Association of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Mutation/Variant/Haplotype and Tumor Necrosis Factor (TNF) Promoter Polymorphism in Hyperlipidemic Pancreatitis

Abstract

Background: The mechanism by which hypertriglyceridemia (HTG) leads to pancreatitis is not clear. We sought to determine whether the genes involved in pancreatic ductal or acinar cell injury, including the cationic trypsinogen gene [protease, serine, 1 (trypsin 1) (PRSS1)], the pancreatic secretory trypsin inhibitor gene [serine peptidase inhibitor, Kazal type 1 (SPINK1)], the cystic fibrosis transmembrane conductance regulator gene [cystic fibrosis transmembrane conductance regulator (ATP-binding cassette subfamily C, member 7) (CFTR)], and inflammation genes such as tumor necrosis factor [tumor necrosis factor, TNF superfamily, member 2 (TNF)] are associated with hyperlipidemic pancreatitis (HLP) in patients with HTG. Methods: We performed genetic analysis of 126 HTG patients in Taiwan (46 with HLP and 80 without HLP). The entire coding and intronic regions of the PRSS1, SPINK1, and CFTR genes were identified by heteroduplex analysis techniques and were confirmed by sequencing analysis. The presence of 125G/C, 1001 + 11C>T, 1540A>G (Met470Val), 2694T>G, and 4521G>A in CFTR, the presence of 272C>T in SPINK1, and TNF promoter polymorphisms (nucleotide positions 1031, 863, 857, 308, and 308) were measured by direct sequencing. Results: Of the 126 HTG patients, 13 (10.3%) carried a CFTR mutation. No PRSS1 or SPINK1 mutations were detected in our patients or in HTG controls. The CFTR gene mutation rates in HTG with and without HLP were 26.1% (12 of 46) and 1.3% (1 of 80), respectively (P <0.0001). The CFTR gene mutations were all Ile556Val. A multivariate analysis of HTG patients indicated that triglycerides, CFTR 470Val, and TNF promoter 863A were independent risk markers for HLP. Conclusions: This genetic study is the first one to address the association of HLP with the CFTR mutation/variant/haplotype and TNF promoter polymorphism in a Chinese HTG population. The results suggest that the occurrence of HLP is multifactorial and polygenic.

Hypertriglyceridemic pancreatitis: Epidemiology, pathophysiology and clinical management

“…30 Several cases of drug-induced HTGP have been reported. HTGP was reported in patients on estrogen therapy in two case studies and one observational study.…”

Recurrent acute pancreatitis: an approach to diagnosis and management

“…53 Mutations in the lipoprotein lipase (LPL) gene have also been identified in patients with HTG-induced pancreatitis. 54 In HTG-related CP, Chang et al 55 have shown a higher frequency of CFTR gene mutations suggesting that the mechanism of pancreatitis may be related to genetic predisposition. In their study of 126 patients with HTG, 13 (10.3%) carried a CFTR gene mutation.…”

Acute Relapsing Pancreatitis with Pseudocyst Formation due to Sporadic Hypertriglyceridemic Pancreatitis: A Case Report

“…Several theories are postulated as mutational abnormalities in genes responsible for pancreatic ductal or acinar cell injury, including the cationic trypsinogen gene [protease, serine, 1 (trypsin 1) (PRSS1)], the pancreatic secretory trypsin inhibitor gene [serine peptidase inhibitor, Kazal type 1 (SPINK1)], the cystic fibrosis transmembrane conductance regulator gene [cystic fibrosis transmembrane conductance regulator (ATP-binding cassette subfamily C, member 7) (CFTR)], and inflammation genes such as tumor necrosis factor [tumor necrosis factor, TNF superfamily, member 2 (TNF)]-all are associated with hyperlipidemic pancreatitis (HLP) in patients with HTG [10].…”