Scientists from Hyderbad-based Centre for Cellular and Molecular Biology (CCMB) have found the role of SPINK1 (serine protease inhibitor, kazal type 1; SPINK1) mutations in chronic pancreatitis.

A team of scientists at CCMB comprising Dr Chandak, MM Idris, KR Mani, S Bhaskar, Dr Lalji Singh came together with medical experts Dr DN Reddy and Dr GV Rao of The Asian Institute of Gastroenterology (Hyderabad), undertook a study on a large group of patients with hereditary pancreatitis (HP) and non-hereditary pancreatitis (alcoholic chronic pancreatitis (ACP) and ICP) to determine if PRSS1 and SPINK1 mutations are associated with chronic pancreatitis in India.

The patients were identified and investigated at the Asian Institute of Gastroenterology. In total, 198 patients (120 ICP, 41 ACP and 31 HP) and 24 unaffected relatives from HP families participated in the study. The Institutional Ethics Committee approved the study following the ICMR guidelines for research on human subjects. The samples were analysed at CCMB. Genomic DNA was isolated from leucocytes following standard protocols and initially all samples were screened for commonly reported mutations in PRSS1 gene. Subsequently, both PRSS1 and SPINK1 genes were sequenced in all the patients and controlled to screen for any novel mutations in these patients.

Mutations in the cationic trypsinogen (protease serine, 1 (trypsin 1); PRSS1) gene are known to be causally associated with recurrent acute and chronic pancreatitis. The team investigated whether mutations in the PRSS1 gene are associated with hereditary and non-hereditary pancreatitis. As a modifier role has been proposed for trypsin inhibitor (serine protease inhibitor, kazal type 1; SPINK 1) mutations, its role was also analysed in these patients.

Dr Giriraj Ratan Chandak, scientist and medical geneticist, CCMB, explained, the team found for the first time, the absence of PRSS1 mutations in Indian patients with chronic pancreatitis of different aetiologies, which confirm observations made previously in Indian TCP patients. This is most likely related to their genetic makeup as no other study from abroad has reported absence of PRSS1 mutations in hereditary as well as in non-hereditary chronic pancreatitis patients. Surprisingly, a simultaneous strong association with SPINK1 mutations, particularly N34S mutation was identified in all types of pancreatitis, albeit the strength of association differed.

Interaction with other factors, such as environmental and nutritional influences, may also play an important role and explain the variability. The study also suggested the possibility of phenomenon of racial specificity since the background prevalence of N34S SPINK1 mutation was varying from the earlier reported frequency from different populations in different countries.

CCMB study finding strongly suggests that irrespective of its aetiology, established mutations in PRSS1 are not a common cause of chronic pancreatitis in the Indian population. However, SPINK1 mutations were found to be strongly associated with all types of chronic pancreatitis. Most patients with a SPINK1 variation had N34S mutation and the prevalence was significantly higher in HP patients (with 73 per cent) compared with ICP patients (32.5 per cent) and ACP patients (26.8 per cent).

The genetic basis of chronic pancreatitis in India has rarely been explored and only a few studies had focused only on tropical calcific pancreatitis.

While Talking to Pharmabiz, Dr Chandak, said that about one third of patients are classified with idiopathic chronic pancreatitis (ICP) as no association with any of the above aetiological factors can be established.

Dr Chandak informed, CCMB has tied up with hospitals and medical colleges at Pune, Sri Nagar, Kolkata, Cochin, Chennai and Ahmedabad to study the patients in the respective states. The team actually started the study during end of 2000.

The findings of the recent study can pave way towards genetic screening for susceptibility for development of the disease. It is estimated that 1.5 per cent to 4 per cent of our population can be affected by chronic pancreatitis in India and is usually seen in the people who are in second and third decades. However, Tropical Calcific Pancreatitis and fibrocalculous pancreatic diabetes can occur in children of 2-3 years of age, he added.

The team is also planning to hunt for other genes which may explain the susceptibility in the remaining percentage of patients, compare pancreatic tissues that are affected verses those not affected, study mechanism of causation of the disease and possibility of developing stem cells. CCMB is associated with various hospitals to study the genetic basis of chronic pancreatitis as well as diabetes mellitus. The team is also focusing its studies on various complex diseases like cardiovascular diseases, bronchial asthma which are of common occurrence and much more common than the single gene disorders, he revealed. His group is already providing molecular diagnosis, susceptibility screening, carrier analysis, prenatal diagnosis and genetic counselling for more than 2 dozen genetic disorders and he hopes to add these common disorders to the ever-growing list of genetic disorders.

The clinical pattern of chronic pancreatitis is characterized by an early stage with recurrent episodes of acute pancreatitis (AP) followed by a late stage with pancreatic calcifications, pancreatic insufficiency and diabetes mellitus in the majority of patients, Dr Chandak said.