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 George & 9 others Matthew 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

74 Citations (Scopus)

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

Fingerprint

Chronic Pancreatitis
Bicarbonates
Cystic Fibrosis
Pancreatitis
Odds Ratio
Chlorides
Kazal Pancreatic Trypsin Inhibitor
Pancreatic Juice
HEK293 Cells
Trypsin
Exons
Genes

Keywords

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

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Combined bicarbonate conductance-impairing variants in CFTR and SPINK1 variants are associated with chronic pancreatitis in patients without cystic fibrosis. / Schneider, Alexander; Larusch, Jessica; Sun, Xiumei; Aloe, Amy; Lamb, Janette; Hawes, Robert; Cotton, Peter; Brand, Randall E.; Anderson, Michelle A.; Money, Mary E.; Banks, Peter A.; Lewis, Michele D.; Baillie, John; Sherman, Stuart; Disario, James; Burton, Frank R.; Gardner, Timothy B.; Amann, Stephen T.; Gelrud, Andres; George, Ryan; Rockacy, Matthew J.; Kassabian, Sirvart; Martinson, Jeremy; Slivka, Adam; Yadav, Dhiraj; Oruc, Nevin; Barmada, M. Michael; Frizzell, Raymond; Whitcomb, David C.

In: Gastroenterology, Vol. 140, No. 1, 01.2011, p. 162-171.

Research output: Contribution to journalArticle

Schneider, A, Larusch, J, Sun, X, Aloe, A, Lamb, J, Hawes, R, Cotton, P, Brand, RE, Anderson, MA, Money, ME, Banks, PA, Lewis, MD, Baillie, J, Sherman, S, Disario, J, Burton, FR, Gardner, TB, Amann, ST, Gelrud, A, George, R, Rockacy, MJ, Kassabian, S, Martinson, J, Slivka, A, Yadav, D, Oruc, N, Barmada, MM, Frizzell, R & Whitcomb, DC 2011, 'Combined bicarbonate conductance-impairing variants in CFTR and SPINK1 variants are associated with chronic pancreatitis in patients without cystic fibrosis', Gastroenterology, vol. 140, no. 1, pp. 162-171. https://doi.org/10.1053/j.gastro.2010.10.045
Schneider, Alexander ; Larusch, Jessica ; Sun, Xiumei ; Aloe, Amy ; Lamb, Janette ; Hawes, Robert ; Cotton, Peter ; Brand, Randall E. ; Anderson, Michelle A. ; Money, Mary E. ; Banks, Peter A. ; Lewis, Michele D. ; Baillie, John ; Sherman, Stuart ; Disario, James ; Burton, Frank R. ; Gardner, Timothy B. ; Amann, Stephen T. ; Gelrud, Andres ; George, Ryan ; Rockacy, Matthew J. ; Kassabian, Sirvart ; Martinson, Jeremy ; Slivka, Adam ; Yadav, Dhiraj ; Oruc, Nevin ; Barmada, M. Michael ; Frizzell, Raymond ; Whitcomb, David C. / Combined bicarbonate conductance-impairing variants in CFTR and SPINK1 variants are associated with chronic pancreatitis in patients without cystic fibrosis. In: Gastroenterology. 2011 ; Vol. 140, No. 1. pp. 162-171.
@article{76557027f6ba449f8b9d1674b3e5a4cf,
title = "Combined bicarbonate conductance-impairing variants in CFTR and SPINK1 variants are associated with chronic pancreatitis in patients without cystic fibrosis",
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.",
keywords = "NAPS2, Pancreas, Patch-Clamp; Epistasis, Polygenic, Risk Factor",
author = "Alexander Schneider and Jessica Larusch and Xiumei Sun and Amy Aloe and Janette Lamb and Robert Hawes and Peter Cotton and Brand, {Randall E.} and Anderson, {Michelle A.} and Money, {Mary E.} and Banks, {Peter A.} and Lewis, {Michele D.} and John Baillie and Stuart Sherman and James Disario and Burton, {Frank R.} and Gardner, {Timothy B.} and Amann, {Stephen T.} and Andres Gelrud and Ryan George and Rockacy, {Matthew J.} and Sirvart Kassabian and Jeremy Martinson and Adam Slivka and Dhiraj Yadav and Nevin Oruc and Barmada, {M. Michael} and Raymond Frizzell and Whitcomb, {David C.}",
year = "2011",
month = "1",
doi = "10.1053/j.gastro.2010.10.045",
language = "English",
volume = "140",
pages = "162--171",
journal = "Gastroenterology",
issn = "0016-5085",
publisher = "W.B. Saunders Ltd",
number = "1",

}

TY - JOUR

T1 - Combined bicarbonate conductance-impairing variants in CFTR and SPINK1 variants are associated with chronic pancreatitis in patients without cystic fibrosis

AU - Schneider, Alexander

AU - Larusch, Jessica

AU - Sun, Xiumei

AU - Aloe, Amy

AU - Lamb, Janette

AU - Hawes, Robert

AU - Cotton, Peter

AU - Brand, Randall E.

AU - Anderson, Michelle A.

AU - Money, Mary E.

AU - Banks, Peter A.

AU - Lewis, Michele D.

AU - Baillie, John

AU - Sherman, Stuart

AU - Disario, James

AU - Burton, Frank R.

AU - Gardner, Timothy B.

AU - Amann, Stephen T.

AU - Gelrud, Andres

AU - George, Ryan

AU - Rockacy, Matthew J.

AU - Kassabian, Sirvart

AU - Martinson, Jeremy

AU - Slivka, Adam

AU - Yadav, Dhiraj

AU - Oruc, Nevin

AU - Barmada, M. Michael

AU - Frizzell, Raymond

AU - Whitcomb, David C.

PY - 2011/1

Y1 - 2011/1

N2 - 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.

AB - 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.

KW - NAPS2

KW - Pancreas

KW - Patch-Clamp; Epistasis

KW - Polygenic

KW - Risk Factor

UR - http://www.scopus.com/inward/record.url?scp=78650425789&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78650425789&partnerID=8YFLogxK

U2 - 10.1053/j.gastro.2010.10.045

DO - 10.1053/j.gastro.2010.10.045

M3 - Article

VL - 140

SP - 162

EP - 171

JO - Gastroenterology

JF - Gastroenterology

SN - 0016-5085

IS - 1

ER -