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 with ICP (sporadic or familial) and controls for variants in SPINK1 associated with chronic pancreatitis (CP) risk (in exon 3) and in all 27 exons of CFTR. The final study group included 53 patients with sporadic ICP, 27 probands with familial ICP, and 150 unrelated controls, plus 503 controls for limited genotyping. CFTR wild-type (wt) 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% controls (odds ratio [OR]=16.5). One variant of CFTR that has not been associated with CF, p.R75Q, was found in 16% of subjects and 5.4% controls (OR=3.4). Co-inheritance of CFTR p.R75Q and SPINK1 variants occurred in 8.75% of patients and 0.15% controls (OR=62.5). Patch-clamp recordings of cells that expressed CFTR p.R75Q demonstrated normal chloride currents but significantly reduced bicarbonate currents (P=0.0001). Conclusions The CFTR variant p.R75Q causes a selective defect in bicarbonate conductance and increases risk for pancreatitis. Co-inheritance of CF-associated, and some not associated, CFTR variants with SPINK1 variants significantly increase risk of ICP.

The Cystic Fibrosis of Exocrine Pancreas

“…In a recent publication, Schneider et al (2011) investigated a large group of patients with "idiopathic" chronic pancreatitis and confirmed other studies that the combination of CFTR and serine protease inhibitor Kazaltype 1 (SPINK1) mutations markedly increase the risk of pancreatitis. However, a novel finding was that the variant R75Q of CFTR increases the risk of pancreatitis markedly.…”

Hereditary Pancreatic Cancer

“…Individuals who carry only one allelic mutation of the CFTR gene still are at an increased risk of chronic pancreatitis three-to fourfold over the general population. Those individuals with heterozygous CFTR mutations typically have coexisting germline mutations in either SPINK1 or CTRC [38]. The CTRC gene carries a risk for chronic pancreatitis but usually in conjunction in individuals with mutations in either CFTR or SPINK1 [39].…”

Targeted mutation screening panels expose systematic population bias in detection of cystic fibrosis risk

“…However, group 2 variants can cause CFTR-related symptoms when present in trans in a group 1 variant in a compound heterozygous genotype. 4,5,[22][23][24][25][26] The partial damaging effects of group 2 variants on the CFTR gene product have been demonstrated in functional and biochemical analyses.…”