Functional significance of SPINK1 promoter variants in chronic pancreatitis

American Journal of Physiology. Gastrointestinal and Liver Physiology
Monique H M DerikxMiklós Sahin-Tóth

Abstract

Chronic pancreatitis is a progressive inflammatory disorder of the pancreas, which often develops as a result of genetic predisposition. Some of the most frequently identified risk factors affect the serine protease inhibitor Kazal type 1 (SPINK1) gene, which encodes a trypsin inhibitor responsible for protecting the pancreas from premature trypsinogen activation. Recent genetic and functional studies indicated that promoter variants in the SPINK1 gene might contribute to disease risk in carriers. Here, we investigated the functional effects of 17 SPINK1 promoter variants using luciferase reporter gene expression assay in four different cell lines, including three pancreatic acinar cell lines (rat AR42J with or without dexamethasone-induced differentiation and mouse 266-6) and human embryonic kidney 293T cells. We found that most variants caused relatively small changes in promoter activity. Surprisingly, however, we observed significant variations in the effects of the promoter variants in the different cell lines. Only four variants exhibited consistently reduced promoter activity in all acinar cell lines, confirming previous reports that variants c.-108G>T, c.-142T>C, and c.-147A>G are risk factors for chronic pancreatitis a...Continue Reading

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Citations

Nov 1, 2018·Endocrinology·Giselle Dominguez GutierrezYurong Xin
Jun 25, 2016·Current Opinion in Gastroenterology·Walter G Park
May 26, 2017·Digestive Diseases and Sciences·Eszter Hegyi, Miklós Sahin-Tóth
Feb 14, 2019·Human Genomics·Xin-Ying TangJian-Min Chen
Jan 21, 2019·Gastroenterology·Julia MayerleMiklós Sahin-Tóth
Sep 20, 2020·Pancreatology : Official Journal of the International Association of Pancreatology (IAP) ... [et Al.]·Emmanuelle GirodonThierry Bienvenu

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