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

2012; Nature Portfolio; Volume: 44; Issue: 12 Linguagem: Inglês

10.1038/ng.2466

1546-1718

David C. Whitcomb, Jessica LaRusch, Alyssa M. Krasinskas, Lambertus Klei, Jill P. Smith, Randall E. Brand, John P. Neoptolemos, Markus M. Lerch, Matt Tector, Bimaljit S. Sandhu, Nalini M. Guda, Lidiya Orlichenko, Samer Alkaade, Stephen T. Amann, Michelle A. Anderson, John Baillie, Peter A. Banks, Darwin L. Conwell, Gregory A. Coté, Peter B. Cotton, James DiSario, Lindsay A. Farrer, Chris E. Forsmark, Marianne Johnstone, Timothy B. Gardner, Andrés Gelrud, William Greenhalf, Jonathan L. Haines, Douglas J. Hartman, Robert A. Hawes, Christopher Lawrence, Michele D. Lewis, Julia Mayerle, Richard Mayeux, Nadine Melhem, Mary E. Money, Thiruvengadam Muniraj, Georgios I. Papachristou, Margaret A. Pericak‐Vance, Joseph Romagnuolo, Gerard D. Schellenberg, Stuart Sherman, Péter Simon, Vijay Singh, Adam Slivka, Donna B. Stolz, Robert Sutton, Frank Ulrich Weiß, C. Mel Wilcox, Narcis Zarnescu, Stephen R. Wisniewski, Michael R. O’Connell, Michelle L. Kienholz, Kathryn Roeder, M. Michael Barmada, Dhiraj Yadav, Bernie Devlin,

Lipid metabolism and disorders

David Whitcomb, Bernie Devlin and colleagues report the results of a genome-wide association study of pancreatitis. They identify common variants at two loci associated with risk of this disease, including one on the X chromosome that shows strong evidence of interaction with alcohol consumption. 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).