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


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.


CONCLUSIONS
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.
Derikx
Monique H M
MH
Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands.
Szmola
Richard
R
te Morsche
Rene H M
RH
Sunderasan
Santhosh
S
Chacko
Ashok
A
Drenth
Joost P H
JP
D000293:Adolescent; D000328:Adult; D002114:Calcinosis / Q000453:epidemiology / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D002919:Chymotrypsinogen / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D007194:India / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D050500:Pancreatitis, Chronic / Q000453:epidemiology / Q000235:genetics*; D012697:Serine Endopeptidases / Q000378:metabolism; D014359:Trypsin Inhibitor, Kazal Pancreatic; D014362:Trypsinogen / Q000235:genetics* / Q000502:physiology; D055815:Young Adult
D002352:Carrier Proteins; C486642:SPINK1 protein, human; C096020:chymotrypsinogen C; D014359:Trypsin Inhibitor, Kazal Pancreatic; D014362:Trypsinogen; D002919:Chymotrypsinogen; D012697:Serine Endopeptidases