Gastroenterology

Gastroenterology

Volume 123, Issue 4, October 2002, Pages 1026-1030
Gastroenterology

Clinical–Liver, Pancreas, and Biliary Tract
SPINK1/PSTI mutations are associated with tropical pancreatitis and type II diabetes mellitus in Bangladesh,☆☆,

https://doi.org/10.1053/gast.2002.36059Get rights and content

Abstract

Background & Aims: Tropical pancreatitis, including tropical calcific pancreatitis and fibrocalculous pancreatic diabetes, is endemic in parts of Asia and Africa. In a preliminary study, we found serine protease inhibitor, Kazal type 1 (SPINK1) mutations in 6 of 8 patients with fibrocalculous pancreatic diabetes in Bangladesh. A more extensive investigation of patients with pancreatic diseases in Bangladesh, including non–insulin-dependent diabetes mellitus, was undertaken. Methods: Patients with fibrocalculous pancreatic diabetes (n = 22), tropical calcific pancreatitis (n = 15), and non–insulin-dependent diabetes mellitus (n = 43) and controls (n = 76) from Bangladesh were studied. DNA was extracted, and the SPINK1 gene was sequenced in all patients and 50 controls. Exon 3 was sequenced in an additional 26 controls. Results: SPINK1 N34S mutations appeared in 1 of 76 controls (1.3%), 12 of 22 patients with fibrocalculous pancreatic diabetes (55%; odds ratio, 83; P < 0.00001), 3 of 15 with tropical calcific pancreatitis (20%; odds ratio, 11.2; P = 0.04), and 6 of 43 with non–insulin-dependent diabetes mellitus (14%; odds ratio, 11.9; P = 0.009). P55S was present in 2 of 76 controls (3%) and in 1 of 22 patients with fibrocalculous pancreatic diabetes (5%; P = not significant). A novel Y54H (160T>C) mutation was identified in 1 of 15 tropical calcific pancreatitis patients. Conclusions: In Bangladesh, the SPINK1 N34S mutation increases the risk of several forms of pancreatic disease, including fibrocalculous pancreatic diabetes, tropical calcific pancreatitis, and non–insulin-dependent diabetes mellitus.

GASTROENTEROLOGY 2002;123:1026-1030

Section snippets

Patients

Patients younger than 40 years of age with a new diagnosis of type II diabetes mellitus between 1996 and 1997 were prospectively selected from the outpatient department of the Bangladesh Institute of Research and Rehabilitation in Diabetes, Endocrine and Metabolic Disorders, a large World Health Organization (WHO) collaborating center in Dhaka, Bangladesh, for the prevention and control of diabetes. All patients underwent a history, physical examination, and oral glucose tolerance test as

Results

The clinical characterization of the patients and controls showed the typical features of patients with FCPD, TCP, and NIDDM and of healthy controls. The primary laboratory findings are summarized in Table 1.

The entire SPINK1 gene and flanking intronic regions were successfully sequenced in all patients and 50 controls. Exon 3 was also successfully sequenced in 26 additional controls. Heterozygous N34S mutations were identified in 1 of 76 controls and 13 of 37 TP patients (11/22 in FCPD

Discussion

SPINK1 serves as an important and specific inhibitor of active trypsin. The role of SPINK1 N34S mutations in predisposing children to pancreatitis was first shown by Witt et al.12 and in familial pancreatitis by Pfützer et al.13 However, the genetics proved complex with pancreatitis seen with both homozygous and heterozygous disease-associated genotypes, even though far less than 1% of N34S carriers express a pancreatitis phenotype.13, 20, 21 Surprisingly, N34S is present in >1% of populations

Acknowledgements

The authors thank all colleagues and staff at the Bangladesh Institute of Research and Rehabilitation in Diabetes, Endocrine and Metabolic Disorders and the Institute of Postgraduate Medicine and Research. Special thanks to Muhmud Hasan, Faruque Pathan, Hassan Ali, Sayeedul Hassan, Nani Gopal Banik, Zafar A. Latif, Tofail Ahmed, M. Anisur Rahman, M. Sumsul Arefin, M. Sawkat Hassan, Motior Rahman, Humayun Kabir Choudhary, Begum Rokeya, Quamrum Nahar, and Shane Ara Begum. The authors also thank

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    A. Schneider, A. Suman, and L. Rossi contributed equally to this work. N. Gyr and D. C. Whitcomb co-directed this project.

    ☆☆

    Address requests for reprints to: David C. Whitcomb, M.D., Ph.D., University of Pittsburgh, Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Room 571, Scaife Hall, 3550 Terrace Street, Pittsburgh, Pennsylvania 15261. e-mail: [email protected]; fax: (412) 383-7236.

    Supported by the Stanley Thomas Johnson Foundation, Berne, Switzerland; the Novartis and Roche Research Foundations; the Freiwillige Akademische Gesellschaft, Basel, Switzerland; and United States National Institutes of Health grant DK54709 (to D.C.W.); Dr Schneider was supported by the University of Heidelberg.

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