Aberrant Methylation of RUNX1 is Associated with the Pathogenesis of Autoimmune Pancreatitis

Abstract

IgG4-related disease (IgG4-RD) is an autoimmune disease of unknown cause. RUNX1 is a transcription factor involved in immune responses, and its dysfunction leads to uncontrolled immune responses. We performed, to our knowledge, the first RUNX1 methylation analysis in type 1 autoimmune pancreatitis (denoted simply as AIP), a representative IgG4-RD. We conducted methylation array analysis on AIP samples using the Illumina Infinium MethylationEPIC array. We identified a potentially important RUNX1 methylation abnormality in AIP, which was further confirmed using the quantitative SYBR green methylation-specific polymerase chain reaction (QSG-MSP) method. Using immunohistochemistry, we analyzed RUNX1 expression in lymphocytes in 11 lymph nodes with AIP (LN-AIP) and 20 lymph nodes with pancreatic ductal adenocarcinoma (PDA; LN-PDA). LN-AIP and LN-PDA refer to lymph nodes from patients with AIP and PDA, respectively. All selected PDA patients lacked lymph node metastases. By array analysis, RUNX1 was more highly methylated in LN-AIP than in LN-PDA (P = 0.0275). RUNX1 was also more highly methylated in LN-AIP than in LN-PDA by QSG-MSP validation (P = 0.0331). Immunohistochemical analysis indicated that RUNX1 expression was significantly lower in LN-AIP than in LN-PDA (P = 0.0250). Aberrant RUNX1 methylation and reduced expression may be characteristic of AIP. Further validation is warranted.