High Prevalence of Serine Protease Inhibitor Kazal Type 1 Gene Variations Detected by Whole Gene Sequencing in Patients with Fibrocalculous Pancreatic Diabetes.

AIM OF STUDY: The aim is to study the prevalence and pattern of serine protease inhibitor Kazal type 1 (SPINK1) gene variations in patients with fibrocalculous pancreatic diabetes (FCPD) using whole gene sequencing.

MATERIALS AND METHODS: A total of 56 consecutive patients of FCPD were recruited for the study. Diagnosis of FCPD was based on the presence of diabetes mellitus in patients having chronic pancreatitis with radiological evidence of ductal calcifications, in the absence of other known causes for pancreatitis. Ethylenediaminetetraacetic acid samples were collected from all patients, and complete gene sequencing was performed for SPINK1 gene using Sanger technique.

RESULTS: Overall 35 patients (62.5%) were detected to have genetic alterations in SPINK1 gene. N34S polymorphism was seen in 23 participants (41.07%) out of which 3 were homozygous. N34S was seen to be in linkage disequilibrium with IVS1 - 37T>C (18/23) and IVS3-69insAAAA (19/23) polymorphisms. Seven patients (12.5%) had a 272 C>T 3'UTR polymorphism while one patient (1.8%) had a P55S polymorphism. Two patients (3.5%) had an IVS3 + 2T>C mutation which has been shown to be associated with loss of function of SPINK protein. Overall 48.2% of FCPD patients had genetic variations that were significant compared to the control population. There was no difference in anthropometric and biochemical parameters between those with or without SPINK1 gene variations.

CONCLUSIONS: Variations in SPINK1 gene are frequently observed in FCPD. N34S polymorphism was the most common variation followed by intronic variations. Two patients had the pathogenic intronic IVS3 + 2T>C mutation. Whole gene sequencing of the SPINK1 gene enabled detection of an additional 7.1% of patients with significant SPINK1 gene variations as compared to targeted screening for the N34S variation.