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Clarifying the clinical relevance of SPINK1 intronic variants in chronic pancreatitis
  1. Wen-Bin Zou1,2,3,4,
  2. Arnaud Boulling2,3,
  3. Emmanuelle Masson2,5,
  4. David N Cooper6,
  5. Zhuan Liao1,4,
  6. Zhao-Shen Li1,4,
  7. Claude Férec2,3,5,7,
  8. Jian-Min Chen2,3,7
  1. 1 Department of Gastroenterology, Changhai Hospital, the Second Military Medical University, Shanghai, China
  2. 2 Institut National de la Santé et de la Recherche Médicale (INSERM), U1078, Brest, France
  3. 3 Etablissement Français du Sang (EFS)—Bretagne, Brest, France
  4. 4 Shanghai Institute of Pancreatic Diseases, Shanghai, China
  5. 5 Laboratoire de Génétique Moléculaire et d'Histocompatibilité, Centre Hospitalier Universitaire (CHU) Brest, Hôpital Morvan, Brest, France
  6. 6 Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, UK
  7. 7 Faculté de Médecine et des Sciences de la Santé, Université de Bretagne Occidentale (UBO), Brest, France
  1. Correspondence to Dr Jian-Min Chen, INSERM U1078 and EFS—Bretagne, 46 rue Félix Le Dantec, Brest 29218, France; Jian-Min.Chen{at} Dr Claude Férec, INSERM U1078, 46 rue Félix Le Dantec, Brest 29218, France; claude.ferec{at} Dr Zhao-Shen Li, Department of Gastroenterology, Changhai Hospital, the Second Military Medical University, 168 Changhai Road, Shanghai 200433, China; zhaoshenli{at}

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Recently, we reported the identification of a functional PRSS1 promoter variant in perfect linkage disequilibrium (LD) with the chronic pancreatitis (CP)-‘protective’ rs10273639.1 This, together with several other recent papers published in Gut,2–4 underscored the importance of functional analysis for improving our understanding of the underlying pathophysiological mechanisms and also more fundamentally for establishing the clinical relevance or otherwise of CP-associated variants from the outset. In many diseases, in vitro functional analysis often represents the only practical means to determine the pathogenicity of patient-derived sequence variants, particularly when they are rare. Herein, we present a new and successful example in the context of CP.

SPINK1 is one of the most extensively studied CP genes, with >100 variants being reported to date.5 Of 19 known intronic variants, the four in LD with the p.Asn34Ser variant have been functionally analysed in the context of both minigene6 and full-length genomic sequence7; none had any detectable effect on pre-mRNA splicing. In addition, the functional consequences of the c.194+2T>C splice donor site variant …

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