6.1　Genetic Disorders

The mutations of the cystic fibrosis transmembrane conductance regulator-gene（CFTR-gene）（Rommens et al.1989）and the identification of mutations of the cationic trypsinogen gene（protease-serine-1 gene，PRSS-1）（Whitcomb et al.1996），the serine protease inhibitor and Kazal type 1 gene（SPINK-1）（Witt et al.2000），has led to identifying the role of the familial/hereditary factors in the development of chronic pancreatitis in Western countries.Furthermore，also in tropical pancreatitis it has been noted that this disease is highly associated with the SPINK-1 N34S mutation（Bhatia et al.2002；Schneider et al.2002）whereas the frequency of CFTR mutations was lower than in white subjects（Bhatia et al.2000）.It is well-known that PRSS 1 mutations are able to induce chronic pancreatitis and the same does not happen for CFTR and SPINK-1 mutations；thus the latter two genes seem to be modifiers able to induce chronic pancreatitis only when other risk factors such as alcohol are present（Schneider et al.2002；Pezzilli et al.2003）.

Another mutation which seems to be related to chronic pancreatitis is the chymotrypsinogen C（CTRC）mutation；the gene protects the pancreas by prematurely degrading activated trypsinogen，and rare mutations are associated with CP in Europe and Asia（LaRusch et al.2015）.(https://www.daowen.com)

Finally，the regulation of calcium levels（intraacinar）is critical for preventing trypsinogen activation and pancreatic injury，and the calcium-sensing receptor gene（CASR）plays a major role in maintaining the calcium homeostasis by means of its effect on the renal tubules and the parathyroid gland.The first report on CASR gene mutations and chronic pancreatitis is that regarding a family comprising five individuals who were all heterozygous for the N34S SPINK1 polymorphism.Two of these five heterozygous individuals developed chronic pancreatitis and both these individuals presented with a T＞C mutation at position 518 in the CASR gene，which is a leucine to proline amino acid change in the extracellular domain of the CASR protein（Felderbauer et al.2003）；this suggests that CASR mutations may be a predisposing genetic factor which increases susceptibility for chronic pancreatitis.

Hereditary chronic pancreatitis is highly related to the development of cancer and the risk of developing pancreatic cancer in these subjects appears to be highest in those patients who have an early onset of hereditary chronic pancreatitis（Raimondi et al.2010）.