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 & 178 others 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, 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 journalArticle

132 Citations (Scopus)

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

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Pancreatitis
Alcohols
Claudin-2
Hemizygote
Alleles
Genome
Trypsinogen
Acinar Cells
Disease Susceptibility
Homozygote
Alcohol Drinking
Genotype
Genes

ASJC Scopus subject areas

  • Genetics

Cite this

Whitcomb, D. C., LaRusch, J., Krasinskas, A. M., Klei, L., Smith, J. P., Brand, R. E., ... Yu, L. (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

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

In: Nature Genetics, Vol. 44, No. 12, 12.2012, p. 1349-1354.

Research output: Contribution to journalArticle

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, Wisniewski, SR, O'Connell, MR, Kienholz, ML, Roeder, K, Barmada, MM, Yadav, D, Devlin, B, Albert, MS, Albin, RL, Apostolova, LG, Arnold, SE, Baldwin, CT, Barber, R, Barnes, LL, Beach, TG, Beecham, GW, Beekly, D, Bennett, DA, Bigio, EH, Bird, TD, Blacker, D, Boxer, A, Burke, JR, Buxbaum, JD, Cairns, NJ, Cantwell, LB, Cao, C, Carney, RM, Carroll, SL, Chui, HC, Clark, DG, Cribbs, DH, Crocco, EA, Cruchaga, C, DeCarli, C, Demirci, FY, Dick, M, Dickson, DW, Duara, R, Ertekin-Taner, N, Faber, KM, Fallon, KB, Farlow, MR, Ferris, S, Foroud, TM, Frosch, MP, Galasko, DR, Ganguli, M, Gearing, M, Geschwind, DH, Ghetti, B, Gilbert, JR, Gilman, S, Glass, JD, Goate, AM, Graff-Radford, NR, Green, RC, Growdon, JH, Hakonarson, H, Hamilton-Nelson, KL, Hamilton, RL, Harrell, LE, Head, E, Honig, LS, Hulette, CM, Hyman, BT, Jicha, GA, Jin, LW, Jun, G, Kamboh, MI, Karydas, A, Kaye, JA, Kim, R, Koo, EH, Kowall, NW, Kramer, JH, Kramer, P, Kukul, WA, LaFerla, FM, Lah, JJ, Leverenz, JB, Levey, AI, Li, G, Lin, CF, Lieberman, AP, Lopez, OL, Lunetta, KL, Lyketsos, CG, MacK, WJ, Marson, DC, Martin, ER, Martiniuk, F, Mash, DC, Masliah, E, McKee, AC, Mesulam, M, Miller, BL, Miller, CA, Miller, JW, Montine, TJ, Morris, JC, Murrel, JR, Naj, AC, Olichney, JM, Parisi, JE, Peskind, E, Petersen, RC, Pierce, A, Poon, WW, Potter, H, Quinn, JF, Raj, A, Raskind, M, Reiman, EM, Reisberg, B, Reitz, C, Ringman, JM, Roberson, ED, Rosen, HJ, Rosenberg, RN, Sano, M, Saykin, AJ, Schneider, JA, Schneider, LS, Seeley, WW, Smith, AG, Sonnen, JA, Spina, S, Stern, RA, Tanzi, RE, Trojanowski, JQ, Troncoso, JC, Tsuang, DW, Valladares, O, Van Deerlin, VM, Van Eldik, LJ, Vardarajan, BN, Vinters, HV, Vonsatte, JP, Wang, LS, Weintraub, S, Welsh-Bohmer, KA, Williamson, J, Woltjer, RL, Wright, CB, Younkin, SG, Yu, CE & Yu, L 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
Whitcomb, David C. ; LaRusch, Jessica ; Krasinskas, Alyssa M. ; Klei, Lambertus ; Smith, Jill P. ; Brand, Randall E. ; Neoptolemos, John P. ; Lerch, Markus M. ; Tector, Matt ; Sandhu, Bimaljit S. ; Guda, Nalini M. ; Orlichenko, Lidiya ; Alkaade, Samer ; Amann, Stephen T. ; Anderson, Michelle A. ; Baillie, John ; Banks, Peter A. ; Conwell, Darwin ; Coté, Gregory A. ; Cotton, Peter B. ; DiSario, James ; Farrer, Lindsay A. ; Forsmark, Chris E. ; Johnstone, Marianne ; Gardner, Timothy B. ; Gelrud, Andres ; Greenhalf, William ; Haines, Jonathan L. ; Hartman, Douglas J. ; Hawes, Robert A. ; Lawrence, Christopher ; Lewis, Michele ; Mayerle, Julia ; Mayeux, Richard ; Melhem, Nadine M. ; Money, Mary E. ; Muniraj, Thiruvengadam ; Papachristou, Georgios I. ; Pericak-Vance, Margaret A. ; Romagnuolo, Joseph ; Schellenberg, Gerard D. ; Sherman, Stuart ; Simon, Peter ; Singh, Vijay P. ; Slivka, Adam ; Stolz, Donna ; Sutton, Robert ; Weiss, Frank Ulrich ; Wilcox, C. Mel ; Zarnescu, Narcis Octavian ; Wisniewski, Stephen R. ; O'Connell, Michael R. ; Kienholz, Michelle L. ; Roeder, Kathryn ; Barmada, M. Michael ; Yadav, Dhiraj ; Devlin, Bernie ; Albert, Marilyn S. ; Albin, Roger L. ; Apostolova, Liana G. ; Arnold, Steven E. ; Baldwin, Clinton T. ; Barber, Robert ; Barnes, Lisa L. ; Beach, Thomas G. ; Beecham, Gary W. ; Beekly, Duane ; Bennett, David A. ; Bigio, Eileen H. ; Bird, Thomas D. ; Blacker, Deborah ; Boxer, Adam ; Burke, James R. ; Buxbaum, Joseph D. ; Cairns, Nigel J. ; Cantwell, Laura B. ; Cao, Chuanhai ; Carney, Regina M. ; Carroll, Steven L. ; Chui, Helena C. ; Clark, David G. ; Cribbs, David H. ; Crocco, Elizabeth A. ; Cruchaga, Carlos ; DeCarli, Charles ; Demirci, F. Yesim ; Dick, Malcolm ; Dickson, Dennis W. ; Duara, Ranjan ; Ertekin-Taner, Nilufer ; Faber, Kelley M. ; Fallon, Kenneth B. ; Farlow, Martin R. ; Ferris, Steven ; Foroud, Tatiana M. ; Frosch, Matthew P. ; Galasko, Douglas R. ; Ganguli, Mary ; Gearing, Marla ; Geschwind, Daniel H. ; Ghetti, Bernardino ; Gilbert, John R. ; Gilman, Sid ; Glass, Jonathan D. ; Goate, Alison M. ; Graff-Radford, Neill R. ; Green, Robert C. ; Growdon, John H. ; Hakonarson, Hakon ; Hamilton-Nelson, Kara L. ; Hamilton, Ronald L. ; Harrell, Lindy E. ; Head, Elizabeth ; Honig, Lawrence S. ; Hulette, Christine M. ; Hyman, Bradley T. ; Jicha, Gregory A. ; Jin, Lee Way ; Jun, Gyungah ; Kamboh, M. Ilyas ; Karydas, Anna ; Kaye, Jeffrey A. ; Kim, Ronald ; Koo, Edward H. ; Kowall, Neil W. ; Kramer, Joel H. ; Kramer, Patricia ; Kukul, Walter A. ; LaFerla, Frank M. ; Lah, James J. ; Leverenz, James B. ; Levey, Allan I. ; Li, Ge ; Lin, Chiao Feng ; Lieberman, Andrew P. ; Lopez, Oscar L. ; Lunetta, Kathryn L. ; Lyketsos, Constantine G. ; MacK, Wendy J. ; Marson, Daniel C. ; Martin, Eden R. ; Martiniuk, Frank ; Mash, Deborah C. ; Masliah, Eliezer ; McKee, Ann C. ; Mesulam, Marsel ; Miller, Bruce L. ; Miller, Carol A. ; Miller, Joshua W. ; Montine, Thomas J. ; Morris, John C. ; Murrel, Jill R. ; Naj, Adam C. ; Olichney, John M. ; Parisi, Joseph E. ; Peskind, Elaine ; Petersen, Ronald C. ; Pierce, Aimee ; Poon, Wayne W. ; Potter, Huntington ; Quinn, Joseph F. ; Raj, Ashok ; Raskind, Murray ; Reiman, Eric M. ; Reisberg, Barry ; Reitz, Christiane ; Ringman, John M. ; Roberson, Erik D. ; Rosen, Howard J. ; Rosenberg, Roger N. ; Sano, Mary ; Saykin, Andrew J. ; Schneider, Julie A. ; Schneider, Lon S. ; Seeley, William W. ; Smith, Amanda G. ; Sonnen, Joshua A. ; Spina, Salvatore ; Stern, Robert A. ; Tanzi, Rudolph E. ; Trojanowski, John Q. ; Troncoso, Juan C. ; Tsuang, Debby W. ; Valladares, Otto ; Van Deerlin, Vivianna M. ; Van Eldik, Linda J. ; Vardarajan, Badri N. ; Vinters, Harry V. ; Vonsatte, Jean Paul ; Wang, Li San ; Weintraub, Sandra ; Welsh-Bohmer, Kathleen A. ; Williamson, Jennifer ; Woltjer, Randall L. ; Wright, Clinton B. ; Younkin, Steven G. ; Yu, Chang En ; Yu, Lei. / Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis. In: Nature Genetics. 2012 ; Vol. 44, No. 12. pp. 1349-1354.
@article{2eddd489ce1a407ca2866181aaf49277,
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} and Wisniewski, {Stephen R.} and O'Connell, {Michael R.} and Kienholz, {Michelle L.} and Kathryn Roeder and Barmada, {M. Michael} and Dhiraj Yadav and Bernie Devlin and Albert, {Marilyn S.} and Albin, {Roger L.} and Apostolova, {Liana G.} and Arnold, {Steven E.} and Baldwin, {Clinton T.} and Robert Barber and Barnes, {Lisa L.} and Beach, {Thomas G.} and Beecham, {Gary W.} and Duane Beekly and Bennett, {David A.} and Bigio, {Eileen H.} and Bird, {Thomas D.} and Deborah Blacker and Adam Boxer and Burke, {James R.} and Buxbaum, {Joseph D.} and Cairns, {Nigel J.} and Cantwell, {Laura B.} and Chuanhai Cao and Carney, {Regina M.} and Carroll, {Steven L.} and Chui, {Helena C.} and Clark, {David G.} and Cribbs, {David H.} and Crocco, {Elizabeth A.} and Carlos Cruchaga and Charles DeCarli and Demirci, {F. Yesim} and Malcolm Dick and Dickson, {Dennis W.} and Ranjan Duara and Nilufer Ertekin-Taner and Faber, {Kelley M.} and Fallon, {Kenneth B.} and Farlow, {Martin R.} and Steven Ferris and Foroud, {Tatiana M.} and Frosch, {Matthew P.} and Galasko, {Douglas R.} and Mary Ganguli and Marla Gearing and Geschwind, {Daniel H.} and Bernardino Ghetti and Gilbert, {John R.} and Sid Gilman and Glass, {Jonathan D.} and Goate, {Alison M.} and Graff-Radford, {Neill R.} and Green, {Robert C.} and Growdon, {John H.} and Hakon Hakonarson and Hamilton-Nelson, {Kara L.} and Hamilton, {Ronald L.} and Harrell, {Lindy E.} and Elizabeth Head and Honig, {Lawrence S.} and Hulette, {Christine M.} and Hyman, {Bradley T.} and Jicha, {Gregory A.} and Jin, {Lee Way} and Gyungah Jun and Kamboh, {M. Ilyas} and Anna Karydas and Kaye, {Jeffrey A.} and Ronald Kim and Koo, {Edward H.} and Kowall, {Neil W.} and Kramer, {Joel H.} and Patricia Kramer and Kukul, {Walter A.} and LaFerla, {Frank M.} and Lah, {James J.} and Leverenz, {James B.} and Levey, {Allan I.} and Ge Li and Lin, {Chiao Feng} and Lieberman, {Andrew P.} and Lopez, {Oscar L.} and Lunetta, {Kathryn L.} and Lyketsos, {Constantine G.} and MacK, {Wendy J.} and Marson, {Daniel C.} and Martin, {Eden R.} and Frank Martiniuk and Mash, {Deborah C.} and Eliezer Masliah and McKee, {Ann C.} and Marsel Mesulam and Miller, {Bruce L.} and Miller, {Carol A.} and Miller, {Joshua W.} and Montine, {Thomas J.} and Morris, {John C.} and Murrel, {Jill R.} and Naj, {Adam C.} and Olichney, {John M.} and Parisi, {Joseph E.} and Elaine Peskind and Petersen, {Ronald C.} and Aimee Pierce and Poon, {Wayne W.} and Huntington Potter and Quinn, {Joseph F.} and Ashok Raj and Murray Raskind and Reiman, {Eric M.} and Barry Reisberg and Christiane Reitz and Ringman, {John M.} and Roberson, {Erik D.} and Rosen, {Howard J.} and Rosenberg, {Roger N.} and Mary Sano and Saykin, {Andrew J.} and Schneider, {Julie A.} and Schneider, {Lon S.} and Seeley, {William W.} and Smith, {Amanda G.} and Sonnen, {Joshua A.} and Salvatore Spina and Stern, {Robert A.} and Tanzi, {Rudolph E.} and Trojanowski, {John Q.} and Troncoso, {Juan C.} and Tsuang, {Debby W.} and Otto Valladares and {Van Deerlin}, {Vivianna M.} and {Van Eldik}, {Linda J.} and Vardarajan, {Badri N.} and Vinters, {Harry V.} and Vonsatte, {Jean Paul} and Wang, {Li San} and Sandra Weintraub and Welsh-Bohmer, {Kathleen A.} and Jennifer Williamson and Woltjer, {Randall L.} and Wright, {Clinton B.} and Younkin, {Steven G.} and Yu, {Chang En} and Lei Yu",
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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

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

UR - http://www.scopus.com/inward/citedby.url?scp=84870511045&partnerID=8YFLogxK

U2 - 10.1038/ng.2466

DO - 10.1038/ng.2466

M3 - Article

VL - 44

SP - 1349

EP - 1354

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 12

ER -