Combined bicarbonate conductance-impairing variants in CFTR and SPINK1 variants are associated with chronic pancreatitis in patients without cystic fibrosis

Alexander Schneider, Jessica Larusch, Xiumei Sun, Amy Aloe, Janette Lamb, Robert Hawes, Peter Cotton, Randall E. Brand, Michelle A. Anderson, Mary E. Money, Peter A. Banks, Michele D. Lewis, John Baillie, Stuart Sherman, James Disario, Frank R. Burton, Timothy B. Gardner, Stephen T. Amann, Andres Gelrud, Ryan GeorgeMatthew J. Rockacy, Sirvart Kassabian, Jeremy Martinson, Adam Slivka, Dhiraj Yadav, Nevin Oruc, M. Michael Barmada, Raymond Frizzell, David C. Whitcomb

Research output: Contribution to journalArticle

80 Scopus citations

Abstract

Background & Aims: Idiopathic chronic pancreatitis (ICP) is a complex inflammatory disorder associated with multiple genetic and environmental factors. In individuals without cystic fibrosis (CF), variants of CFTR that inhibit bicarbonate conductance but maintain chloride conductance might selectively impair secretion of pancreatic juice, leading to trypsin activation and pancreatitis. We investigated whether sequence variants in the gene encoding the pancreatic secretory trypsin inhibitor SPINK1 further increase the risk of pancreatitis in these patients. Methods: We screened patients and controls for variants in SPINK1 associated with risk of chronic pancreatitis and in all 27 exons of CFTR. The final study group included 53 patients with sporadic ICP, 27 probands with familial ICP, 150 unrelated controls, 375 additional controls for limited genotyping. CFTR wild-type and p.R75Q were cloned and expressed in HEK293 cells, and relative conductances of HCO3 and Cl were measured. Results: SPINK1 variants were identified in 36% of subjects and 3% of controls (odds ratio [OR], 18.1). One variant of CFTR not associated with CF, p.R75Q, was found in 16% of subjects and 5.3% of controls (OR, 3.4). Coinheritance of CFTR p.R75Q and SPINK1 variants occurred in 8.75% of patients and 0.38% of controls (OR, 25.1). Patch-clamp recordings of cells that expressed CFTR p.R75Q showed normal chloride currents but significantly reduced bicarbonate currents (P = .0001). Conclusions: The CFTR variant p.R75Q causes a selective defect in bicarbonate conductance and increases risk of pancreatitis. Coinheritance of p.R75Q or CF causing CFTR variants with SPINK1 variants significantly increases the risk of ICP.

Original languageEnglish (US)
Pages (from-to)162-171
Number of pages10
JournalGastroenterology
Volume140
Issue number1
DOIs
StatePublished - Jan 2011

    Fingerprint

Keywords

  • NAPS2
  • Pancreas
  • Patch-Clamp; Epistasis
  • Polygenic
  • Risk Factor

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Schneider, A., Larusch, J., Sun, X., Aloe, A., Lamb, J., Hawes, R., Cotton, P., Brand, R. E., Anderson, M. A., Money, M. E., Banks, P. A., Lewis, M. D., Baillie, J., Sherman, S., Disario, J., Burton, F. R., Gardner, T. B., Amann, S. T., Gelrud, A., ... Whitcomb, D. C. (2011). Combined bicarbonate conductance-impairing variants in CFTR and SPINK1 variants are associated with chronic pancreatitis in patients without cystic fibrosis. Gastroenterology, 140(1), 162-171. https://doi.org/10.1053/j.gastro.2010.10.045