Analysis of tumour necrosis factor alpha and interleukin 10 promotor variants in patients with chronic pancreatitis

Objective: Cationic trypsinogen gene mutations are strong risk factors of hereditary pancreatitis. However, 20% of subjects with a trypsinogen mutation never get pancreatitis and the cause of this incomplete penetrance is unknown. We investigated the influence of interleukin 10 (IL10) and tumour necrosis factor alpha (TNFα) promoter variants on the manifestation of chronic pancreatitis of different underlying causes and in pancreatic cancer. Methods: A total of 335 German patients with chronic pancreatitis were investigated. In 157 patients the disease was related to alcohol abuse; the other cases were of non-alcoholic origin. In the latter group, the serine protease inhibitor, Kazal type 1 (SPINK1) mutation N34S was found in 72 patients and the trypsinogen mutations N29I or R122H were present in 60 patients; in the remaining 46 patients no mutation was found. In addition, we studied 208 patients with pancreatic cancer. As controls, 116 healthy blood donors and 25 healthy carriers of the trypsinogen mutations N29I or R122H were Investigated. After DNA extraction from blood leucocytes, genotyping for the cytokine polymorphisms was performed by induced heteroduplex generators and/or direct DNA sequencing of the IL10 and TNFα promotor regions. Results: The frequencies of the promotor polymorphisms of IL10-627A, IL10-1117A, TNF-238A and TNF-308A in patients with alcoholic chronic pancreatitis, idiopathic pancreatitis, SPINK1-N34S-associated chronic pancreatitis and pancreatic cancer did not differ significantly from the control group. The variant TNF-238A was two to four times more frequent in index patients with trypsinogen mutations than in all other groups. The analysis of the allelic frequencies of whole families with trypsinogen mutations revealed that all subjects with the TNF-238A variant suffered from chronic pancreatitis, whereas all intrafamilial controls with wild-type TNF were unaffected. Conclusions: TNFα and IL10 pro motor variants are not associated with a manifestation of chronic pancreatitis or pancreatic cancer. The variant TNF-238A, however, might be a relevant risk factor for disease manifestation in families with hereditary pancreatitis.