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Eur J Gastroenterol Hepatol. 2009 Aug;21(8):889-94. doi: 10.1097/MEG.0b013e32832183cf.

Tropical calcific pancreatitis and its association with CTRC and SPINK1 (p.N34S) variants.

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1
Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands.

Abstract

BACKGROUND:

Tropical calcific pancreatitis (TCP) is a relatively common form of chronic pancreatitis in parts of Asia and Africa. The SPINK1 variant p.N34S is strongly associated with TCP, but other genetic factors remain to be defined. Chymotrypsinogen C (CTRC) degrades trypsinogen and loss-of-function variants have been found in European patients with chronic pancreatitis. Preliminary data indicate that CTRC might increase the risk for TCP.

MATERIALS AND METHODS:

We selected 150 Indian TCP patients and 150 Indian controls to perform mutational screening of the complete coding region of CTRC and exon 3 of SPINK1. We performed in-silico analysis and functional studies of novel CTRC variants.

RESULTS:

We identified eight variants among this sample. Three were synonymous and c.180 C>T was significantly enriched in patients (odds ratio=2.09; 95% confidence interval=1.19-3.67; P=0.03). We identified a novel nonsynonymous CTRC (p.G61R) variant in one of 146 patients (0.7%), but absent from controls. In-silico analysis showed that this variant affected a conserved residue, and functional analysis showed that p.G61R results in a complete loss of CTRC secretion from transiently transfected human embryonic kidney 293T cells. SPINK1 p.N34S was present in 31.8% of patients compared with 4.7% in controls, there was no significant cosegregation with CTRC variants.

CONCLUSION:

The contribution of CTRC variants to TCP is relatively small, but the identification of novel loss-of-function variants (p.G61R) underscores the importance of the trypsinogen pathway in causing TCP.

PMID:
19404200
DOI:
10.1097/MEG.0b013e32832183cf
[Indexed for MEDLINE]
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