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. Cotton; James 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

doi:10.1038/ng.2466

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

272 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 language	English (US)
Pages (from-to)	1349-1354
Number of pages	6
Journal	Nature Genetics
Volume	44
Issue number	12
DOIs	https://doi.org/10.1038/ng.2466
State	Published - Dec 2012

Funding

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.). 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. 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’. 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 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).

ASJC Scopus subject areas

Genetics

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10.1038/ng.2466

Cite this

Whitcomb, D. C., LaRusch, J., Krasinskas, A. M., Klei, L., Smith, J. P., Brand, R. E., Neoptolemos, J. P., Lerch, M. M., Tector, M., Sandhu, B. S., Guda, N. M., Orlichenko, L., Alkaade, S., Amann, S. T., Anderson, M. A., Baillie, J., Banks, P. A., Conwell, D., Coté, G. A., ... Zarnescu, N. O. (2012). Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis. Nature Genetics, 44(12), 1349-1354. https://doi.org/10.1038/ng.2466

@article{3affe4fca71043359e1b0b75c1687c62,

title = "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).",

author = "Whitcomb, {David C.} and Jessica LaRusch and Krasinskas, {Alyssa M.} and Lambertus Klei and Smith, {Jill P.} and Brand, {Randall E.} and Neoptolemos, {John P.} and Lerch, {Markus M.} and Matt Tector and Sandhu, {Bimaljit S.} and Guda, {Nalini M.} and Lidiya Orlichenko and Samer Alkaade and Amann, {Stephen T.} and Anderson, {Michelle A.} and John Baillie and Banks, {Peter A.} and Darwin Conwell and Cot{\'e}, {Gregory A.} and Cotton, {Peter B.} and James DiSario and Farrer, {Lindsay A.} and Forsmark, {Chris E.} and Marianne Johnstone and Gardner, {Timothy B.} and Andres Gelrud and William Greenhalf and Haines, {Jonathan L.} and Hartman, {Douglas J.} and Hawes, {Robert A.} and Christopher Lawrence and Michele Lewis and Julia Mayerle and Richard Mayeux and Melhem, {Nadine M.} and Money, {Mary E.} and Thiruvengadam Muniraj and Papachristou, {Georgios I.} and Pericak-Vance, {Margaret A.} and Joseph Romagnuolo and Schellenberg, {Gerard D.} and Stuart Sherman and Peter Simon and Singh, {Vijay P.} and Adam Slivka and Donna Stolz and Robert Sutton and Weiss, {Frank Ulrich} and Wilcox, {C. Mel} and Zarnescu, {Narcis Octavian}",

note = "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{\textquoteright}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 {\textquoteleft}High throughput genotyping for studying the genetic contributions to human disease{\textquoteright}. Funding Information: on Aging (NIH-NIA) supported this work through the following grants: ADGC, U01AG032984 and RC2AG036528; National Alzheimer{\textquoteright}s Coordinating Center (NACC), U01AG016976; National Cell Repository for Alzheimer{\textquoteright}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).",

year = "2012",

month = dec,

doi = "10.1038/ng.2466",

language = "English (US)",

volume = "44",

pages = "1349--1354",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "12",

}

Whitcomb, DC, LaRusch, J, Krasinskas, AM, Klei, L, Smith, JP, Brand, RE, Neoptolemos, JP, Lerch, MM, Tector, M, Sandhu, BS, Guda, NM, Orlichenko, L, 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 2012, 'Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis', Nature Genetics, vol. 44, no. 12, pp. 1349-1354. https://doi.org/10.1038/ng.2466

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

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

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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 -

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

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