Bicarbonate defective CFTR variants increase risk for chronic pancreatitis: A meta-analysis

Abstract

Introduction Cystic fibrosis transmembrane conductance regulator (CFTR) plays a central role in pancreatic ductal fluid secretion by mediating Cl- and HCO3- ion transport across the apical membrane. Severe CFTR mutations that diminish chloride conductance cause cystic fibrosis (CF) if both alleles are affected, whereas heterozygous carrier status increases risk for chronic pancreatitis (CP). It has been proposed that a subset of CFTR variants characterized by a selective bicarbonate conductance defect (CFTRBD) may be associated with CP but not CF. However, a rigorous genetic analysis of the presumed association has been lacking. Aims To investigate the role of heterozygous CFTRBD variants in CP by meta-analysis of published case-control studies. Materials and methods A systematic search was conducted in the MEDLINE, Embase, Scopus, and CENTRAL databases for published studies that reported the CFTRBD variants p.R74Q, p.R75Q, p.R117H, p.R170H, p.L967S, p.L997F, p.D1152H, p.S1235R, and p.D1270N in CP patients and controls. Results Twenty-two studies were eligible for quantitative synthesis. Combined analysis of the 9 CFTRBD variants indicated enrichment in CP patients versus controls (OR = 2.31, 95% CI = 1.17–4.56). Individual analysis of CFTRBD variants revealed no association of p.R75Q with CP (OR = 1.12, 95% CI = 0.89–1.40), whereas variants p.R117H and p.L967S were significantly overrepresented in cases relative to controls (OR = 3.16, 95% CI = 1.94–5.14, and OR = 3.88, 95% CI = 1.32–11.47, respectively). The remaining 6 low-frequency variants gave inconclusive results when analyzed individually, however, their pooled analysis indicated association with CP (OR = 2.08, 95% CI = 1.38–3.13). Conclusion Heterozygous CFTRBD variants, with the exception of p.R75Q, increase CP risk about 2-4-fold.

A De Novo CaSR Missense Variant in Combination with Two Inherited Missense Variants in CFTR and SPINK1 Detected in a Patient with Chronic Pancreatitis

“…In particular, p.Arg117His and p.Leu967Ser were significantly overrepresented in cases relative to controls, whereas p.Arg74Gln, p.Arg75Gln, p.Arg170His, p.Asp1152His, p.Ser1235Arg, p.Asp1270Asn and p.Leu997Phe were not found to be in statistically significant association with chronic pancreatitis when analyzed individually, due to their relatively rare occurrence. However, although their pooled analysis indicated a modest association, Berke and colleagues state that the effect of the individual variants cannot be determined with confidence until more data becomes available [ 19 ]. Indeed, despite the fact that the homozygosity for p.Leu997Phe does not give rise to any clinical symptoms, if it is present in compound heterozygosity with another known pathogenic variant, it may contribute to the appearance of CFTR-related pathologies (CFTR2 database: (accessed on 2 May 2021)).…”

Exploring the key genetic association between chronic pancreatitis and pancreatic ductal adenocarcinoma through integrated bioinformatics

“…This is a key link in the transportation of nutrients and trace elements. It has been demonstrated that CFTR dysfunction significantly increases the risk of CP ( Berke et al, 2022 ; Phadke and Sellers, 2022 ). Meanwhile, mutations in CFTR are associated with a modest increase in risk for PDAC ( McWilliams et al, 2010 ; Hennig et al, 2019 ).…”

Pancreatic Diseases: Genetics and Modeling Using Human Pluripotent Stem Cells

“…Studies have shown that the CFTR p.Arg75Gln variant increases the risk of CP but not the risk of CF by decreasing permeability of HCO3 − without compromising Cl − transport, especially when it occurs together with the SPINK1 p.Asn34Ser mutation (91,98). However, CFTR p.Arg75Gln mutation alone is not sufficient to cause CP (99).…”