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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. 1 Institut National de la Santé et de la Recherche Médicale (INSERM), U1078 Brest, France
  2. 2 Laboratoire de Génétique Moléculaire et d’Histocompatibilité, Centre Hospitalier Universitaire (CHU) Brest, Hôpital Morvan, Brest, France
  3. 3 Etablissement Français du Sang (EFS) – Bretagne, Brest, France
  4. 4 Faculté de Médecine et des Sciences de la Santé, Université de Bretagne Occidentale (UBO), Brest, France
  5. 5 Institute 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}

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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 relative strength of their genetic effects. The risk-associated [rs4726576C; rs10273639C] allele (whose frequency was found to be 0.54 and 0.57, respectively in healthy French individuals of European ancestry3 and controls from the North American Pancreatitis Study 2)7 had only a modest genetic effect, defined as having an OR of <1.5 in accordance with ref 8 with respect to the clinical phenotype. By contrast, the PRSS1 duplication/triplication CNVs, which have never been reported in normal populations, can be classified as disease-causative.

Supplementary Material

Supplementary material

Despite their evident clinical importance, PRSS1 CNVs have not so far been analysed by many research groups. Apart from the technical difficulties inherent in detecting CNVs, particularly those characterised by an increased copy number, there may be another reason, namely the PRSS1 duplication and triplication CNVs found in French Caucasian patients with hereditary, familial or sporadic chronic pancreatitis4 5 arose from a common founder chromosome.9 However, a PRSS1 CNV was also identified in 1 of 75 Chinese children with idiopathic chronic pancreatitis.10 Although the breakpoints of this CNV have not yet been characterised, the Chinese data provided the first evidence that pathogenic PRSS1 CNVs have more than one independent origin. Indeed, during our routine screening of young French patients with chronic pancreatitis or acute recurrent pancreatitis (see methods in online supplementary note), we identified and characterised four novel and non-identical PRSS1 duplication CNVs (figure 1): #2 in a Caucasian patient with a family history of the disease; #3 in a Maghrebian patient with sporadic pancreatitis; #4 in a Caucasian patient plus two family members (brother and father) and #5 in a sporadic pancreatitis patient from French Guiana.

Figure 1

Schematic illustration of the PRSS1 (as well as PRSS2) duplication CNVs whose breakpoints have been characterised at the nucleotide sequence level. The start and end positions of each duplicated segment are indicated in accordance with human GRCh38/hg38. The critical region contained within these duplicated sequences is indicated by vertical dotted lines. Whereas #3, #4 and #5 are simple duplications, #1 and #2 are complex duplications. In #1, only the functionally relevant duplicated segment is shown; this duplicated allele gave rise to the previously known triplication allele.9 In #2, an insertion was present in the aberrant chromosomal junction. Sequences spanning the aberrant chromosomal junctions of the four novel PRSS1 duplication CNVs are provided in  online supplementary figure S1. CNVs, copy number variants.

In summary, the recent publications on common PRSS1 promoter variants1–3 and the ongoing discovery of rare PRSS1 CNVs serve to emphasise the key role of increased PRSS1 expression in the aetiology of pancreatitis. Our new findings demonstrating multiple independent origins for PRSS1 CNVs, taken together with the earlier Chinese findings,10 suggest that, irrespective of their ethnogeographic origin, PRSS1 CNVs could be present in those patients with pancreatitis in whom a genetic risk factor has not yet been identified.


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  • Contributors EM, J-MC and CF: designed the study. EM: performed the analysis. J-MC: drafted the manuscript. DNC: critically revised the manuscript. All authors: analysed the data and approved the final manuscript.

  • Funding Support for this study came from the Association des Pancréatites Chroniques Héréditaires, the Association de Transfusion Sanguine et de Biogénétique Gaetan Saleun, and the Institut National de la Santé et de la Recherche Médicale (INSERM), France.

  • Competing interests None declared.

  • Ethics approval Ethical Committee of the University of Brest.

  • Provenance and peer review Not commissioned; internally peer reviewed.

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