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

被引：253

作者：

Whitcomb, David C. ^{[1
,2
,3
]}

LaRusch, Jessica ^{[1
]}

Krasinskas, Alyssa M. ^{[4
]}

Klei, Lambertus ^{[5
]}

Smith, Jill P. ^{[6
]}

Brand, Randall E. ^{[1
]}

Neoptolemos, John P. ^{[7
]}

Lerch, Markus M. ^{[9
]}

Tector, Matt ^{[8
]}

Sandhu, Bimaljit S. ^{[10
]}

Guda, Nalini M. ^{[8
]}

Orlichenko, Lidiya ^{[1
]}

Alkaade, Samer ^{[11
]}

Amann, Stephen T. ^{[12
]}

Anderson, Michelle A. ^{[13
]}

Baillie, John ^{[14
]}

Banks, Peter A.

Conwell, Darwin ^{[15
]}

Cote, Gregory A. ^{[16
]}

Cotton, Peter B. ^{[17
]}

DiSario, James ^{[18
]}

Farrer, Lindsay A. ^{[19
,90
,91
,96
]}

Forsmark, Chris E. ^{[20
]}

Johnstone, Marianne ^{[7
]}

Gardner, Timothy B. ^{[21
]}

Gelrud, Andres ^{[1
]}

Greenhalf, William ^{[7
]}

Haines, Jonathan L. ^{[22
,23
]}

Hartman, Douglas J. ^{[4
]}

Hawes, Robert A. ^{[17
]}

Lawrence, Christopher ^{[17
]}

Lewis, Michele ^{[24
]}

Mayerle, Julia ^{[9
]}

Mayeux, Richard ^{[25
,26
]}

Melhem, Nadine M. ^{[5
]}

Money, Mary E. ^{[27
]}

Muniraj, Thiruvengadam ^{[28
,29
]}

Papachristou, Georgios I. ^{[1
]}

Pericak-Vance, Margaret A. ^{[30
,31
]}

Romagnuolo, Joseph ^{[17
]}

Schellenberg, Gerard D. ^{[32
]}

Sherman, Stuart ^{[16
]}

Simon, Peter ^{[9
]}

Singh, Vijay P. ^{[1
]}

Slivka, Adam ^{[1
]}

Stolz, Donna ^{[2
]}

Sutton, Robert ^{[7
]}

Weiss, Frank Ulrich ^{[9
]}

Wilcox, C. Mel ^{[33
]}

Zarnescu, Narcis Octavian ^{[1
]}

机构：

[1] Univ Pittsburgh, Sch Med, Div Gastroenterol Hepatol & Nutr, Pittsburgh, PA 15260 USA

[2] Univ Pittsburgh, Sch Med, Dept Cell Biol & Physiol, Pittsburgh, PA USA

[3] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA

[4] Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA USA

[5] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA

[6] Penn State Univ, Div Gastroenterol & Liver Dis, Hershey, PA USA

[7] Univ Liverpool, Inst Translat Med, Natl Inst Hlth Res Liverpool Pancreas Biomed Res, Dept Mol & Clin Canc Med, Liverpool L69 3BX, Merseyside, England

[8] St Lukes Med Ctr, Aurora Hlth Care Syst, Milwaukee, WI USA

[9] Univ Med Greifswald, Dept Med A, Greifswald, Germany

[10] Virginia Commonwealth Univ, Med Ctr, Div Gastroenterol Hepatol & Nutr, Richmond, VA USA

[11] St Louis Univ, Dept Med, St Louis, MO USA

[12] N Mississippi Med Ctr, Tupelo, MS USA

[13] Univ Michigan, Div Gastroenterol, Ann Arbor, MI 48109 USA

[14] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA

[15] Brigham & Womens Hosp, Div Gastroenterol, Boston, MA 02115 USA

[16] Indiana Univ, Med Ctr, Dept Med, Indianapolis, IN USA

[17] Med Univ S Carolina, Ctr Digest Dis, Charleston, SC 29425 USA

[18] Univ Utah, Hlth Sci Ctr, Dept Med, Salt Lake City, UT 84132 USA

[19] Boston Univ, Sch Med, Dept Med, Biomed Genet Sect, Boston, MA 02118 USA

[20] Univ Florida, Dept Med, Gainesville, FL USA

[21] Dartmouth Hitchcock Med Ctr, Div Gastroenterol & Hepatol, Dept Med, Hanover, NH USA

[22] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA

[23] Vanderbilt Univ, Vanderbilt Ctr Human Genet Res, Nashville, TN USA

[24] Mayo Clin, Div Gastroenterol & Hepatol, Jacksonville, FL 32224 USA

[25] Columbia Univ, Dept Neurol, Gertrude H Sergievsky Ctr, New York, NY USA

[26] Columbia Univ, Dept Neurol, Taub Inst Alzheimers Dis & Aging Brain, New York, NY USA

[27] Meritus Med Ctr, Hagerstown, MD USA

[28] Yale Univ, Dept Internal Med, Derby, CT USA

[29] Griffin Hosp, Derby, CT USA

[30] Univ Miami, John P Hussman Inst Human Genom, Miami, FL USA

[31] Univ Miami, Dept Human Genet, Dr John T Macdonald Fdn, Miami, FL USA

[32] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA USA

[33] Univ Alabama Birmingham, Dept Med, Div Gastroenterol & Hepatol, Birmingham, AL 35294 USA

[34] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Epidemiol Data Ctr, Pittsburgh, PA USA

[35] Carnegie Mellon Univ, Dept Stat, Pittsburgh, PA 15213 USA

[36] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA

[37] Univ Michigan, Dept Neurol, Ann Arbor, MI USA

[38] VA Ann Arbor Healthcare Syst VAAAHS, GRECC, Ann Arbor, MI USA

[39] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA

[40] Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA

[41] Boston Univ, Genet Program, Dept Med, Boston, MA USA

[42] Univ N Texas, Hlth Sci Ctr, Dept Pharmacol & Neurosci, Ft Worth, TX USA

[43] Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA

[44] Rush Univ, Med Ctr, Dept Behav Sci, Chicago, IL USA

[45] Banner Sun Hlth Res Inst, Civin Lab Neuropathol, Phoenix, AZ USA

[46] Univ Washington, Natl Alzheimers Coordinating Ctr, Seattle, WA 98195 USA

[47] Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL USA

[48] Northwestern Univ, Dept Pathol, Chicago, IL 60611 USA

[49] Univ Washington, Dept Neurol, Seattle, WA USA

[50] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA

来源：

NATURE GENETICS | 2012年 / 44卷 / 12期

基金：

美国国家卫生研究院;

关键词：

HEREDITARY PANCREATITIS; CLAUDIN-2; EXPRESSION; RECURRENT ACUTE; ACTIVATION; DIAGNOSIS; PROMOTER;

D O I：

10.1038/ng.2466

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 x 10(-12)) and X-linked CLDN2 (P < 1 x 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).

引用

页码：1349 / 1354

页数：6

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