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 language | English |
---|---|
Pages (from-to) | 1349-1354 |
Number of pages | 6 |
Journal | Nature Genetics |
Volume | 44 |
Issue number | 12 |
DOIs | |
State | Published - Dec 2012 |
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In: Nature Genetics, Vol. 44, No. 12, 12.2012, p. 1349-1354.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis
AU - Whitcomb, David C.
AU - LaRusch, Jessica
AU - Krasinskas, Alyssa M.
AU - Klei, Lambertus
AU - Smith, Jill P.
AU - Brand, Randall E.
AU - Neoptolemos, John P.
AU - Lerch, Markus M.
AU - Tector, Matt
AU - Sandhu, Bimaljit S.
AU - Guda, Nalini M.
AU - Orlichenko, Lidiya
AU - Alkaade, Samer
AU - Amann, Stephen T.
AU - Anderson, Michelle A.
AU - Baillie, John
AU - Banks, Peter A.
AU - Conwell, Darwin
AU - Coté, Gregory A.
AU - Cotton, Peter B.
AU - DiSario, James
AU - Farrer, Lindsay A.
AU - Forsmark, Chris E.
AU - Johnstone, Marianne
AU - Gardner, Timothy B.
AU - Gelrud, Andres
AU - Greenhalf, William
AU - Haines, Jonathan L.
AU - Hartman, Douglas J.
AU - Hawes, Robert A.
AU - Lawrence, Christopher
AU - Lewis, Michele
AU - Mayerle, Julia
AU - Mayeux, Richard
AU - Melhem, Nadine M.
AU - Money, Mary E.
AU - Muniraj, Thiruvengadam
AU - Papachristou, Georgios I.
AU - Pericak-Vance, Margaret A.
AU - Romagnuolo, Joseph
AU - Schellenberg, Gerard D.
AU - Sherman, Stuart
AU - Simon, Peter
AU - Singh, Vijay P.
AU - Slivka, Adam
AU - Stolz, Donna
AU - Sutton, Robert
AU - Weiss, Frank Ulrich
AU - Wilcox, C. Mel
AU - Zarnescu, Narcis Octavian
AU - Wisniewski, Stephen R.
AU - O'Connell, Michael R.
AU - Kienholz, Michelle L.
AU - Roeder, Kathryn
AU - Barmada, M. Michael
AU - Yadav, Dhiraj
AU - Devlin, Bernie
AU - Albert, Marilyn S.
AU - Albin, Roger L.
AU - Apostolova, Liana G.
AU - Arnold, Steven E.
AU - Baldwin, Clinton T.
AU - Barber, Robert
AU - Barnes, Lisa L.
AU - Beach, Thomas G.
AU - Beecham, Gary W.
AU - Beekly, Duane
AU - Bennett, David A.
AU - Bigio, Eileen H.
AU - Bird, Thomas D.
AU - Blacker, Deborah
AU - Boxer, Adam
AU - Burke, James R.
AU - Buxbaum, Joseph D.
AU - Cairns, Nigel J.
AU - Cantwell, Laura B.
AU - Cao, Chuanhai
AU - Carney, Regina M.
AU - Carroll, Steven L.
AU - Chui, Helena C.
AU - Clark, David G.
AU - Cribbs, David H.
AU - Crocco, Elizabeth A.
AU - Cruchaga, Carlos
AU - DeCarli, Charles
AU - Demirci, F. Yesim
AU - Dick, Malcolm
AU - Dickson, Dennis W.
AU - Duara, Ranjan
AU - Ertekin-Taner, Nilufer
AU - Faber, Kelley M.
AU - Fallon, Kenneth B.
AU - Farlow, Martin R.
AU - Ferris, Steven
AU - Foroud, Tatiana M.
AU - Frosch, Matthew P.
AU - Galasko, Douglas R.
AU - Ganguli, Mary
AU - Gearing, Marla
AU - Geschwind, Daniel H.
AU - Ghetti, Bernardino
AU - Gilbert, John R.
AU - Gilman, Sid
AU - Glass, Jonathan D.
AU - Goate, Alison M.
AU - Graff-Radford, Neill R.
AU - Green, Robert C.
AU - Growdon, John H.
AU - Hakonarson, Hakon
AU - Hamilton-Nelson, Kara L.
AU - Hamilton, Ronald L.
AU - Harrell, Lindy E.
AU - Head, Elizabeth
AU - Honig, Lawrence S.
AU - Hulette, Christine M.
AU - Hyman, Bradley T.
AU - Jicha, Gregory A.
AU - Jin, Lee Way
AU - Jun, Gyungah
AU - Kamboh, M. Ilyas
AU - Karydas, Anna
AU - Kaye, Jeffrey A.
AU - Kim, Ronald
AU - Koo, Edward H.
AU - Kowall, Neil W.
AU - Kramer, Joel H.
AU - Kramer, Patricia
AU - Kukul, Walter A.
AU - LaFerla, Frank M.
AU - Lah, James J.
AU - Leverenz, James B.
AU - Levey, Allan I.
AU - Li, Ge
AU - Lin, Chiao Feng
AU - Lieberman, Andrew P.
AU - Lopez, Oscar L.
AU - Lunetta, Kathryn L.
AU - Lyketsos, Constantine G.
AU - MacK, Wendy J.
AU - Marson, Daniel C.
AU - Martin, Eden R.
AU - Martiniuk, Frank
AU - Mash, Deborah C.
AU - Masliah, Eliezer
AU - McKee, Ann C.
AU - Mesulam, Marsel
AU - Miller, Bruce L.
AU - Miller, Carol A.
AU - Miller, Joshua W.
AU - Montine, Thomas J.
AU - Morris, John C.
AU - Murrel, Jill R.
AU - Naj, Adam C.
AU - Olichney, John M.
AU - Parisi, Joseph E.
AU - Peskind, Elaine
AU - Petersen, Ronald C.
AU - Pierce, Aimee
AU - Poon, Wayne W.
AU - Potter, Huntington
AU - Quinn, Joseph F.
AU - Raj, Ashok
AU - Raskind, Murray
AU - Reiman, Eric M.
AU - Reisberg, Barry
AU - Reitz, Christiane
AU - Ringman, John M.
AU - Roberson, Erik D.
AU - Rosen, Howard J.
AU - Rosenberg, Roger N.
AU - Sano, Mary
AU - Saykin, Andrew J.
AU - Schneider, Julie A.
AU - Schneider, Lon S.
AU - Seeley, William W.
AU - Smith, Amanda G.
AU - Sonnen, Joshua A.
AU - Spina, Salvatore
AU - Stern, Robert A.
AU - Tanzi, Rudolph E.
AU - Trojanowski, John Q.
AU - Troncoso, Juan C.
AU - Tsuang, Debby W.
AU - Valladares, Otto
AU - Van Deerlin, Vivianna M.
AU - Van Eldik, Linda J.
AU - Vardarajan, Badri N.
AU - Vinters, Harry V.
AU - Vonsatte, Jean Paul
AU - Wang, Li San
AU - Weintraub, Sandra
AU - Welsh-Bohmer, Kathleen A.
AU - Williamson, Jennifer
AU - Woltjer, Randall L.
AU - Wright, Clinton B.
AU - Younkin, Steven G.
AU - Yu, Chang En
AU - Yu, Lei
N1 - Funding Information: Technical support was provided by K. Stello, S. Das, D. Dwyer, A. Rowland, P.A. Blake, M. Ross, C. McGovern, L. Kish, H. Nawaz, S. Solomon, S. Boggiano, R. Ostroff, M. Goss and J. Timm. Data management was provided by L. Silfies and D. Protivnak. Clinical support was provided by S. Boggaino, M. Hendricks, B. Elinoff, L. McHenry, G. Lehman, J. Watkins, E. Fogel and L. Lazzell-Pannell. Additional samples were provided by F. Burton (deceased; St. Louis University School of Medicine); S. Lo (Cedars-Sinai Medical Center, University of California, Los Angeles); M.T. DeMeo (Rush University Medical Center); W.M. Steinberg (Washington Hospital Center); M.L. Kochman (University of Pennsylvania); B. Etemad (Ochsner Medical Center); and H. Zeh, A.J. Moser and K.K. Lee (University of Pittsburgh). This publication was made possible by grants R56DK061451 (D.C.W.), R01DK054709 (D.C.W.), T32DK063922 (D.C.W.), R01MH057881 (B.D. and K.R.), R01CA117926 (J.P.S.), R01DK077906 (D.C.W. and D.Y.), UL1RR024153 and UL1TR000005 from the US National Institutes of Health (NIH). Its contents are solely the responsibility of the authors and do not necessarily represent the official view of the NIH. This project used the University of Pittsburgh Genomics and Proteomics Core Laboratories (UL1RR024153, UL1RR024153 and UL1TR000005) and the University of Pittsburgh Cancer Institute (UPCI) Clinical Genomics Immunoproteomics and Sequencing Facility (NIH P30CA047904). J.L. was supported by Digestive Disease Training Program T32DK063922 (D.C.W.). N.O.Z. was supported by the American Gastroenterology Association John I Isenberg International Scholar Award. The Liverpool cohort was supported by the National Institute for Health Research (NIHR) Biomedical Research Unit award. Additional support was provided by the National Pancreas Foundation (D.C.W.), the Frieda G. and Saul F. Shapira BRCA-Associated Cancer Research Program (D.C.W.) and the Wayne Fusaro Pancreatic Cancer Research Fund (D.C.W.) and Gift of Life Foundation (J.P.S.). Funding Information: of Medicine, P50AG005138 and P01AG002219; New York University, P30AG08051, MO1RR00096 and UL1RR029893; Northwestern University, P30AG013854; Oregon Health & Science University, P30AG008017 and R01AG026916; Rush University, P30AG010161, R01AG019085, R01AG15819, R01AG17917 and R01AG30146; University of Alabama at Birmingham, P50AG016582 and UL1RR02777; University of Arizona, R01AG031581; University of California, Davis, P30AG010129; University of California, Irvine, P50AG016573, P50AG016575, P50AG016576 and P50AG016577; University of California, Los Angeles, P50AG016570; University of California, San Diego, P50AG005131; University of California, San Francisco, P50AG023501 and P01AG019724; University of Kentucky, P30AG028383 and AG05144; University of Michigan, P50AG008671; University of Pennsylvania, P30AG010124; University of Pittsburgh, P50AG005133 and AG030653; University of Southern California, P50AG005142; University of Texas Southwestern, P30AG012300; University of Miami, R01AG027944, AG010491, AG027944, AG021547 and AG019757; University of Washington, P50AG005136; Vanderbilt University, R01AG019085; and Washington University, P50AG005681 and P01AG03991. The Kathleen Price Bryan Brain Bank at the Duke University Medical Center is funded by National Institute of Neurological Disorders and Stroke (NINDS) grant NS39764 and National Institute of Mental Health (NIMH) grant MH60451 and by GlaxoSmithKline. We thank D.S. Snyder and M. Miller who are ex officio ADGC members. Funding Information: Control group 2 genotypes were obtained from the Genome-Wide Association Study of Parkinson Disease: Genes and Environment, database of Genotypes and Phenotypes (dbGaP) study phs000196.v2.p1. This NeuroGenetics Research Consortium (NGRC) is a gene-environment study of Parkinson’s disease. The principal investigator is H. Payami (New York State Department of Health Wadsworth Center, Albany, New York, USA), and the co-investigators are J. Nutt (Oregon Health & Sciences University, Portland, Oregon, USA); C. Zabetian (University of Washington and Puget Sound Veterans Medical Center, Seattle, Washington, USA); S. Factor (Emory University, Atlanta, Georgia, USA); E. Molho (Albany Medical Center, Albany, New York, USA); and D. Higgins (Albany Medical Center and Albany Veterans Medical Center, Albany, New York, USA). Funding was provided by NIH grant R01NS36960. Genotyping was performed by the Genotyping Center at the Johns Hopkins University Center for Inherited Disease Research (CIDR). Funding for genotyping was provided by NIH grant HHSN268200782096C. The NIH contract for the project is entitled ‘High throughput genotyping for studying the genetic contributions to human disease’. Funding Information: on Aging (NIH-NIA) supported this work through the following grants: ADGC, U01AG032984 and RC2AG036528; National Alzheimer’s Coordinating Center (NACC), U01AG016976; National Cell Repository for Alzheimer’s Disease (NCRAD), U24AG021886; Banner Sun Health Research Institute, P30AG019610; Boston University, P30AG013846, U01AG10483, R01CA129769, R01MH080295, R01AG017173, R01AG025259 and R01AG33193; Columbia University, P50AG008702 and R37AG015473; Duke University, P30AG028377 and AG05128; Emory University, AG025688; Indiana University, P30AG10133; Johns Hopkins University, P50AG005146 and R01AG020688; Massachusetts General Hospital, P50AG005134; Mayo Clinic, P50AG016574; Mount Sinai School Funding Information: The German cohort was supported by the Alfried-Krupp-von-Bohlen-und-Hahlbach-Foundation (Graduate Schools of Tumour Biology and Free Radical Biology), the Deutsche Krebshilfe/Dr. Mildred-Scheel-Stiftung (109102), the Deutsche Forschungsgemeinschaft (DFG GRK840-E3/E4, MA 4115/1-2/3 and NI 1297/1-1), the Federal Ministry of Education and Research (BMBF GANI-MED 03152061A and BMBF 0314107) and the European Union (EU-FP-7; EPC-TM and EU-FP7-REGPOT-2010-1).
PY - 2012/12
Y1 - 2012/12
N2 - 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).
AB - 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).
UR - http://www.scopus.com/inward/record.url?scp=84870511045&partnerID=8YFLogxK
U2 - 10.1038/ng.2466
DO - 10.1038/ng.2466
M3 - Article
C2 - 23143602
AN - SCOPUS:84870511045
SN - 1061-4036
VL - 44
SP - 1349
EP - 1354
JO - Nature Genetics
JF - Nature Genetics
IS - 12
ER -