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Nat Genet. 2012 Dec;44(12):1349-54. doi: 10.1038/ng.2466. Epub 2012 Nov 11.

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

Collaborators (141)

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, Kukull 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, Murrell 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.

Author information

1
Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. whitcomb@pitt.edu

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).

PMID:
23143602
PMCID:
PMC3510344
DOI:
10.1038/ng.2466
[Indexed for MEDLINE]
Free PMC Article

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