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. Author manuscript; available in PMC: 2013 Jun 17.
Published in final edited form as: Minerva Gastroenterol Dietol. 2012 Dec;58(4):299–308.

Genetics of Pancreatitis with a focus on the Pancreatic Ducts

Jessica LaRusch 1, David C Whitcomb 1,2,3
PMCID: PMC3684070  NIHMSID: NIHMS467905  PMID: 23207607

Abstract

Genetic risk for acute pancreatitis (AP), recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) are increasingly recognized. The exocrine pancreas is composed of both acinar cells and duct cells, with genetic factors associated with AP, RAP and CP linked to one cell type or the other. Increased susceptibility to pancreatitis occurs when the normal physiological mechanisms that allow the pancreas to respond to common stresses or injury are altered. Currently, most our knowledge about genetics focuses on three genes that play critical roles in pancreatic function (PRSS1, CFTR, SPINK1) such that isolated defects lead to disease. However, recent data suggest that more complex combination of genetic and environmental factors are also as important, or more important than Mendelian genetic risk. Understanding of complex interactions requires modeling of these factors so that the response to stresses or injury can be simulated and critical interactions understood. A simple duct cell model is given to illustration the relationship between CFTR, CASR, aquaporins, claudins, and SPINK1, and how they interact. The role of CFTR variants in pancreatic diseases is then discussed.

I. Introduction

Acute pancreatitis (AP) and chronic pancreatitis (CP) are terms to describe inflammatory syndromes of the pancreas. AP is a sudden onset defined clinically by typical abdominal pain, elevated serum levels of digestive enzymes (>3× normal) and typical changes on abdominal imaging (1, 2). CP is defined by irreversible damage to the pancreas as a result of inflammation (3, 4), usually characterized by chronic inflammation with variable pain, calcifications, necrosis, fatty replacement, fibrosis and scarring and other complications (4, 5). Although once considered to be two distinct diseases, it is now clear that AP and CP are often linked, usually by recurrent acute pancreatitis (RAP) as an intermediate step (6–8). The problems in approaching chronic pancreatitis from a medical perspective are that most patients with risk factors such as heavy alcohol use do not develop pancreatitis (9), and that the development, progression and severity of CP are unpredictable.

Recently, the idea that genetic factors could represent many of the hidden variables that determine susceptibility, progression and outcomes has generated great interest. Here we highlight new findings that bring insight into the reasons for unpredictability in the past, the new technologies that provide new dimensions of information, and new frameworks for evaluating patients that will be needed for accurate predicting of disease etiology, activity, progression, and effective, personalized interventions in the future.

Early Genetic Discoveries Related to Pancreatitis

The 1996 discovery that mutations in the PRSS1 gene cause hereditary pancreatitis (10) opened the field of pancreatitis genetics. Since then substantial effort has been expended to elucidate the role of genetics in familial and sporadic pancreatitis and other pancreatic diseases. Within a few years of the discovery of the PRSS1 gene, an association between seemingly sporadic pancreatitis and mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR) (11, 12) were made and in the pancreatic secretory trypsin inhibitor gene (SPINK1) were identified (13, 14). However, progress in the years following these major discoveries has been slow (15–17). Variants with a much lower risk than PRSS1, CFTR and SPINK1 were also reported in the calcium sensing receptor gene (CASR) (18, 19) and the chymotrypsinogen C gene (CTRC) (20, 21), but these are uncommon variants and only have small independent effects. Thus, the initial enthusiasm for genetic discovery has been tempered by uncertainty in clinical application and decision-making.

Enabling Technologies for Human Genetics

In contrast to slow process in discovering new pancreatitis genes, there have been incredible technical advances in genetics including massive parallel genotyping with high density single nucleotide polymorphism (SNP) chips used for genome-wide association studies (GWAS), and more recently massive parallel genomic DNA sequencing, known as next generation sequencing (NGS). As with many complex genetic disorders, the interpretation of GWAS and NGS data will be challenging using the current framework of thinking.

Complex Genetic Risk

Given the high variability of the onset and progression of disease and the limited environmental factors that affect the pancreas, a substantial portion of the disease burden in RAP and CP must be due to genetic factors. Mendelian varieties of pancreatitis (autosomal dominant - HP and autosomal recessive - CF) are well documented but represent only a small fraction of patients, leaving the majority with unknown genetic etiologies, most likely complex and multigenic.

Mendelian inheritance is straightforward in research and clinical settings because there is usually one dominant gene that leads to a defined, albeit complex syndrome for the majority of patients. Simple Mendelian disorders are often congenital or become symptomatic early in life. However, these types of diseases are less common in adult onset disease. Adult onset diseases with genetic susceptibility are more often complex disorders, and they require large amount of genetic data in many people to discover, especially if there are multiple environmental factors compounding the complexity of the disease. Since these complex disorders cannot be addressed using simple models, the question remains as to whether or not genotyping an individual patient is useful and will aid or influence therapeutic decisions. This review addresses the emerging role of complex trait genetics in the diagnosis and treatment of pancreatic disorders based on modeling and simulation rather viewing each factor independently in individual patients (see perspective (22)). Here we focus on the pancreatic duct and three key genes with pancreatitis-associated variants: CFTR, CASR and SPINK1. In addition, we review one of the foundations for a new framework to understand pancreatic diseases linked to pancreatic duct dysfunction that will allow multiple factors in a single patient to be integrated and analyzed (e.g. personalized medicine).

Trypsinogen and Pancreatic Injury

The exocrine pancreas has two major cell types; the acinar cells and the duct cells. These cells work together to produce pancreatic digestive enzymes (acinar cells) and to flush the secreted zymogens out of the pancreas and into the duodenum where the zymogens are activated by trypsin, and large nutrients are then digested.

Previous genetic studies and complementary experimental studies have supported the hypothesis that pancreatic injury is initiated by premature activation of trypsinogen to trypsin within the pancreas. Supporting genetic evidence includes the findings that the strongest risk for pancreatitis includes gain-of-function mutations in the cationic trypsinogen gene (PRSS1) (10, 23), presumed loss of function mutations in the pancreatic secretory trypsin inhibitor gene (SPINK1) (13, 14, 24), and loss-of-function in the gene key trypsin degrading enzyme (CTRC) (20, 21). One could argue that these genetic variants that result in recurrent acute pancreatitis (RAP) and eventually chronic pancreatitis (CP) are most relevant to the acinar cell. However, another set of mechanisms linked to the duct cell appears to produce the same clinical syndromes.

II. Pancreatic Duct Biology

The pancreatic ducts are an arborizing network of fluid-filled tubes that connect each acinar cell to the duodenum. The intercalated ducts are immediately connected to the acinar cells and centroacinar cells and have the highest amount of CFTR expression (25). As the intercalated ducts from adjacent acini coalesce they form interlobular ducts, with intralobular ducts forming interlobular ducts, interlobar ducts and finally the main pancreatic duct. The characteristics of the duct cells and ductal structure also change to facilitate fluid transport. Throughout the duct, the ductal epithelial cells form an effective barrier between the interstitial space and the duct lumen so that specific molecules that can only cross the epithelial cell barrier under highly regulated conditions.

CFTR in the pancreas

The physiology of the pancreatic ducts has recently been reviewed in detail (26). Figure 1 highlights some of the key molecules involved in duct cell mediated fluid secretion, including CFTR and CASR. CFTR plays a critical physiologic role in anion conductance across the epithelial cell barrier and into the duct lumen via the apical (luminal) membrane. This fact is supported by the effect of severe CFTR mutations that result in chronic pancreatitis beginning in utero in the autosomal recessive syndrome of cystic fibrosis.

Figure 1. Pancreatic Duct cell – duct model.

Figure 1

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An organizational model of the pancreatic duct cell illustrating the relationship between key proteins. CLDN-2 and CLDN-4 are genes coding for claudin-2 and claudin-4 which are the primary claudins that make up the tight junction in the proximal duct cells. PAR2 is a protease-activated receptor that senses trypsin activity in the duct. PAR2 and CASR are believed to regulate CFTR opening to clear trypsin or excessive calcium from the duct. cAMP is the primary regulator of CFTR.

A fundamental principal of cell physiology is that the type of ion that is conducted through channels is dependent on the electrochemical gradient across the cell membrane and the characteristics of the channel. CFTR (also know as ABCC7(26)) is an anion-specific channel, so it specifically facilitates conductance of chloride (Cl−), bicarbonate (HCO3−) and other anions. The direction of ion movement across the membrane is determined by the concentration of the ion on each side of the membrane and the electrical potential. Ions can only be secreted or absorbed across epithelial cell barrier if there is a channel or molecular mechanism to transport the both the apical (luminal) and basolateral (plasma) membranes. Interestingly, the body can use CFTR to secrete Cl− in the lung and HC03− in the pancreatic duct, while its absorbs Cl− in the sweat gland. The differences are all related to cell organization, membrane potential and electrochemical gradients.

CFTR is a channel that can conduct either chloride or bicarbonate in the pancreas. The pancreatic duct cells secrete bicarbonate because of the sodium-bicarbonate cotransporter (NBC [also known as NBCn1-A, NBC3 or SLC4A7] (26)) on the basolateral border of the duct cells which provides a continuous flow of bicarbonate into the duct under physiologic conditions, with the absence of high-conductance chloride transport pathway across the basolateral membrane. Thus, in the bicarbonate-secreting cells of the pancreas, the only anion that can efficiently cross both basolateral and apical membranes is bicarbonate (Figure 1).

A second important feature of CFTR is that it is a regulated anion channel. Opening of the CFTR channel occurs through activation of the duct cell by the duodenal hormone secretin, by the neuropeptide vasoactive intestinal polypeptide (VIP) that increase cyclic AMP (cAMP) or factors that increase intracellular calcium (27). CFTR is regulated by channel gating and activation, PKA mediated phosphorylation of the R domain of CFTR allows for channel gating, while activation is determined by local cAMP and Ca++ levels (28). Recently Park et al (29) demonstrated that the relative conductance of chloride and bicarbonate through CFTR was dynamically regulated by the WNK1, SPAK/OSR1 system which, with low intracellular chloride concentrations, changes CFTR into a bicarbonate channel and inhibits the chloride-bicarbonate antiporter (SLC26a6).

Water secretion in pancreatic ducts

CFTR is the primary molecule for secretion of bicarbonate, but how is sodium and water added to make sodium-bicarbonate-rich pancreatic juice? There are two known pathways for water to cross the epithelial cell barrier; between the cells (paracellular) and through the cells (transcellular). Once thought to be a passive event, transcellular water transport is regulated by a family of membrane proteins called aquaporins. The pancreas expresses a number of different aquaporin proteins, AQP7 in the beta cells, AQP8 and AQP12 are found in the acini, while primarily AQP1 and to a lesser extent AQP5 is expressed on the apical and lateral regions of the ductal cells, co-localizing with CFTR (30). The GTP-regulated AQP1 has also been identified as an important factor in the swelling of zymogen granules in the ductal acini (31). Investigation of the role of AQP1 in pancreatitis has yielded complex results, in that AQP1 has been shown to be overexpressed cases of autoimmune pancreatitis (32, 33), but down regulated in models of acute necrotizing pancreatitis (34). Thus, in the pancreatic duct AQP1 and AQP5 are expressed and provide a possible pathway for water flow across the duct epithelium.

Claudins in the Pancreas

The paracellular pathway may be more important for high volume fluid flow than trans-epithelial secretion, as seen with active pancreatic juice secretion. Regulation of diffusion of water and ions between endothelial cells occurs at the tight junction, which defines the site of transition between apical and basolateral membranes (35). The tight junctions are formed by proteins called claudins. The claudins are a family of ~24 related regulated proteins with four trans-membrane domains form the tight junction and determine transepithelial resistance and ion selectivity (reviewed in (36, 37)). Although claudins have not been extensively studied in the pancreas, several claudins, including caludin-1, -2, -3 and -4 are expressed in mouse and human pancreas (38).

Claudin-2 is normally expressed at low levels the duct cells of the exocrine pancreas as well as islets. Claudin-2 differs from other claudins expressed in the pancreas because it forms low-resistence cation-selective ion and water channels between endothelial cells(39, 40), which facilitates sodium and water movement into the duct lumen. The CLDN2 promoter includes an NFkB binding site (41), and gene expression is enhanced in other cells under conditions associated with injury or stress (42–44). Claudin-2 is also highly regulated, and can be inserted into, and removed from the tight junction rapidly (45). It is possible that claudin-2 is the molecule that is expressed during active secretion under physiologic conditions, and also with injury or stress to facilitate sodium and water secretion to match CFTR. However, this remains an area where more investigation is needed.

Calcium sensing receptor in the pancreatic ducts

The CaSR is a seven exon, 1078 amino acid, plasma membrane-bound G protein coupled receptor that senses extracellular calcium levels and is expressed in many cells and tissues (46). CaSR is expressed on the luminal side of the ducts (Figure 1) and increases cyclic-AMP and activate bicarbonate secretion through CFTR (47) (46)). Thus, CaSR appears to sense and regulate pancreatic juice calcium concentrations by triggering ductal electrolyte and fluid secretion when levels are elevated (48). Whereas high concentrations of calcium in pancreatic juice increases risk of trypsinogen activation and stabilization of trypsin, which in turn causes acute pancreatitis, a functional CaSR washing out high calcium duct fluid is critical for healthy physiology (16). Both loss-of-function and gain of function mutations have been identified (see http://www.casrdb.mcgill.ca/), with gain-of-function being linked to alcohol use (19), while loss-of-function are linked to CFTR variants (16).

SPINK1

A major suicide inhibitor of activated trypsin is the pancreatic secretory trypsin inhibitor (PSTI) coded by the in the serine protease inhibitor, Kazal-type, 1 gene (SPINK1). SPINK1 is synthesized by the acinar cells in parallel to trypsinogen and follows trypsinogen in the secretory pathway through the ducts. SPINK1 is upregulated during pancreatitis, and controls further pancreatic injury in the duct cells by inhibiting trypsin. SPINK1 inactivating mutations have been shown to be rare but strong risk factors for CP (49–51), suggesting that it is the loss-of-function that is related to pathology. The common SPINK1 N43S variant has also been repeated reported as a risk factor although the mechanism is still not known. The location of PSTI’s effect in protecting from pancreatitis could be in the acinar cell and/or duct.

III. Genetics of Pancreatitis

The primary genetic variant linking pancreatitis to the duct is CFTR. CFTR variants are associated with CF, but also with sporadic and familial pancreatitis when they are in combination with mild variants or other genes expressed in the ducts (e.g. CASR) or whose product play a critical role in protecting the duct from trypsin activity (e.g. SPINK1).

Cystic Fibrosis and Pancreatitis

CF is the most common cause of pancreatic disease in children and the most common lethal autosomal recessive disease in North America. CF impacts multiple organ systems, including sino-pulmonary, reproductive and gastrointestinal, with a highly variable phenotype. Due to the extensive nature of this disease and the large amount of scientific literature regarding genetic diagnosis of CF specifically including recent and comprehensive reviews (52–54), we will focus on the impact of genetics in pancreatic dysfunction in CF.

Evaluation of the pancreas is often overlooked in CF, despite being the first and most critically damaged organ. Typical cases of CF are often diagnosed due to extensive pancreatic scarring and fibrosis that occurred in utero, leading to loss of pancreatic exocrine function, pancreatic insufficiency (PI- pancreatic enzymes below 10% of normal), malabsorption and failure to thrive in infancy. Pancreatic enzyme replacement therapy corrects malabsorption, substituting for pancreatic exocrine function, but does not address the root cause or prevent further damage to any remaining exocrine tissue. Although primarily scar tissue, the pancreas continues to be subject to further damage, as evidenced by the eventual loss of pancreatic endocrine function leading to CF related diabetes (CFRD) in many as 50% of CF adults (55, 56).

In recent years, there has been an increase in the number of CF patients diagnosed later in life, or even as adults, these patients are most often pancreatic sufficient (PS), with enzyme levels above 10% of normal, but still have chronic pancreatic damage, further evidenced by a one in five incidence of acute pancreatitis attacks (57). Cases of idiopathic chronic pancreatitis (ICP) but no other CF symptoms (11, 12) with corresponding CFTR mutations have also been reported, leading to the consideration of pancreatitis as a CF-related disorder. While the impact of any single CFTR mutation in pancreatitis has been questioned (58), the evidence indicates that CFTR is a critical factor in maintaining balance between pH, juice volume and enzymes in the pancreatic ducts. Additionally, CFTR mutations associate with disease especially with additional risk factors along the etiological pathway (59, 60), demonstrating epistasis that is indicative of a complex genetic disorder.

The role of CFTR mutation type in CF related pancreatic disease

The most common CF-causing mutation is a three nucleotide deletion in the regulatory domain (F508del) resulting in protein misfolding and degradation (61). Fifty percent of CF patients are homozygous, and 80% carry at least one F508del allele. Nearly two thousand CFTR variants have been identified, but very few are clearly determined to be CF causing. Most novel and rare mutations have not been functionally studied and have uncertain impact on disease. CF mutation type generally determines the extent of damage and disease in the pancreas but not the lungs, ilium or liver (62, 63).

Because of the high (and increasing) number of CFTR mutations identified in CF and CF-related disorders, mutation databases are an important tool the most complete is available with very limited phenotypic and no functional information (www.genet.sickkids.on.ca), serving as a complete repository of reported mutations. Recently opened to the public, a new resource serves as a functional and phenotypic repository of selected CFTR mutations (CFTR2.org), a phenotypic database compilation of CF patient phenotypes and in vitro functional studies on specific mutations, reports the influence of a mutation on CF phenotype, lung function and frequency of pancreatic insufficiency for CF patients only, not isolated pancreatitis. Many mutations report uncertain or variable clinical consequences, but some are categorized definitely as CF-causing or non-CF causing. The complexity of considering CFTR mutations in pancreatitis is revealed in that specific statement in light of recent findings of a moderately frequent CFTR variant Arg75Gln, with selective loss of bicarbonate but not chloride conduction resulting in elevated risk for pancreatitis but not CF (59). Indeed, the frequency of rare and novel CFTR mutations in isolated pancreatitis (64) argues for more investigation and thorough functional studies of new mutations.

CFTR mutation specific therapies

An exciting new breakthrough in the CF field has been the development of new small molecule correctors and potentiators for specific CFTR mutations. These drugs have been reported and reviewed in a number of articles in detail, both in ongoing clinical trials and approved by FDA F508del and G551D (65), G542X, W1282X and all other premature termination mutations (66, 67), leading us to speculate on the impact or utility of these drugs on pancreatitis.

The primary therapeutic endpoint of CFTR correction therapy is lung function, although sweat chloride or nasal potential difference is often measured as a short term surrogate indicating that these therapies may have bioavailability throughout the entire body, including the pancreas. CFTR correction in CF patients is likely to also impact any remaining pancreatic tissue, which will have consequences for pancreatic sufficient CF patients especially. If these therapies become mainstream, patients may get them earlier and earlier, possibly before the onset of PI, possibly resulting in more PS patients, a reduction in CFRD but more acute pancreatitis attacks. If these drugs are effective for CF patients, will they also be useful in CF-related diseases, such as pancreatitis with CFTR dysfunction?

Ductal morphology and Genetic Risk Factors

Pancreas divisum (PD) is a frequent anatomical variation of the pancreatic ducts, occurring during development when the ventral and dorsal pancreatic buds fail to fuse, physically impeding normal ductal flow. PD has been repeatedly shown to be more two to three times common in CP than normal subjects (68), however since it is estimated to be present in 5–10% of the normal population (69) it is a benign variation in over 95% of carriers while simultaneously a risk factor for CP. Much like CFTR and SPINK1 mutations discussed above, PD is a complex risk factor for ductal pancreatic disease seen often in conjunction with other similar risk factors, this was demonstrated in the last year when Bertin et al (70) (PMID 22158025) showed that PD frequency was not significantly different between healthy subjects and patients with alcoholic or idiopathic CP(5–7%), but twice as frequent in patients with PRSS1 or SPINK1 mutations (16%) and almost seven times as common in carriers of CFTR variants (47%). With the recognition that multiple genes play a complex role in the development of ductal pancreatitis and the burgeoning future of personalized medicine one must also include physiological and environmental risk factors along with genetics.

Complex genotypes in RAP and CP

Pancreatitis is a complex disorder, so it is not surprising that various combinations of risk factors in more that on gene in a critical system may lead to disease. Except for cases of autosomal dominant mutations in PRSS1 causing hereditary pancreatitis, a single mutation in any of the other genes discussed above is still only a risk factor, pointing to a possible mechanism, but not by itself disease-causing. Due to advances in sequencing and the building of large pancreatitis study cohorts in recent years, an increasing number of reports note multiple factors in individual patients (58, 59). Synchronous risk factors in pancreatitis most often have a shared pathway, resulting in a failure in a specific and limited system. Fortunately, we can take advantage of this new understanding of synchronous risk factors using advanced in modeling of the pancreatic ductal system (71), which can predict new candidate genes and use subgroup analysis to identify patients with a high likelihood of mutations in these novel genes. In reviewing the frequency of complex mutations among CP patients, we expect that almost all patients have a complex genetic etiology stemming from genes that are only risk factors in specific genetic backgrounds, leaving us with much more to discover.

Table 1.

CFTR and Susceptibility to Pancreatitis.

CFTRsev/CFTRsev (0%) = cystic fibrosis
CFTRsev/CFTRm-v (<10%) = atypical CF, high pancreatitis risk
CFTRsev/CFTRR75Q = SCP and limited atypical CF features
CFTRsev or R75Q/SPINK1 = SCP only
CFTRsev/PD = SCP only
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Pancreatic injury can occur through multiple mechanisms. Superscripts: sev = severe mutation, m-v = mild variable mutations, R75Q = a CFTR mutation that selectively limits bicarbonate conductance, but not chloride (representative of a new class of CFTR variants). CF, cystic fibrosis; SCP, sporadic chronic pancreatitis, usually classified as idiopathic chronic pancreatitis prior to genetic testing. PD, pancreas divisum. (Adapted from DC Whitcomb, CFTR Mutations in Cystic Fibrosis and Idiopathic Pancreatitis. PancreasFest 2012, Pittsburgh, PA July 26, 2012 with permission).

References

  • 1.Banks PA, Freeman ML. Practice guidelines in acute pancreatitis. Am J Gastroenterol. 2006 Oct;101(10):2379–2400. doi: 10.1111/j.1572-0241.2006.00856.x. [DOI] [PubMed] [Google Scholar]
  • 2.Pandol SJ, Saluja AK, Imrie CW, Banks PA. Acute pancreatitis: bench to the bedside. Gastroenterology. 2007 Mar;132(3):1127–1151. doi: 10.1053/j.gastro.2007.01.055. [DOI] [PubMed] [Google Scholar]
  • 3.Singer MV, Gyr K, Sarles H. Revised classification of pancreatitis. Gastroenterology; Report of the Second International Symposium on the Classification of Pancreatitis; March 28–30, 1984; Marseille, France. 1985. Sep, pp. 683–685. [PubMed] [Google Scholar]
  • 4.Etemad B, Whitcomb DC. Chronic pancreatitis: Diagnosis, classification, and new genetic developments. Gastroenterology. 2001;120:682–707. doi: 10.1053/gast.2001.22586. [DOI] [PubMed] [Google Scholar]
  • 5.Dimagno MJ, Dimagno EP. Chronic pancreatitis. Curr Opin Gastroenterol. 2012 Jul 9; doi: 10.1097/MOG.0b013e3283567dea. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Whitcomb DC. Hereditary Pancreatitis: New insights into acute and chronic pancreatitis. Gut. 1999;45:317–322. doi: 10.1136/gut.45.3.317. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Stevens T, Conwell DL, Zuccaro G. Pathogenesis of chronic pancreatitis: an evidence-based review of past theories and recent developments. Am J Gastroenterol. 2004 Nov;99(11):2256–2270. doi: 10.1111/j.1572-0241.2004.40694.x. [DOI] [PubMed] [Google Scholar]
  • 8.Yadav D, Whitcomb DC. The role of alcohol and smoking in pancreatitis. Nat Rev Gastroenterol Hepatol. 2010 Mar;7(3):131–145. doi: 10.1038/nrgastro.2010.6. [DOI] [PubMed] [Google Scholar]
  • 9.Yadav D, Eigenbrodt ML, Briggs MJ, Williams DK, Wiseman EJ. Pancreatitis: prevalence and risk factors among male veterans in a detoxification program. Pancreas. 2007 May;34(4):390–398. doi: 10.1097/mpa.0b013e318040b332. [DOI] [PubMed] [Google Scholar]
  • 10.Whitcomb DC, Gorry MC, Preston RA, Furey W, Sossenheimer MJ, Ulrich CD, et al. Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nature Genetics. 1996;14(2):141–145. doi: 10.1038/ng1096-141. [DOI] [PubMed] [Google Scholar]
  • 11.Sharer N, Schwarz M, Malone G, Howarth A, Painter J, Super M, et al. Mutations of the cystic fibrosis gene in patients with chronic pancreatitis. New England Journal of Medicine. 1998;339(10):645–652. doi: 10.1056/NEJM199809033391001. [DOI] [PubMed] [Google Scholar]
  • 12.Cohn JA, Friedman KJ, Noone PG, Knowles MR, Silverman LM, Jowell PS. Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis. N Engl J Med. 1998;339(10):653–658. doi: 10.1056/NEJM199809033391002. [DOI] [PubMed] [Google Scholar]
  • 13.Pfutzer RH, Barmada MM, Brunskill AP, Finch R, Hart PS, Neoptolemos J, et al. SPINK1/PSTI polymorphisms act as disease modifiers in familial and idiopathic chronic pancreatitis. Gastroenterology. 2000 Sep;119(3):615–623. doi: 10.1053/gast.2000.18017. [DOI] [PubMed] [Google Scholar]
  • 14.Witt H, Luck W, Hennies HC, Classen M, Kage A, Lass U, et al. Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis. Nature Genetics. 2000;25(2):213–216. doi: 10.1038/76088. [DOI] [PubMed] [Google Scholar]
  • 15.Chen JM, Ferec C. Chronic pancreatitis: genetics and pathogenesis. Annu Rev Genomics Hum Genet. 2009;10:63–87. doi: 10.1146/annurev-genom-082908-150009. [DOI] [PubMed] [Google Scholar]
  • 16.Larusch J, Whitcomb DC. Genetics of pancreatitis. Curr Opin Gastroenterol. 2011 Sep;27(5):467–474. doi: 10.1097/MOG.0b013e328349e2f8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Chen JM, Ferec C. Genetics and pathogenesis of chronic pancreatitis: The 2012 update. Clin Res Hepatol Gastroenterol. 2012 Jun 29; doi: 10.1016/j.clinre.2012.05.003. [DOI] [PubMed] [Google Scholar]
  • 18.Felderbauer P, Hoffmann P, Einwachter H, Bulut K, Ansorge N, Schmitz F, et al. A novel mutation of the calcium sensing receptor gene is associated with chronic pancreatitis in a family with heterozygous SPINK1 mutations. BMC Gastroenterol. 2003;3(1):34. doi: 10.1186/1471-230X-3-34. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Muddana V, Lamb J, Greer JB, Elinoff B, Hawes RH, Cotton PB, et al. Association between calcium sensing receptor gene polymorphisms and chronic pancreatitis in a US population: Role of serine protease inhibitor Kazal 1type and alcohol. World J Gastroenterol. 2008 Jul 28;14(28):4486–4491. doi: 10.3748/wjg.14.4486. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Masson E, Chen JM, Scotet V, Le Marechal C, Ferec C. Association of rare chymotrypsinogen C (CTRC) gene variations in patients with idiopathic chronic pancreatitis. Hum Genet. 2008 Feb;123(1):83–91. doi: 10.1007/s00439-007-0459-3. [DOI] [PubMed] [Google Scholar]
  • 21.Rosendahl J, Witt H, Szmola R, Bhatia E, Ozsvari B, Landt O, et al. Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis. Nat Genet. 2008 Jan;40(1):78–82. doi: 10.1038/ng.2007.44. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Whitcomb DC. What is personalized medicine and should does it replace? Nat Rev Gastroenterol Hepatol. 2012;9(7):418–424. doi: 10.1038/nrgastro.2012.100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Whitcomb DC. Genetic aspects of pancreatitis. Annu Rev Med. 2010;61:413–424. doi: 10.1146/annurev.med.041608.121416. [DOI] [PubMed] [Google Scholar]
  • 24.Shimosegawa T, Kume K, Masamune A. SPINK1 gene mutations and pancreatitis in Japan. J Gastroenterol Hepatol. 2006 Oct;21(Suppl 3):S47–S51. doi: 10.1111/j.1440-1746.2006.04594.x. [DOI] [PubMed] [Google Scholar]
  • 25.Marino CR, Matovcik LM, Gorelick FS, Cohn JA. Localization of the cystic fibrosis transmembrane conductance regulator in pancreas. Journal of Clinical Investigation. 1991;88(2):712–716. doi: 10.1172/JCI115358. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Lee MG, Ohana E, Park HW, Yang D, Muallem S. Molecular mechanism of pancreatic and salivary gland fluid and HCO3 secretion. Physiol Rev. 2012 Jan;92(1):39–74. doi: 10.1152/physrev.00011.2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Lee MG, Ohana E, Park HW, Yang D, Muallem S. Molecular Mechanism of Pancreatic and Salivary Gland Fluid and HCOFormula Secretion. Physiol Rev. 2012 Jan;92(1):39–74. doi: 10.1152/physrev.00011.2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Frizzell RA, Hanrahan JW. Physiology of epithelial chloride and fluid secretion. Cold Spring Harb Perspect Med. 2012 Jun;2(6):a009563. doi: 10.1101/cshperspect.a009563. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Park HW, Nam JH, Kim JY, Namkung W, Yoon JS, Lee JS, et al. Dynamic regulation of CFTR bicarbonate permeability by [Cl−]i and its role in pancreatic bicarbonate secretion. Gastroenterology. 2010 Aug;139(2):620–631. doi: 10.1053/j.gastro.2010.04.004. [DOI] [PubMed] [Google Scholar]
  • 30.Burghardt B, Elkaer ML, Kwon TH, Racz GZ, Varga G, Steward MC, et al. Distribution of aquaporin water channels AQP1 and AQP5 in the ductal system of the human pancreas. Gut. 2003 Jul;52(7):1008–1016. doi: 10.1136/gut.52.7.1008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Cho SJ, Sattar AK, Jeong EH, Satchi M, Cho JA, Dash S, et al. Aquaporin 1 regulates GTP-induced rapid gating of water in secretory vesicles. Proceedings of the National Academy of Sciences of the United States of America. 2002 Apr 2;99(7):4720–4724. doi: 10.1073/pnas.072083499. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Ko SB, Mizuno N, Yatabe Y, Yoshikawa T, Ishiguro H, Yamamoto A, et al. Corticosteroids correct aberrant CFTR localization in the duct and regenerate acinar cells in autoimmune pancreatitis. Gastroenterology. 2010 May;138(5):1988–1996. doi: 10.1053/j.gastro.2010.01.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Ko SB, Mizuno N, Yatabe Y, Yoshikawa T, Ishiguro H, Yamamoto A, et al. Aquaporin 1 water channel is overexpressed in the plasma membranes of pancreatic ducts in patients with autoimmune pancreatitis. J Med Invest. 2009;56(Suppl):318–321. doi: 10.2152/jmi.56.318. [DOI] [PubMed] [Google Scholar]
  • 34.Feng DX, Peng W, Chen YF, Chen T, Tian JY, Si HR, et al. Down-Regulation of Aquaporin 1 in Rats With Experimental Acute Necrotizing Pancreatitis. Pancreas. 2012 Apr 4; doi: 10.1097/MPA.0b013e318249938e. [DOI] [PubMed] [Google Scholar]
  • 35.Anderson JM. Molecular structure of tight junctions and their role in epithelial transport. News Physiol Sci. 2001 Jun;16:126–130. doi: 10.1152/physiologyonline.2001.16.3.126. [DOI] [PubMed] [Google Scholar]
  • 36.Angelow S, Ahlstrom R, Yu AS. Biology of claudins. Am J Physiol Renal Physiol. 2008 Oct;295(4):F867–F876. doi: 10.1152/ajprenal.90264.2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Angelow S, Yu AS. Cysteine mutagenesis to study the structure of claudin-2 paracellular pores. Ann N Y Acad Sci. 2009 May;1165:143–147. doi: 10.1111/j.1749-6632.2009.04038.x. [DOI] [PubMed] [Google Scholar]
  • 38.Lee JH, Kim KS, Kim TJ, Hong SP, Song SY, Chung JB, et al. Immunohistochemical analysis of claudin expression in pancreatic cystic tumors. Oncol Rep. 2011 Apr;25(4):971–978. doi: 10.3892/or.2011.1132. [DOI] [PubMed] [Google Scholar]
  • 39.Van Itallie CM, Holmes J, Bridges A, Gookin JL, Coccaro MR, Proctor W, et al. The density of small tight junction pores varies among cell types and is increased by expression of claudin-2. J Cell Sci. 2008 Feb 1;121(Pt 3):298–305. doi: 10.1242/jcs.021485. [DOI] [PubMed] [Google Scholar]
  • 40.Amasheh S, Meiri N, Gitter AH, Schoneberg T, Mankertz J, Schulzke JD, et al. Claudin-2 expression induces cation-selective channels in tight junctions of epithelial cells. J Cell Sci. 2002 Dec 15;115(Pt 24):4969–4976. doi: 10.1242/jcs.00165. [DOI] [PubMed] [Google Scholar]
  • 41.Sakaguchi T, Gu X, Golden HM, Suh E, Rhoads DB, Reinecker HC. Cloning of the human claudin-2 5'-flanking region revealed a TATA-less promoter with conserved binding sites in mouse and human for caudal-related homeodomain proteins and hepatocyte nuclear factor-1alpha. J Biol Chem. 2002 Jun 14;277(24):21361–21370. doi: 10.1074/jbc.M110261200. [DOI] [PubMed] [Google Scholar]
  • 42.Mankertz J, Amasheh M, Krug SM, Fromm A, Amasheh S, Hillenbrand B, et al. TNFalpha up-regulates claudin-2 expression in epithelial HT-29/B6 cells via phosphatidylinositol-3-kinase signaling. Cell Tissue Res. 2009 Apr;336(1):67–77. doi: 10.1007/s00441-009-0751-8. [DOI] [PubMed] [Google Scholar]
  • 43.Suzuki T, Yoshinaga N, Tanabe S. Interleukin-6 (IL-6) regulates claudin-2 expression and tight junction permeability in intestinal epithelium. J Biol Chem. 2011 Sep 9;286(36):31263–31271. doi: 10.1074/jbc.M111.238147. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Mankertz J, Hillenbrand B, Tavalali S, Huber O, Fromm M, Schulzke JD. Functional crosstalk between Wnt signaling and Cdx-related transcriptional activation in the regulation of the claudin-2 promoter activity. Biochem Biophys Res Commun. 2004 Feb 20;314(4):1001–1007. doi: 10.1016/j.bbrc.2003.12.185. [DOI] [PubMed] [Google Scholar]
  • 45.Dukes JD, Whitley P, Chalmers AD. The PIKfyve Inhibitor YM201636 Blocks the Continuous Recycling of the Tight Junction Proteins Claudin-1 and Claudin-2 in MDCK cells. PloS one. 2012;7(3):e28659. doi: 10.1371/journal.pone.0028659. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Riccardi D, Brown EM. Physiology and pathophysiology of the calcium-sensing receptor in the kidney. Am J Physiol Renal Physiol. 2010 Mar;298(3):F485–F499. doi: 10.1152/ajprenal.00608.2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Bruce JI, Yang X, Ferguson CJ, Elliott AC, Steward MC, Case RM, et al. Molecular and functional identification of a Ca2+ (polyvalent cation)-sensing receptor in rat pancreas. J Biol Chem. 1999 Jul 16;274(29):20561–20568. doi: 10.1074/jbc.274.29.20561. [DOI] [PubMed] [Google Scholar]
  • 48.Racz GZ, Kittel A, Riccardi D, Case RM, Elliott AC, Varga G. Extracellular calcium sensing receptor in human pancreatic cells. Gut. 2002 Nov;51(5):705–711. doi: 10.1136/gut.51.5.705. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Le Marechal C, Chen JM, Le Gall C, Plessis G, Chipponi J, Chuzhanova NA, et al. Two novel severe mutations in the pancreatic secretory trypsin inhibitor gene (SPINK1) cause familial and/or hereditary pancreatitis. Hum Mutat. 2004 Feb;23(2):205. doi: 10.1002/humu.9212. [DOI] [PubMed] [Google Scholar]
  • 50.Boulling A, Keiles S, Masson E, Chen JM, Ferec C. Functional analysis of eight missense mutations in the SPINK1 gene. Pancreas. 2012 Mar;41(2):329–330. doi: 10.1097/MPA.0b013e3182277b83. [DOI] [PubMed] [Google Scholar]
  • 51.Larusch J, Barmada MM, Solomon S, Whitcomb DC. Whole exome sequencing identifies multiple, complex etiologies in an idiopathic hereditary pancreatitis kindred. JOP : Journal of the pancreas. 2012;13(3):258–262. [PMC free article] [PubMed] [Google Scholar]
  • 52.Lobo J, Rojas-Balcazar JM, Noone PG. Recent advances in cystic fibrosis. Clin Chest Med. 2012 Jun;33(2):307–328. doi: 10.1016/j.ccm.2012.02.006. [DOI] [PubMed] [Google Scholar]
  • 53.Salvatore D, Buzzetti R, Baldo E, Forneris MP, Lucidi V, Manunza D, et al. An overview of international literature from cystic fibrosis registries. Part 3. Disease incidence, genotype/phenotype correlation, microbiology, pregnancy, clinical complications, lung transplantation, and miscellanea. Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society. 2011 Mar;10(2):71–85. doi: 10.1016/j.jcf.2010.12.005. [DOI] [PubMed] [Google Scholar]
  • 54.Farrell PM, Rosenstein BJ, White TB, Accurso FJ, Castellani C, Cutting GR, et al. Guidelines for diagnosis of cystic fibrosis in newborns through older adults: Cystic Fibrosis Foundation consensus report. The Journal of pediatrics. 2008 Aug;153(2):S4–S14. doi: 10.1016/j.jpeds.2008.05.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Noronha RM, Calliari LE, Damaceno N, Muramatu LH, Monte O. Update on diagnosis and monitoring of cystic fibrosis-related diabetes mellitus (CFRD) Arquivos brasileiros de endocrinologia e metabologia. 2011 Nov;55(8):613–621. doi: 10.1590/s0004-27302011000800016. [DOI] [PubMed] [Google Scholar]
  • 56.Waugh N, Royle P, Craigie I, Ho V, Pandit L, Ewings P, et al. Screening for cystic fibrosis-related diabetes: a systematic review. Health Technol Assess. 2012 May;16(24):iii–iv. 1–179. doi: 10.3310/hta16240. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Ooi CY, Dorfman R, Cipolli M, Gonska T, Castellani C, Keenan K, et al. Type of CFTR mutation determines risk of pancreatitis in patients with cystic fibrosis. Gastroenterology. 2011 Jan;140(1):153–161. doi: 10.1053/j.gastro.2010.09.046. [DOI] [PubMed] [Google Scholar]
  • 58.Rosendahl J, Landt O, Bernadova J, Kovacs P, Teich N, Bodeker H, et al. CFTR, SPINK1, CTRC and PRSS1 variants in chronic pancreatitis: is the role of mutated CFTR overestimated? Gut. 2012 Mar 17; doi: 10.1136/gutjnl-2011-300645. [DOI] [PubMed] [Google Scholar]
  • 59.Schneider A, Larusch J, Sun X, Aloe A, Lamb J, Hawes R, et al. Combined Bicarbonate Conductance-Impairing Variants in CFTR and SPINK1 Variants Are Associated With Chronic Pancreatitis in Patients Without Cystic Fibrosis. Gastroenterology. 2011 Jan;140(1):162–171. doi: 10.1053/j.gastro.2010.10.045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.Bertin C, Pelletier AL, Vullierme MP, Bienvenu T, Rebours V, Hentic O, et al. Pancreas Divisum Is Not a Cause of Pancreatitis by Itself But Acts as a Partner of Genetic Mutations. The American journal of gastroenterology. 2011 Dec 13;107(2):31–37. doi: 10.1038/ajg.2011.424. [DOI] [PubMed] [Google Scholar]
  • 61.Cutting GR, Kasch LM, Rosenstein BJ, Zielenski J, Tsui LC, Antonarakis SE, et al. A cluster of cystic fibrosis mutations in the first nucleotide-binding fold of the cystic fibrosis conductance regulator protein. Nature. 1990 Jul 26;346(6282):366–369. doi: 10.1038/346366a0. [DOI] [PubMed] [Google Scholar]
  • 62.Zielenski J, Tsui LC. Cystic fibrosis: genotypic and phenotypic variations. Annual Review of Genetics. 1995;29:777–807. doi: 10.1146/annurev.ge.29.120195.004021. (Ann Rev Genet) [DOI] [PubMed] [Google Scholar]
  • 63.Rowntree RK, Harris A. The phenotypic consequences of CFTR mutations. Ann Hum Genet. 2003;67(Pt 5):471–485. doi: 10.1046/j.1469-1809.2003.00028.x. [DOI] [PubMed] [Google Scholar]
  • 64.Amato F, Bellia C, Cardillo G, Castaldo G, Ciaccio M, Elce A, et al. Extensive molecular analysis of patients bearing CFTR-related disorders. The Journal of molecular diagnostics : JMD. 2012 Jan;14(1):81–89. doi: 10.1016/j.jmoldx.2011.09.001. [DOI] [PubMed] [Google Scholar]
  • 65.Van Goor F, Hadida S, Grootenhuis PD, Burton B, Stack JH, Straley KS, et al. Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809. Proceedings of the National Academy of Sciences of the United States of America. 2011 Nov 15;108(46):18843–18848. doi: 10.1073/pnas.1105787108. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 66.Wilschanski M, Miller LL, Shoseyov D, Blau H, Rivlin J, Aviram M, et al. Chronic ataluren (PTC124) treatment of nonsense mutation cystic fibrosis. Eur Respir J. 2011 Jul;38(1):59–69. doi: 10.1183/09031936.00120910. [DOI] [PubMed] [Google Scholar]
  • 67.Wilschanski M, Yahav Y, Yaacov Y, Blau H, Bentur L, Rivlin J, et al. Gentamicin-induced correction of CFTR function in patients with cystic fibrosis and CFTR stop mutations. The New England journal of medicine. 2003 Oct 9;349(15):1433–1441. doi: 10.1056/NEJMoa022170. [DOI] [PubMed] [Google Scholar]
  • 68.Dhar A, Goenka MK, Kochhar R, Nagi B, Bhasin DK, Singh K. Pancrease divisum: five years' experience in a teaching hospital. Indian J Gastroenterol. 1996 Jan;15(1):7–9. [PubMed] [Google Scholar]
  • 69.Delhaye M, Engelholm L, Cremer M. Pancreas divisum: congenital anatomic variant or anomaly? Contribution of endoscopic retrograde dorsal pancreatography. Gastroenterology. 1985 Nov;89(5):951–958. doi: 10.1016/0016-5085(85)90193-3. [DOI] [PubMed] [Google Scholar]
  • 70.Bertin C, Pelletier AL, Vullierme MP, Bienvenu T, Rebours V, Hentic O, et al. Pancreas divisum is not a cause of pancreatitis by itself but acts as a partner of genetic mutations. The American journal of gastroenterology. 2012 Feb;107(2):311–317. doi: 10.1038/ajg.2011.424. [DOI] [PubMed] [Google Scholar]
  • 71.Whitcomb DC, Ermentrout GB. A mathematical model of the pancreatic duct cell generating high bicarbonate concentrations in pancreatic juice. Pancreas. 2004;29(2):E30–E40. doi: 10.1097/00006676-200408000-00016. [DOI] [PubMed] [Google Scholar]

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