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 | |
| State | Published - Dec 2012 |
ASJC Scopus subject areas
- Genetics
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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 journal › Article
}
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
C2 - 23143602
AN - SCOPUS:84870511045
VL - 44
SP - 1349
EP - 1354
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 12
ER -