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PRSS1 copy number variants and promoter polymorphisms in pancreatitis: common pathogenetic mechanism, different genetic effects
  1. Emmanuelle Masson1,2,
  2. Jian-Min Chen1,3,
  3. David N Cooper4,
  4. Claude Férec1,2,3,5
  1. 1Institut National de la Santé et de la Recherche Médicale (INSERM), U1078 Brest, France
  2. 2Laboratoire de Génétique Moléculaire et d’Histocompatibilité, Centre Hospitalier Universitaire (CHU) Brest, Hôpital Morvan, Brest, France
  3. 3Etablissement Français du Sang (EFS) – Bretagne, Brest, France
  4. 4Faculté de Médecine et des Sciences de la Santé, Université de Bretagne Occidentale (UBO), Brest, France
  5. 5Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, UK
  1. Correspondence to Dr Jian-Min Chen, INSERM U1078, EFS–Bretagne, 46 rue Félix Le Dantec, 29218 Brest, France; jian-min.chen{at}univ-brest.fr

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We have read with interest three related papers that were recently published in this journal.1–3 Taken together, the findings reported in these papers (summarised in online supplementary note) suggest that loss-of-function PRSS1 promoter variants can protect against pancreatitis. The other side of the coin is however that gain-of-function PRSS1 promoter variants predispose to pancreatitis. It therefore follows that the risk-associated [rs4726576C; rs10273639C] allele shares a common pathogenetic mechanism with the previously reported trypsinogen duplication and triplication copy number variants (CNVs)4 5 as both types of variant predispose to pancreatitis by increasing PRSS1 expression; this mechanism is quite distinct from either the increased activation and/or stability of trypsin(ogen) or misfolding-induced endoplasmic reticulum stress caused by disease-associated PRSS1 missense mutations.6 However, despite both serving to increase PRSS1 expression, the promoter variant and the CNVs differ significantly in terms of the …

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