Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis.
Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis.
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DOI：
10.1038/ng.2466
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发表时间：
2012-12
期刊：
影响因子：
30.8
通讯作者：
Yu, Lei
中科院分区：
文献类型：
--
作者：
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;Cote, 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;Kukull, 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.;Murrell, 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.;Vonsattel, 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
胰腺炎是一种复杂的、进行性破坏性的炎症性疾病。长期以来，酒精被认为是主要的致病因子，但自从发现罕见的PRSS 1，CFTR和SPINK 1变异与胰腺炎风险相关以来，遗传贡献一直受到关注。我们现在报告了两个显著的全基因组关联，通过两阶段的全基因组研究（第1阶段，676例病例和4507例对照;第2阶段，910例病例和4170例对照），在PRSS 1-PRSS 2（1× 10 -12）和x连锁CLDN 2（p < 1×10-21）中鉴定和复制。PRSS 1变异体通过改变初级胰蛋白酶原基因的表达影响易感性。CLDN 2风险等位基因与胰腺腺泡细胞中紧密连接蛋白-2的非典型定位相关。纯合子（或半合子男性）CLDN 2基因型赋予最大的风险，其等位基因与酒精消费相互作用以放大风险。这些结果可以部分解释男性酒精相关胰腺炎的高频率-男性半合子频率为0.26，女性纯合子为0.07。
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 significant genome-wide associations identified and replicated at PRSS1-PRSS2 (1×10-12) and x-linked CLDN2 (p < 1×10-21) through a two-stage genome-wide study (Stage 1, 676 cases and 4507 controls; Stage 2, 910 cases and 4170 controls). The PRSS1 variant affects 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 male) 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 hemizygous frequency is 0.26, female homozygote is 0.07.
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影响因子：
5.8
作者：
Johnson, Andrew D.;Handsaker, Robert E.;de Bakker, Paul I. W.
通讯作者：
de Bakker, Paul I. W.
影响因子：
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作者：
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影响因子：
65.1
作者：
Whitcomb, David C.
通讯作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
--
作者：
Yadav D;Hawes RH;Brand RE;Anderson MA;Money ME;Banks PA;Bishop MD;Baillie J;Sherman S;DiSario J;Burton FR;Gardner TB;Amann ST;Gelrud A;Lawrence C;Elinoff B;Greer JB;O'Connell M;Barmada MM;Slivka A;Whitcomb DC;North American Pancreatic Study Group
通讯作者：
North American Pancreatic Study Group