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

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).

DOI: 10.1038/ng.2466

Extracted Key Phrases

3 Figures and Tables

020040020132014201520162017
Citations per Year

789 Citations

Semantic Scholar estimates that this publication has 789 citations based on the available data.

See our FAQ for additional information.

Cite this paper

@inproceedings{Whitcomb2012CommonGV, title={Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis}, author={David C . Whitcomb and Jessica Larusch and Alyssa M. Krasinskas and Lambertus L Klei and Jill Palmer Smith and Randall E. Brand and John P Neoptolemos and Markus M. Lerch and Matt Tector and Bimaljit Singh Sandhu and Nalini M. Guda and Lidiya S. Orlichenko and Samer Alkaade and Stephen T. Amann and Michelle A. Anderson and John Baillie and Peter A. Banks and Darwin L. Conwell and Gregory A. Cot{\'e} and Peter B. Cotton and James A. Disario and Lindsay A. Farrer and Chris E. Forsmark and Marianne Johnstone and Timothy B. Gardner and Andres Gelrud and William Greenhalf and Jonathan L. Haines and Douglas J. Hartman and Robert A. Hawes and Christopher H D Lawrence and Michele D. Lewis and Julia V Mayerle and Richard Mayeux and Nadine M. Melhem and Mary E. Money and Thiruvengadam Muniraj and Georgios Ioannis Papachristou and Margaret A. Pericak-Vance and Joseph Romagnuolo and Gerard D. Schellenberg and Stuart S Sherman and P{\'e}ter Simon and Vijay Kumar Singh and Adam A Slivka and Donna B Stolz and Robert Sutton and Frank Ulrich Weiss and C Mel Wilcox and Narcis Octavian Zarnescu and Stephen R. Wisniewski and Michael Richard O'Connell and Michelle Kienholz and Kathryn Roeder and M. Michael Barmada and Dhiraj Yadav and Bernie J Devlin and Marilyn S. Albert and Roger L Albin and Liana G. Apostolova and Steven Edward Arnold and C. T. Baldwin and R. Barber and L. Barnes and Thomas Beach and Gary W. Beecham and Duane L Beekly and David A. Bennett and Eileen Bigio and Thomas D. Bird and Deborah Blacker and Adam L. Boxer and James R Burke and Joseph D. Buxbaum and Nigel J. Cairns and Laura B. Cantwell and Chuanhai Cao and Regina M. Carney and Steven L. Carroll and Helena Chui and David G. Clark and David H. Cribbs and Elizabeth A. Crocco and Carlos Cruchaga and Charles DeCarli and Fatma Yesim Demirci and Malcolm C Dick and Dennis W Dickson and Ranjan Duara and Nil{\"{u}fer Ertekin-Taner and Kelley M. Faber and Kenneth B. Fallon and Martin R. Farlow and Steven H. Ferris and Tatiana Foroud and Matthew P. Frosch and Douglas R. Galasko and Mary Ganguli and Marla Gearing and Daniel H. Geschwind and Bernardino Ghetti and John R. Gilbert and Sid Gilman and Jonathan D. Glass and Alison M. Goate and Neill R. Graff-Radford and Robert C. Green and John Growdon and Hakon Hakonarson and Kara L. Hamilton-Nelson and Ronald L. Hamilton and Lindy E. Harrell and Elizabeth Head and Lawrence S. Honig and Christine M. Hulette and Bradley T. Hyman and Gregory A. Jicha and Lee-way Jin and Gyungah R. Jun and M. Kamboh and Anna M. Karydas and Jeffrey A. Kaye and Ronald C. Kim and Edward H. Koo and Neil W. Kowall and Joel H. Kramer and Patricia Kramer and Walter Kukull and Frank M Laferla and James J. Lah and James Ba Leverenz and Allan I. Levey and Ge Li and Chiao-Feng Lin and Andrew P. Lieberman and Oscar L. Lopez and Kathryn L. Lunetta and Constantine Lyketsos and Wendy J. Mack and Daniel C. Marson and Eden R. Martin and Frank T. Martiniuk and Deborah C. Mash and Eliezer Masliah and Ann C. McKee and Marsel M. Mesulam and Bruce L. Miller and Carol Miller and Joshua W. Miller and Thomas J. Montine and John C. Morris and Jill R. Murrell and Adam C Naj and John M. Olichney and Joseph E. Parisi and E. R. Peskind and Ronald C. Petersen and Aimee L Pierce and Wayne W S Poon and Huntington Potter and Joseph F. Quinn and Ashok B Raj and Murray A. Raskind and Eric Reiman and Barry Reisberg and Christiane Reitz and John M. Ringman and Erik D Roberson and Howard J. Rosen and Roger N . Rosenberg and Mary C Sano and Andrew J. Saykin and Julie A Schneider and L . S . Schneider and William W. Seeley and Amanda G. Smith and Joshua A. Sonnen and Salvatore Spina and Robert A. Stern and Rudolph E. Tanzi and John Q. Trojanowski and Juan Troncoso and Debby W. Tsuang and Otto Valladares and Vivianna M Van Deerlin and Linda J. Van Eldik and Badri Narayan Vardarajan and Harry V . Vinters and Jean Paul G. Vonsattel and Li-San Wang and Sandra Weintraub and Kathleen Welsh-Bohmer and Jennifer Elaine Williamson and Randall L. Woltjer and Clinton Wright and Steven G. Younkin and Chang-En Yu and Lei Yu}, booktitle={Nature Genetics}, year={2012} }