Combined bicarbonate conductance-impairing variants in CFTR and SPINK1 variants are associated with chronic pancreatitis in patients without cystic fibrosis.
OBJECTIVE
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 HCO(3)(-) 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.
Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Alexander
A
Schneider
Jessica
J
Larusch
Xiumei
X
Sun
Amy
A
Aloe
Janette
J
Lamb
Robert
R
Hawes
Peter
P
Cotton
Randall E
RE
Brand
Michelle A
MA
Anderson
Mary E
ME
Money
Peter A
PA
Banks
Michele D
MD
Lewis
John
J
Baillie
Stuart
S
Sherman
James
J
Disario
Frank R
FR
Burton
Timothy B
TB
Gardner
Stephen T
ST
Amann
Andres
A
Gelrud
Ryan
R
George
Matthew J
MJ
Rockacy
Sirvart
S
Kassabian
Jeremy
J
Martinson
Adam
A
Slivka
Dhiraj
D
Yadav
Nevin
N
Oruc
M Michael
MM
Barmada
Raymond
R
Frizzell
David C
DC
Whitcomb
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D001639:Bicarbonates / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D027963:Chloride-Bicarbonate Antiporters / Q000235:genetics; D015331:Cohort Studies; D003550:Cystic Fibrosis / Q000235:genetics*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D050500:Pancreatitis, Chronic / Q000235:genetics*; D014359:Trypsin Inhibitor, Kazal Pancreatic; D055815:Young Adult
D001639:Bicarbonates; D002352:Carrier Proteins; D027963:Chloride-Bicarbonate Antiporters; C486642:SPINK1 protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D014359:Trypsin Inhibitor, Kazal Pancreatic