4Genetic factors in chronic pancreatitis; implications for diagnosis, management and prognosis
Introduction
This review aims to give an overview of the genes and mutations that play a role in the pathogenesis of chronic pancreatitis (CP). It has become clear over the past several years that the molecular underpinnings of CP are driven by genetic mutations in the trypsin enzyme cascade. Indeed, the elucidation of genes that are associated with CP has greatly improved our understanding of the disease. This review will provide insight in the historical background that comes with the discovery of these genetic mutations. In addition we will discuss how these genetic mutations contribute to the pathogenesis of the various forms of CP, and lastly we aim to delineate some of the implications these discoveries have for current clinical practise. The mutations will be discussed in context of the different subtypes of CP such as alcoholic (ACP), idiopathic (ICP), hereditary (HCP) and tropical (TCP) CP.
Section snippets
How are genes discovered
The genes involved in CP have been discovered through a mix of genetic approaches. The PRSS1 gene, that has been linked to HCP, was discovered by classical forward genetic linkage analysis. This approach is hypothesis free and assumes no prior knowledge on the pathogenesis of the disease. Here linkage analysis with polymorphic markers is used to detect linkage between markers and a disease locus within a family. Once a locus has been detected, sequencing of the genes from the linked interval is
Historical background
More than a century ago, it was Dr. Chiari who postulated in 1896 that pancreatitis is caused by premature activated trypsin resulting in autodigestion of the pancreas.
An important observation, 65 years later, that contributed to the discovery of the HCP gene was the finding that the disease clustered in families in an autosomal dominant fashion [1]. Indeed, in 1996, the genetic locus for HCP was identified on chromosome 7q35 in a large family [2], and this finding was confirmed in other
Pancreatitis subtypes and their genes
In this section we will outline the different subtypes of CP and the mutations that are the most important in their aetiology (Textbox 1).
Implications for diagnosis, management and prognosis
Diagnosing CP, especially just after the onset of the disease, is a very difficult task. The diagnosis is often made only several years after the first pancreatitis attack when functional and structural abnormalities of the pancreas surface and are detected with laboratory studies and imaging.
But what about genetic testing? Until now genetic testing in CP patients is not part of any standard diagnostic procedure, with the possible exception of PRSS1 mutations in HCP cases.
The presence of a
Summary
We have shown that a variety of genetic variations in genes that are implicated in the trypsin pathway are responsible for a large proportion of HCP, TCP and ICP cases. Apart from genes such as PRSS1, SPINK1, CTRC that have been consistently linked to various CP categories, CFTR is a gene that underlies a significant proportion of ICP, but also ACP patients. Other genes have yielded inconsistent results or are only responsible for a subset of CP patients. The first genes that have been
Conflict of interest
None
Acknowledgement
The authors would like to thank Dr. Richard Szmola for his help and suggestions, especially with the figures. Further they would like to thank Dr. Aura van Esch for her critical appraisal, her suggestions and comments on this review.
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Meta-analysis of the impact of SPINK1 p.N34S gene variation in Caucasic patients with chronic pancreatitis. An update
2017, Digestive and Liver DiseaseCitation Excerpt :Chronic pancreatitis is an irreversible and progressive pancreatic inflammation characterized by replacement of exocrine and endocrine pancreatic tissue with fibrotic tissue, resulting in loss of endocrine and exocrine functions [1]. Chronic pancreatitis is a complex trait resulting from a combination of both endogenous and environmental factors (alcohol and smoking habits) and their interaction with multiple genes [2]. Complex traits depend on multiple genetic and environmental factors interacting with each other to leave an individual more or less susceptible to the disease.
Investigation at the micrometer scale of pancreatic calcifications in chronic pancreatitis by μFTIR spectroscopy and field emission scanning electron microscopy
2016, Comptes Rendus ChimieCitation Excerpt :Although they are usually diagnosed earlier than toxic chronic pancreatitis (alcohol related for instance), there is no specific clinical sign and fastidious sequencing of multiple genes is required when the diagnosis is suspected. PRSS1, SPINK1, and CFTR to some extent are the most frequently mutated genes in hereditary pancreatitis [34]. The PRSS1 gene encodes the cationic trypsinogen that represents 2/3 of the total trypsinogen in the pancreatic juice.
SPINK1 mutation in a pediatric patient with chronic pancreatitis: A case report
2015, Revista de Gastroenterologia de MexicoAnalysis of risk factors for pancreatic duct stones formation in patients with alcoholic chronic pancreatitis
2014, PancreatologyCitation Excerpt :ACP has been identified as a multi-factorial disease, where developmental, dietary, and environmental factors interact with the genetic profile of the individual [17]. Genetic contributions have been of special interest since the discovery that rare PRSS1, CFTR, and SPINK1 variants were associated with pancreatitis risk [18]. Recently, key findings, including the relationship between pancreas divisum and CFTR mutations, and the discovery of a pancreatitis modifier gene on the X chromosome, provided new clues to why the vast majority of patients with alcoholic pancreatitis were men [19].
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2013, Gastroenterologia y Hepatologia