrine functions. The prevalence of the disease is largely dependent on culture and geography. The etiological risk-factors associated with CP are multiple and involve both genetic and environmental factors. Throughout this review the M-ANNHEIM classification system will be used, comprising a detailed description of risk factors such as: alcohol-consumption, nicotine-consumption, nutritional factors, hereditary factors, efferent duct factors, immunological factors and miscellaneous and rare metabolic factors. Increased knowledge of the different etiological factors may encourage the use of further advanced diagnostic tools, which potentially will help clinicians to diagnose CP at an earlier stage. However, in view of the multi factorial disease and the complex clinical picture, it is not surprising that treatment of patients with CP is challenging and often unsuccessful.
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Graziani R, Frulloni L, Cicero C, Manfredi R, Ambrosetti MC, Mautone S, Pozzi Mucelli R. Bull's-eye pattern of pancreatic-duct stones on multidetector computed tomography and gene-mutation-associated pancreatitis (GMAP). Radiol Med 2012; 117:1275-86. [PMID: 23090249 DOI: 10.1007/s11547-012-0888-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2011] [Accepted: 01/13/2012] [Indexed: 01/28/2023]
Abstract
PURPOSE This study prospectively assessed whether the presence of a bull's-eye pattern of pancreatic-duct stones on multidetector computed tomography (MDCT) correlated with gene-mutation-associated pancreatitis (GMAP) and whether other signs suggestive of GMAP can be detected with MDCT. MATERIALS AND METHODS Forty-seven patients with chronic calcific pancreatitis underwent genetic testing for CFTR, SPINK1 and PRSS1 mutations and an MDCT scan of the abdomen. Qualitative analysis assessed the presence or absence of pancreatic-duct stones with bull's-eye appearance. Quantitative analysis included the number and maximum diameter of stones and the diameter of the main pancreatic duct. RESULTS Fifteen of 47 patients (32%) were positive for gene mutations (GMAP patients). The bull's-eye pattern was found in 10/15 patients (67%) with GMAP and in 4/32 (12%) patients with chronic pancreatitis not associated with GMAP (NGMAP; p<0.0001). The mean diameter of duct stones was 15 mm in patients with GMAP and 10 mm in patients with NGMAP (p<0.04). CONCLUSIONS The presence of duct stones with a bull's-eye pattern correlates with GMAP. Duct stones with diameter ≥15 mm are another sign suggestive of GMAP.
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Affiliation(s)
- R Graziani
- Istituto di Radiologia, Università di Verona, P.le L.A. Scuro 10, 37134, Verona, Italy.
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Is Post-ERCP Pancreatitis a Genetically Predisposed Complication? Gastroenterol Res Pract 2012; 2012:473960. [PMID: 22934106 PMCID: PMC3426223 DOI: 10.1155/2012/473960] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2012] [Revised: 06/19/2012] [Accepted: 07/09/2012] [Indexed: 01/29/2023] Open
Abstract
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.
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Abstract
Several diseases have been clinically or genetically related to cystic fibrosis (CF), but a consensus definition is lacking. Here, we present a proposal for consensus guidelines on cystic fibrosis transmembrane conductance regulator (CFTR)-related disorders (CFTR-RDs), reached after expert discussion and two dedicated workshops. A CFTR-RD may be defined as "a clinical entity associated with CFTR dysfunction that does not fulfil diagnostic criteria for CF". The utility of sweat testing, mutation analysis, nasal potential difference, and/or intestinal current measurement for the differential diagnosis of CF and CFTR-RD is discussed. Algorithms which use genetic and functional diagnostic tests to distinguish CF and CFTR-RDs are presented. According to present knowledge, congenital bilateral absence of vas deferens (CBAVD), acute recurrent or chronic pancreatitis and disseminated bronchiectasis, all with CFTR dysfunction, are CFTR-RDs.
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da Costa MZG, Guarita DR, Ono-Nita SK, Paranaguá-Vezozzo DC, Felga GEG, Pedroso MRA, de Souza MMT, Nasser PD, Ferreira CDS, Carrilho FJ. Genetic risk for alcoholic chronic pancreatitis. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2011; 8:2747-57. [PMID: 21845156 PMCID: PMC3155327 DOI: 10.3390/ijerph8072747] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/07/2011] [Accepted: 06/20/2011] [Indexed: 12/14/2022]
Abstract
In recent years many studies have examined the genetic predisposition to pancreatic diseases. Pancreatic disease of an alcoholic etiology was determined to be a multi-factorial disease, where environmental factors interact with the genetic profile of the individual. In this review we discuss the main results from studies examining the frequency of genetic mutations in alcoholic chronic pancreatitis.
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Gasiorowska A, Talar-Wojnarowska R, Czupryniak L, Smolarz B, Romanowicz-Makowska H, Kulig A, Malecka-Panas E. 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. Dig Dis Sci 2011; 56:894-901. [PMID: 20676769 PMCID: PMC3041903 DOI: 10.1007/s10620-010-1349-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2010] [Accepted: 07/12/2010] [Indexed: 12/12/2022]
Abstract
BACKGROUND The 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. AIMS The 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. METHODS The 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). RESULTS PRSS1 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. CONCLUSIONS Those 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.
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Affiliation(s)
- Anita Gasiorowska
- Department of Digestive Tract Diseases, Medical University of Lodz, Kopcinskiego 22, 90-153 Lodz, Poland
| | - Renata Talar-Wojnarowska
- Department of Digestive Tract Diseases, Medical University of Lodz, Kopcinskiego 22, 90-153 Lodz, Poland
| | - Leszek Czupryniak
- Diabetology and Metabolic Diseases, Medical University of Lodz, Kopcinskiego 22, 90-153 Lodz, Poland
| | - Beata Smolarz
- Laboratory of Molecular Genetics, Institute of Polish Mother’s Memorial Hospital, Rzgowska 281/289, 93-338 Lodz, Poland
| | - Hanna Romanowicz-Makowska
- Laboratory of Molecular Genetics, Institute of Polish Mother’s Memorial Hospital, Rzgowska 281/289, 93-338 Lodz, Poland
| | - Andrzej Kulig
- Laboratory of Molecular Genetics, Institute of Polish Mother’s Memorial Hospital, Rzgowska 281/289, 93-338 Lodz, Poland
| | - Ewa Malecka-Panas
- Department of Digestive Tract Diseases, Medical University of Lodz, Kopcinskiego 22, 90-153 Lodz, Poland
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Wang GP, Xu CS. Pancreatic secretory trypsin inhibitor: More than a trypsin inhibitor. World J Gastrointest Pathophysiol 2010; 1:85-90. [PMID: 21607145 PMCID: PMC3097947 DOI: 10.4291/wjgp.v1.i2.85] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2010] [Revised: 04/15/2010] [Accepted: 04/22/2010] [Indexed: 02/06/2023] Open
Abstract
Kazal-type serine protease inhibitor is one of the most important and widely distributed protease inhibitor families. Pancreatic secretory trypsin inhibitor (PSTI), also known as serine protease inhibitor Kazal type I(SPINK1), binds rapidly to trypsin, inhibits its activity and is likely to protect the pancreas from prematurely activated trypsinogen. Therefore, it is an important factor in the onset of pancreatitis. Recent studies found that PSTI/SPINK1 is also involved in self-regulation of acinar cell phagocytosis, proliferation and growth of a variety of cell lines. In addition, it takes part in the response to inflammatory factor or injury and is highly related to adult type II citrullinemia.
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Genetic factors in chronic pancreatitis; implications for diagnosis, management and prognosis. Best Pract Res Clin Gastroenterol 2010; 24:251-70. [PMID: 20510827 DOI: 10.1016/j.bpg.2010.02.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2010] [Accepted: 02/05/2010] [Indexed: 01/31/2023]
Abstract
Chronic pancreatitis (CP) is a clinical situation with persisting inflammation leading to destruction of the pancreas ensuing endocrine and exocrine failure. There are 4 subtypes: hereditary, idiopathic, alcoholic and tropical pancreatitis. Genetic factors can explain a significant proportion of CP cases. The PRSS1 gene, encoding cationic trypsinogen, was found to be correlated with hereditary CP. This signalled the extensive search for other candidate genes within the trypsin pathway. Genes like SPINK1 and CTRC are associated with CP and should be considered as important contributing factors rather than causative. The search for candidate genes not part of the trypsin pathway has been less successful and the only gene consistently associated with CP is the Cystic Fibrosis Transmembrane Regulator. In this review we will discuss the various CP subtypes in relation to the respective genetic variants. This review will also address the implications of genetic testing in daily clinical practise.
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Cavestro GM, Zuppardo RA, Bertolini S, Sereni G, Frulloni L, Okolicsanyi S, Calzolari C, Singh SK, Sianesi M, Del Rio P, Leandro G, Franzè A, Di Mario F. Connections between genetics and clinical data: Role of MCP-1, CFTR, and SPINK-1 in the setting of acute, acute recurrent, and chronic pancreatitis. Am J Gastroenterol 2010; 105:199-206. [PMID: 19844201 DOI: 10.1038/ajg.2009.611] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVES 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.
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Mora J, Comas L, Ripoll E, Gonçalves P, Queraltó JM, González-Sastre F, Farré A. Genetic mutations in a Spanish population with chronic pancreatitis. Pancreatology 2009; 9:644-51. [PMID: 19657220 DOI: 10.1159/000181177] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2008] [Accepted: 10/29/2008] [Indexed: 12/11/2022]
Abstract
BACKGROUND/AIMS Mutations in the PRSS1 and the SPINK1 genes have variably been associated with alcohol-related, idiopathic and hereditary chronic pancreatitis (CP). The aim of this study was to determine for the first time the significance of PRSS1, SPINK1 mutations and genetic variants of AAT in a group of Spanish patients with CP. METHODS 104 consecutive patients with CP were included, as well as 84 healthy control subjects. The R122H and N29I mutations in the PRSS1 gene, the N34S mutation in the SPINK1 gene and PiS and PiZ mutations in the AAT gene were analyzed by RFLP-PCR methods. RESULTS No R122H mutation was found in the PRSS1 gene, and N29I mutation was detected in 7.7% of CP patients. A N29I mutation was observed in 3.9% of patients with alcohol-related pancreatitis (ACP). A total of 5.8% of CP patients were identified with the N34S mutation. Genotype MS, SS and MZ were detected in 18.3, 3.8 and 1.3% of CP patients, respectively. CONCLUSION The percentage of N29I mutations in ACP patients was higher than that reported in other studies, while the percentage of N34S and AAT mutations in ACP and idiopathic CP patients was similar.
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Affiliation(s)
- Josefina Mora
- Department of Clinical Chemistry, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
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Abstract
Chronic pancreatitis (CP) is a persistent inflammation of the pancreas. Over the past 12 years, genetic studies of hereditary, familial, and idiopathic forms of CP have made great progress in defining the disease pathogenesis. Identification of gain-of-function missense and copy number mutations in the cationic trypsinogen gene (PRSS1) and loss-of-function variants in both the pancreatic secretory trypsin inhibitor (SPINK1) and chymotrypsinogen C (CTRC) genes has firmly established the pivotal role of prematurely activated trypsin within the pancreas in the etiology of CP. Loss-of-function variants in the cystic fibrosis transmembrane conductance regulator (CFTR) and calcium-sensing receptor (CASR) genes also increase the risk of CP. Here, we review recent developments in this rapidly evolving field, highlight the importance of gene-gene and gene-environment interactions in causing the disease, and discuss the opportunities and challenges in identifying novel genetic factors that affect susceptibility/resistance to CP.
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Affiliation(s)
- Jian-Min Chen
- Institut National de la Santé et de la Recherche Médicale (INSERM), U613, Brest, France.
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da Costa MZG, Guarita DR, Ono-Nita SK, Nogueira JDA, Nita ME, Paranaguá-Vezozzo DC, de Souza MT, do Carmo EP, Teixeira ACDS, Carrilho FJ. CFTR polymorphisms in patients with alcoholic chronic pancreatitis. Pancreatology 2008; 9:173-81. [PMID: 19077469 DOI: 10.1159/000178889] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2007] [Accepted: 07/01/2008] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Pancreas susceptibility to alcohol is variable and only 5-10% of chronic alcohol abusers develop chronic pancreatitis; the role of genetic factors in this process is unknown. The CFTR gene encodes a protein that acts on epithelial cells and plays a key role in normal exocrine pancreatic function. METHODS This study investigated the frequency of polymorphisms in intron 8 of the CFTR gene in patients with alcoholic chronic pancreatitis. Three groups of patients were studied: group A - 68 adult alcoholics with a diagnosis of chronic pancreatitis; group B - 68 adult alcoholics without pancreatic disease or liver cirrhosis and group C - 104 healthy nonalcoholic adults. RESULTS T5/T7 genotype was more frequent in group A (11.8%) than in group B (2.9%) (p = 0.0481), and there was no statistical difference when groups A and C (5.8%) were compared (p = 0.1317). The haplotype combination (TG)10-T7/(TG)11-T7 was more frequent in groups B (23.5%) and C (20.2%) than in group A (7.3%) (p = 0.0080 and 0.0162). CONCLUSION There are differences when these three groups are compared and individuals with T5/T7 genotype might have a greater risk of developing chronic pancreatitis when they become chronic alcoholics.
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Clinical and radiological outcome of patients suffering from chronic pancreatitis associated with gene mutations. Pancreas 2008; 37:371-6. [PMID: 18953248 DOI: 10.1097/mpa.0b013e31817f52a1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES Cystic fibrosis transmembrane conductance regulator (CFTR), cationic trypsinogen gene (PRSS1), and serine protease inhibitor kazal type 1 (SPINK1) gene mutations have been associated with chronic pancreatitis (CP). The aim of this study was to compare clinical and radiological findings in sporadic CP with (CPgm) and without (CPwt) gene mutations. METHODS Data from patients observed between 2001 and 2006 were collected. All patients were tested for 25 CFTR gene mutations, for R122H and N29I on the PRSS1 gene, and for N34S mutation on the SPINK1 gene. RESULTS We found 34 (17.2%) of 198 patients with CPgm, 23 (11.6%) of them on the CFTR gene, 11 (5.6%) on the SPINK1, and none on the PRSS1 gene. The age at clinical onset was younger in CPgm (36.2 +/- 17.2 years) than in CPwt (44 +/- 12.6 years; P = 0.005). There were more heavy drinkers among CPwt (33%) than among CPgm (9%; P = 0.003), and the same applied to smokers (69% vs 33%, respectively; P < 0.0001). In CPgm group, the onset of pancreatic calcifications was observed more frequently in drinkers and/or smokers. Exocrine and endocrine insufficiency occurred less frequently and later in CPgm than in CPwt patients. CONCLUSIONS Clinical and radiological outcome differ in CPgm compared with CPwt. Alcohol, even in small quantities, and cigarette smoking influence the onset of pancreatic calcifications.
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Abstract
Pancreatitis (necroinflammation of the pancreas) has both acute and chronic manifestations. Gallstones are the major cause of acute pancreatitis, whereas alcohol is associated with acute as well as chronic forms of the disease. Cases of true idiopathic pancreatitis are steadily diminishing as more genetic causes of the disease are discovered. The pathogenesis of acute pancreatitis has been extensively investigated over the past four decades; the general current consensus is that the injury is initiated within pancreatic acinar cells subsequent to premature intracellular activation of digestive enzymes. Repeated attacks of acute pancreatitis have the potential to evolve into chronic disease characterized by fibrosis and loss of pancreatic function. Our knowledge of the process of scarring has advanced considerably with the isolation and study of pancreatic stellate cells, now established as the key cells in pancreatic fibrogenesis. The present review summarizes recent developments in the field particularly with respect to the progress made in unraveling the molecular mechanisms of acute and chronic pancreatic injury secondary to gallstones, alcohol and genetic factors. It is anticipated that continued research in the area will lead to the identification and characterization of molecular pathways that may be therapeutically targeted to prevent/inhibit the initiation and progression of the disease.
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Affiliation(s)
- Alain Vonlaufen
- Pancreatic Research Group, South Western Sydney Clinical School, Liverpool Hospital and The University of New South Wales, Sydney, Australia
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Abstract
UNLABELLED The aim of this study was to determine whether mutations in SPINK1/PRSS1 genes are associated with benign pancreatic hyperenzymemia (BPH). METHODS Sixty-eight subjects with BPH (including 13 familial cases) were studied. In all, we sequenced germline DNA for all the exons and intro-exon boundaries of PRSS1 and SPINK1. RESULTS Nine (13.2%) of the 68 subjects harbored PRSS1 or SPINK1 mutations. As to PRSS1, no hereditary pancreatitis-associated variant was detected, whereas previously undescribed mutations (p.Ala148Val and c.40+1G>A) were respectively found in 2 subjects (2.9%). SPINK1 mutations were detected in 7 subjects (10.3%). Five of them exhibited known mutations (3 p.Asn34Ser, 1 p.Pro55Ser, and 1 c.88-23A>T), whereas 2 had a newly found variant (p.Arg67Gly and c.*32C>T, respectively). Only 2 familial BPH, belonging to 2 different families, were found to carry a mutation (1 with p.Ala148Val for PRSS1 and 1 with p.Asn34Ser for SPINK1). CONCLUSIONS No known mutations of PRSS1 have been found in BPH, whereas the frequency of known SPINK1 variants is similar to that reported in the general population. No segregation of PRSS1/SPINK1 variants occurs in BPH families. Benign pancreatic hyperenzymemia cannot be explained by mutations in genes whose variants are known to be associated with pancreatitis or by mutations in other PRSS1/SPINK1 genes.
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Aoun E, Chang CCH, Greer JB, Papachristou GI, Barmada MM, Whitcomb DC. Pathways to injury in chronic pancreatitis: decoding the role of the high-risk SPINK1 N34S haplotype using meta-analysis. PLoS One 2008; 3:e2003. [PMID: 18414673 PMCID: PMC2289874 DOI: 10.1371/journal.pone.0002003] [Citation(s) in RCA: 106] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2008] [Accepted: 03/04/2008] [Indexed: 01/18/2023] Open
Abstract
Background The complex interactions between recurrent trypsin-mediated pancreatic injury, alcohol-associated pancreatic injury and SPINK1 polymorphisms in chronic pancreatitis (CP) are undefined. We hypothesize that CP occurs as a result of multiple pathological mechanisms (pathways) that are initiated by different metabolic or environmental factors (etiologies) and may be influenced differentially by downstream genetic risk factors. We tested this hypothesis by evaluating the differences in effect size of the high risk SPINK1 N34S haplotype on CP from multiple etiologies after combining clinical reports of SPINK1 N34S frequency using meta-analysis. Methods and Findings The Pubmed and the Embase databases were reviewed. We studied 24 reports of SPINK1 N34S in CP (2,421 cases, 4,857 controls) using reported etiological factors as surrogates for pathways and multiple meta-analyses to determine the differential effects of SPINK1 N34S between alcoholic and non-alcoholic etiologies. Using estimates of between-study heterogeneity, we sub-classified our 24 studies into four specific clusters. We found that SPINK1 N34S is strongly associated with CP overall (OR 11.00; 95% CI: 7.59–15.93), but the effect of SPINK1 N34S in alcoholic CP (OR 4.98, 95% CI: 3.16–7.85) was significantly smaller than in idiopathic CP (OR 14.97, 95% C.I. = 9.09–24.67) or tropical CP (OR 19.15, 95% C.I. = 8.83–41.56). Studies analyzing familial CP showed very high heterogeneity suggestive of a complex etiology with an I2 = 80.95%. Conclusion The small effect of SPINK1 N34S in alcoholic subjects suggests that CP is driven through a different pathway that is largely trypsin-independent. The results also suggest that large effect sizes of SPINK1 N34S in small candidate gene studies in CP may be related to a mixture of multiple etiologic pathways leading to the same clinical endpoint.
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Affiliation(s)
- Elie Aoun
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Chung-Chou H. Chang
- Department of General Internal Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
- Department of Biostatistics, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Julia B. Greer
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Georgios I. Papachristou
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - M. Michael Barmada
- Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - David C. Whitcomb
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
- Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
- * To whom correspondence should be addressed. E-mail:
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Abstract
The observation that only a minority of heavy drinkers develop pancreatitis has prompted an intensive search for a trigger factor/cofactor/susceptibility factor that may precipitate a clinical attack. Putative susceptibility factors examined so far include diet, smoking, amount and type of alcohol consumed, the pattern of drinking and lipid intolerance. In addition, a range of inherited factors have been assessed including blood group antigens, human leukocyte antigen serotypes, alpha-1-antitrypsin phenotypes and several genotypes. The latter group comprises mutations/polymorphisms in genes related to alcohol-metabolizing enzymes, detoxifying enzymes, pancreatic digestive enzymes, pancreatic enzyme inhibitors, cystic fibrosis and cytokines. Disappointingly, despite this concerted research effort, no clear association has been established between the above factors and alcoholic pancreatitis. Experimentally, the secretagogue cholecystokinin (CCK) has been investigated as a candidate 'trigger' for alcoholic pancreatitis. However, the clinical relevance of CCK as a trigger factor has to be questioned, as it is difficult to envisage a situation in humans where abnormally high levels of CCK would be released into the circulation to trigger pancreatitis in alcoholics. In contrast, bacterial endotoxemia is a candidate cofactor that does have relevance to the clinical situation. Plasma lipopolysaccharide (LPS, an endotoxin) levels are significantly higher in drinkers (either after chronic alcohol intake or a single binge) compared to non-drinkers. We have recently shown that alcohol-fed animals challenged with otherwise innocuous doses of LPS exhibit significant pancreatic injury. Moreover, repeated LPS exposure in alcohol-fed rats leads to progressive injury to the gland characterized by significant pancreatic fibrosis. These studies support the concept that endotoxin may be an important factor in the initiation and progression of alcoholic pancreatitis. Scope remains for further studies examining proteins related to cellular anti-oxidant defenses, minor cystic fibrosis (CF) mutations and trans-heterozygosity involving a combination of mutations of different genes (such as CFTR alterations combined with SPINK1 or PRSS1 variants), as potential triggers of alcoholic pancreatitis.
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Affiliation(s)
- Minoti V Apte
- Pancreatic Research Group, South-western Sydney Clinical School, Liverpool Hospital, The University of New South Wales, Sydney, Australia
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30
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Abstract
Only a small proportion of heavy drinking individuals develop pancreatitis. The environmental and host cofactors shown to have an association with alcoholic pancreatitis are smoking and race. The known genetic variations and polymorphisms do not seem to play an important role in alcoholic pancreatitis. Newer developments in the understanding of complex disorders allow clinicians to understand better the role of cofactors and interactions between known and yet unknown environmental and genetic factors in causing alcoholic pancreatitis.
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Affiliation(s)
- Dhiraj Yadav
- Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
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Piepoli A, Gentile A, Valvano MR, Barana D, Oliani C, Cotugno R, Quitadamo M, Andriulli A, Perri F. Lack of association between UGT1A7, UGT1A9, ARP, SPINK1 and CFTR gene polymorphisms and pancreatic cancer in Italian patients. World J Gastroenterol 2006; 12:6343-8. [PMID: 17072959 PMCID: PMC4088144 DOI: 10.3748/wjg.v12.i39.6343] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate simultaneously UGT1A7, UGT1A9, ARP, SPINK and CFTR genes to verify whether genetic polymorphisms predispose to the development of pancreatic cancer (PC).
METHODS: Genomic DNA of 61 pancreatic cancer patients and 105 healthy controls (HC) were analyzed. UGT1A7 genotyping was determined by PCR-RFLP analysis. Specific PCR and sequencing were used to analyze genetic variants of UGT1A9, ARP, SPINK1 and CFTR genes.
RESULTS: Four different alleles (*1: WT; *2: N129K and R131K; *3: N129K, R131K, and W208R; and *4: W208R) in UGT1A7 and three different alleles (*1: WT; *4: Y242X; and *5: D256N) in UGT1A9 were detected. All UGT1A polymorphisms were observed at similar frequency in PC patients and HC. Seven different alleles in ARP were found in PC patients and HC at similar frequency. The SPINK1 mutations N34S and P55S occurred in five PC patients with a prevalence (4.1%) not significantly different from that observed (2.0%) in HC. The only CFTRΔF508 mutation was recognized in three PC patients with a prevalence (4.9%) similar to HC.
CONCLUSION: UGT1A7, UGT1A9, ARP, SPINK1 and CFTR gene polymorphisms are not associated with PC in Italian patients.
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Affiliation(s)
- Ada Piepoli
- Research Laboratory Department of Gastroenterology, "Casa Sollievo della Sofferenza" Hospital, IRCCS, San Giovanni Rotondo, Italy.
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32
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Liddle RA. Pathophysiology of SPINK mutations in pancreatic development and disease. Endocrinol Metab Clin North Am 2006; 35:345-56, x. [PMID: 16632097 DOI: 10.1016/j.ecl.2006.02.012] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The endogenous pancreatic trypsin inhibitor, SPINK, is believed to limit enzyme activity in the pancreas and reduce the risk of pancreatitis. Recently, mutations in the SPINK1 gene have been associated with development of both acute and chronic pancreatitis. In most patients with SPINK1 mutations, the genetic variants do not cause the disease independently, but may act in concert with other genetic or environmental factors. Recent studies, using mice in which the trypsin inhibitor gene has been deleted or overexpressed, provide novel insights into the role of SPINK in pancreatic development and pancreatitis.
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Affiliation(s)
- Rodger A Liddle
- Department of Medicine, Duke University and Durham VA Medical Centers, Box 3913, Durham, NC 27710, USA.
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33
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Ahmed SA, Wray C, Rilo HLR, Choe KA, Gelrud A, Howington JA, Lowy AM, Matthews JB. Chronic pancreatitis: recent advances and ongoing challenges. Curr Probl Surg 2006; 43:127-238. [PMID: 16530053 DOI: 10.1067/j.cpsurg.2005.12.005] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Affiliation(s)
- Syed A Ahmed
- University of Cincinnati Medical Center, Ohio, USA
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Stanziale P, Savino M, De Bonis P, Granatiero M, Zelante L, Bisceglia L. Indirect CFTR mutation identification by PCR/OLA anomalous electropherograms. ACTA ACUST UNITED AC 2006; 9:285-91. [PMID: 16379540 DOI: 10.1089/gte.2005.9.285] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Mutations of CFTR gene are responsible for cystic fibrosis (CF) and other clinical conditions such as congenital absence of the vas deferens (CAVD), chronic pancreatitis (IP), and idiopathic disseminated bronchiectasis (DBE) classified as CFTR-related disorders. The PCR/OLA assay is designed to detect 31 known mutations including the 24 most common CF mutations worldwide, as identified by the CF Consortium. In order to define the CFTR genotype a series of 1812 individuals from central-southern Italy with and without CF manifestations were screened by using the PCR/OLA assay. Here we report the description of five cases of anomalous electropherograms obtained after PCR/OLA analysis, that led to the identification, in the homozygous state, of two point mutations (D110H and S589N) not included in the assay test panel, a large gene deletion (CFTRdel14b_17b), and an exonic polymorphism (c.4002A > G). Haplotype and real time PCR analysis were also performed in the subject carrying the large CFTR deletion. The study demonstrates that the PCR/OLA assay, besides being an efficient and user-friendly method to screen known mutations in the CFTR gene, may also function as a mutation/polymorphism-scanning assay, at least for certain nucleotide changes located in some critical regions of the gene.
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Affiliation(s)
- Pietro Stanziale
- Medical Genetics Service, IRCCS Hospital Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
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Affiliation(s)
- Frédérique Maire
- Fédération Médico-Chirurgicale d'Hépato-Gastroentérologie, Hôpital Beaujon, 100, Bd du Général Leclerc, 92118 Clichy Cedex, France.
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36
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Lee KH, Ryu JK, Yoon WJ, Lee JK, Kim YT, Yoon YB. Mutation analysis of SPINK1 and CFTR gene in Korean patients with alcoholic chronic pancreatitis. Dig Dis Sci 2005; 50:1852-6. [PMID: 16187186 DOI: 10.1007/s10620-005-2950-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2005] [Accepted: 02/18/2005] [Indexed: 01/27/2023]
Abstract
Several genetic mutations have been reported to increase susceptibility to chronic pancreatitis. However, their roles in alcoholic chronic pancreatitis are controversial. We investigated the prevalence of SPINK1 N34S and new CFTR Q1352H mutations in alcoholic chronic pancreatitis in Korea. Forty-three patients with alcoholic chronic pancreatitis were enrolled and 35 healthy individuals served as controls. The SPINK1 N34S mutation was detected by the PCR-RFLP technique. The CFTR Q1352H mutation was examined with PCR direct sequencing. Mean age of chronic pancreatitis and control groups was 53.2 and 51.3 years, respectively. A SPINK1 N34S was detected as a heterozygote in one (2.4%) patient with alcoholic chronic pancreatitis and a heterozygote CFTR Q1352H was detected in one other patient. In the control population, neither SPINK1 nor CFTR mutation was detected. This study shows that SPINK1 N34S and CFTR Q1352H mutations are uncommon and do not play an important role in chronic alcoholic pancreatitis in Korea.
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Affiliation(s)
- Kwang Hyuck Lee
- Department of Internal Medicine, Seoul National University College of Medicine, Liver Research Institute, Seoul, Korea
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37
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Abstract
SPINKI is thought to play an important role in protecting the pancreas against excessive trypsinogen activation. SPINK1 mutations are associated with the development of acute and chronic pancreatitis and have been detected in all forms of chronic pancreatitis. The strong association of mutations in the PRSS1 gene and in the SPINKI gene with chronic pancreatitis supports the concept of intracellular trypsin activation as an initiating and extremely important step in the development of pancreatitis. The N34S mutation represents the most frequently observed pancreatitis-associated SPINKI variant. Because the SPINKI N34Smutation is very common in the general population, it is unlikely that this mutation alone can initiate the development of chronic pancreatitis. Thus, it rather appears that in most patients with SPINKI-associated chronic pancreatitis, this genetic variant acts as disease modifier or within a polygenic model with other yet unidentified genes or environmental co-factors. The possible interaction of mutations in the SPINK1 gene with other pancreatitis-associated susceptibility genes has to be investigated in future research efforts. The most promising candidate gene for such an interaction is the CFTR gene, because genetic alterations within the CFTRgene are also common in the general population and already have been associated with chronic pancreatitis.
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Affiliation(s)
- Alexander Schneider
- Department of Medicine II (Gastroenterology, Hepatology and Infectious Diseases), University Hospital of Heidelberg at Mannheim, Theodor-Kutzer-Ufer 1-3 D-68135, Mannheim, Germany.
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38
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Abstract
In summary, SPINK1 is thought to play an important role in protecting the pancreas against excessive trypsinogen activation. SPINK1 mutations are associated with the development of acute and chronic pancreatitis and have been detected in all forms of chronic pancreatitis. The strong association of mutations in the PRSS1 gene and in the SPINK1 gene with chronic pancreatitis supports the concept of intracellular trypsin activation as an initiating and extremely important step in the development of pancreatitis. The N34S mutation represents the most frequently observed pancreatitis-associated SPINK1 variant. Because the SPINK1 N34S mutation is very common in the general population, it is unlikely that this mutation alone can initiate the development of chronic pancreatitis. Thus, it rather appears that in most patients with SPINK1-associated chronic pancreatitis, this genetic variant acts as disease modifier or within a polygenic model with other yet unidentified genes or environmental cofactors. The possible interaction of mutations in the SPINK1 gene with other pancreatitis-associated susceptibility genes has to be investigated in future research efforts. The most promising candidate gene for such an interaction is the CFTR gene, because genetic alterations within the CFTR gene are also common in the general population and already have been associated with chronic pancreatitis.
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Affiliation(s)
- Alexander Schneider
- Department of Medicine II (Gastroenterology, Hepatology and Infectious Diseases), University Hospital of Heidelberg at Mannheim, Theodor-Kutzer-Ufer 1-3 D-68135, Mannheim, Germany.
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