Impact of diet and genes on murine autoimmune pancreatitis

  • Robert Jaster
    Department of Medicine II Division of Gastroenterology Rostock University Medical Center Rostock Germany
  • Yask Gupta
    Lübeck Institute of Experimental Dermatology and Center for Research on Inflammation of the Skin University of Lübeck Lübeck Germany
  • Sarah Rohde
    Department of Medicine II Division of Gastroenterology Rostock University Medical Center Rostock Germany
  • Luise Ehlers
    Department of Medicine II Division of Gastroenterology Rostock University Medical Center Rostock Germany
  • Horst Nizze
    Institute of Pathology Rostock University Medical Center Rostock Germany
  • Artem Vorobyev
    Lübeck Institute of Experimental Dermatology and Center for Research on Inflammation of the Skin University of Lübeck Lübeck Germany
  • Ralf J. Ludwig
    Lübeck Institute of Experimental Dermatology and Center for Research on Inflammation of the Skin University of Lübeck Lübeck Germany
  • Saleh M. Ibrahim
    Lübeck Institute of Experimental Dermatology and Center for Research on Inflammation of the Skin University of Lübeck Lübeck Germany

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<jats:title>Abstract</jats:title><jats:p>The impact of environmental factors, such as diet, and the genetic basis of autoimmune pancreatitis (AIP) are largely unknown. Here, we used an experimental murine AIP model to identify the contribution of diet to AIP development, as well as to fine‐map AIP‐associated genes in outbred mice prone to develop the disease. For this purpose, we fed mice of an autoimmune‐prone intercross line (AIL) three different diets (control, calorie‐reduced and western diet) for 6 months, at which point the mice were genotyped and phenotyped for AIP. Overall, 269 out of 734 mice (36.6%) developed AIP with signs of parenchymal destruction, equally affecting mice of both sexes. AIP prevalence and severity were reduced by approximately 50% in mice held under caloric restriction compared to those fed control or western diet. We identified a quantitative trait locus (QTL) on chromosome 4 to be associated with AIP, which is located within a previously reported QTL. This association does not change when considering diet or sex as an additional variable for the mapping. Using whole‐genome sequences of the AIL founder strains, we resolved this QTL to a single candidate gene, namely <jats:italic>Map3k7</jats:italic>. Expression of <jats:italic>Map3k7</jats:italic> was largely restricted to islet cells as well as lymphocytes found in the exocrine pancreas of mice with AIP. Our studies suggest a major impact of diet on AIP. Furthermore, we identify <jats:italic>Map3k7</jats:italic> as a novel susceptibility gene for experimental AIP. Both findings warrant clinical translation.</jats:p>

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