Combined Bicarbonate Conductance-Impairing Variants in CFTR and SPINK1 Variants Are Associated With Chronic Pancreatitis in Patients Without Cystic Fibrosis
2011
Background & Aims Idiopathic chronic pancreatitis (ICP) is a complex
inflammatory disorderassociated with multiple genetic and environmental factors. In individuals without cystic fibrosis (CF), variants of CFTR that inhibit
bicarbonateconductance 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 inhibitorSPINK1 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
bicarbonatecurrents ( P = .0001). Conclusions The CFTR variant p.R75Q causes a selective defect in
bicarbonateconductance and increases risk of pancreatitis. Coinheritance of p.R75Q or CF causing CFTR variants with SPINK1 variants significantly increases the risk of ICP.
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