Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis.

Journal Article (Journal Article)

Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR and SPINK1 variants were associated with pancreatitis risk. We now report two associations at genome-wide significance identified and replicated at PRSS1-PRSS2 (P < 1 × 10(-12)) and X-linked CLDN2 (P < 1 × 10(-21)) through a two-stage genome-wide study (stage 1: 676 cases and 4,507 controls; stage 2: 910 cases and 4,170 controls). The PRSS1 variant likely affects disease susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous in males) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men (male hemizygote frequency is 0.26, whereas female homozygote frequency is 0.07).

Full Text

Duke Authors

Cited Authors

  • Whitcomb, DC; LaRusch, J; Krasinskas, AM; Klei, L; Smith, JP; Brand, RE; Neoptolemos, JP; Lerch, MM; Tector, M; Sandhu, BS; Guda, NM; Orlichenko, L; Alzheimer's Disease Genetics Consortium, ; Alkaade, S; Amann, ST; Anderson, MA; Baillie, J; Banks, PA; Conwell, D; Coté, GA; Cotton, PB; DiSario, J; Farrer, LA; Forsmark, CE; Johnstone, M; Gardner, TB; Gelrud, A; Greenhalf, W; Haines, JL; Hartman, DJ; Hawes, RA; Lawrence, C; Lewis, M; Mayerle, J; Mayeux, R; Melhem, NM; Money, ME; Muniraj, T; Papachristou, GI; Pericak-Vance, MA; Romagnuolo, J; Schellenberg, GD; Sherman, S; Simon, P; Singh, VP; Slivka, A; Stolz, D; Sutton, R; Weiss, FU; Wilcox, CM; Zarnescu, NO; Wisniewski, SR; O'Connell, MR; Kienholz, ML; Roeder, K; Barmada, MM; Yadav, D; Devlin, B

Published Date

  • December 2012

Published In

Volume / Issue

  • 44 / 12

Start / End Page

  • 1349 - 1354

PubMed ID

  • 23143602

Pubmed Central ID

  • PMC3510344

Electronic International Standard Serial Number (EISSN)

  • 1546-1718

Digital Object Identifier (DOI)

  • 10.1038/ng.2466


  • eng

Conference Location

  • United States