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

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 Conwell, Gregory A. Coté, Peter B. CottonJames DiSario, Lindsay A. Farrer, Chris E. Forsmark, Marianne Johnstone, Timothy B. Gardner, Andres Gelrud, William Greenhalf, Jonathan L. Haines, Douglas J. Hartman, Robert A. Hawes, Christopher Lawrence, Michele Lewis, Julia Mayerle, Richard Mayeux, Nadine M. Melhem, Mary E. Money, Thiruvengadam Muniraj, Georgios I. Papachristou, Margaret A. Pericak-Vance, Joseph Romagnuolo, Gerard D. Schellenberg, Stuart Sherman, Peter Simon, Vijay P. Singh, Adam Slivka, Donna Stolz, Robert Sutton, Frank Ulrich Weiss, C. Mel Wilcox, Narcis Octavian Zarnescu, Stephen R. Wisniewski, Michael R. O'Connell, Michelle L. Kienholz, Kathryn Roeder, M. Michael Barmada, Dhiraj Yadav, Bernie Devlin, Marilyn S. Albert, Roger L. Albin, Liana G. Apostolova, Steven E. Arnold, Clinton T. Baldwin, Robert Barber, Lisa L. Barnes, Thomas G. Beach, Gary W. Beecham, Duane Beekly, David A. Bennett, Eileen H. Bigio, Thomas D. Bird, Deborah Blacker, Adam Boxer, James R. Burke, Joseph D. Buxbaum, Nigel J. Cairns, Laura B. Cantwell, Chuanhai Cao, Regina M. Carney, Steven L. Carroll, Helena C. Chui, David G. Clark, David H. Cribbs, Elizabeth A. Crocco, Carlos Cruchaga, Charles DeCarli, F. Yesim Demirci, Malcolm Dick, Dennis W. Dickson, Ranjan Duara, Nilufer Ertekin-Taner, Kelley M. Faber, Kenneth B. Fallon, Martin R. Farlow, Steven Ferris, Tatiana M. Foroud, Matthew P. Frosch, Douglas R. Galasko, Mary Ganguli, Marla Gearing, Daniel H. Geschwind, Bernardino Ghetti, John R. Gilbert, Sid Gilman, Jonathan D. Glass, Alison M. Goate, Neill R. Graff-Radford, Robert C. Green, John H. Growdon, Hakon Hakonarson, Kara L. Hamilton-Nelson, Ronald L. Hamilton, Lindy E. Harrell, Elizabeth Head, Lawrence S. Honig, Christine M. Hulette, Bradley T. Hyman, Gregory A. Jicha, Lee Way Jin, Gyungah Jun, M. Ilyas Kamboh, Anna Karydas, Jeffrey A. Kaye, Ronald Kim, Edward H. Koo, Neil W. Kowall, Joel H. Kramer, Patricia Kramer, Walter A. Kukul, Frank M. LaFerla, James J. Lah, James B. Leverenz, Allan I. Levey, Ge Li, Chiao Feng Lin, Andrew P. Lieberman, Oscar L. Lopez, Kathryn L. Lunetta, Constantine G. Lyketsos, Wendy J. MacK, Daniel C. Marson, Eden R. Martin, Frank Martiniuk, Deborah C. Mash, Eliezer Masliah, Ann C. McKee, Marsel Mesulam, Bruce L. Miller, Carol A. Miller, Joshua W. Miller, Thomas J. Montine, John C. Morris, Jill R. Murrel, Adam C. Naj, John M. Olichney, Joseph E. Parisi, Elaine Peskind, Ronald C. Petersen, Aimee Pierce, Wayne W. Poon, Huntington Potter, Joseph F. Quinn, Ashok Raj, Murray Raskind, Eric M. Reiman, Barry Reisberg, Christiane Reitz, John M. Ringman, Erik D. Roberson, Howard J. Rosen, Roger N. Rosenberg, Mary Sano, Andrew J. Saykin, Julie A. Schneider, Lon S. Schneider, William W. Seeley, Amanda G. Smith, Joshua A. Sonnen, Salvatore Spina, Robert A. Stern, Rudolph E. Tanzi, John Q. Trojanowski, Juan C. Troncoso, Debby W. Tsuang, Otto Valladares, Vivianna M. Van Deerlin, Linda J. Van Eldik, Badri N. Vardarajan, Harry V. Vinters, Jean Paul Vonsatte, Li San Wang, Sandra Weintraub, Kathleen A. Welsh-Bohmer, Jennifer Williamson, Randall L. Woltjer, Clinton B. Wright, Steven G. Younkin, Chang En Yu, Lei Yu

Research output: Contribution to journalArticlepeer-review

168 Scopus citations

Abstract

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).

Original languageEnglish (US)
Pages (from-to)1349-1354
Number of pages6
JournalNature genetics
Volume44
Issue number12
DOIs
StatePublished - Dec 2012

ASJC Scopus subject areas

  • Genetics

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