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Title | Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis. |
Publication Type | Journal Article |
Year of Publication | 2012 |
Authors | 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 FUlrich, C Wilcox M, Zarnescu NOctavian, Wisniewski SR, O'Connell MR, Kienholz ML, Roeder K, M Barmada M, Yadav D, Devlin B |
Corporate Authors | Alzheimer's Disease Genetics Consortium |
Journal | Nat Genet |
Volume | 44 |
Issue | 12 |
Pagination | 1349-54 |
Date Published | 2012 Dec |
ISSN | 1546-1718 |
Keywords | Claudins, Female, Gene Frequency, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Homozygote, Humans, Male, Mutation, Pancreatitis, Alcoholic, Sex Factors, Trypsin, Trypsinogen |
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). |
DOI | 10.1038/ng.2466 |
Alternate Journal | Nat. Genet. |
PubMed ID | 23143602 |
PubMed Central ID | PMC3510344 |
Grant List | AG010491 / AG / NIA NIH HHS / United States AG019757 / AG / NIA NIH HHS / United States AG021547 / AG / NIA NIH HHS / United States AG025688 / AG / NIA NIH HHS / United States AG027944 / AG / NIA NIH HHS / United States AG030653 / AG / NIA NIH HHS / United States AG05128 / AG / NIA NIH HHS / United States AG05144 / AG / NIA NIH HHS / United States HHSN268200782096C / / PHS HHS / United States M01RR00096 / RR / NCRR NIH HHS / United States MH60451 / MH / NIMH NIH HHS / United States NS39764 / NS / NINDS NIH HHS / United States P01AG002219 / AG / NIA NIH HHS / United States P01AG019724 / AG / NIA NIH HHS / United States P01AG03991 / AG / NIA NIH HHS / United States P30 AG010124 / AG / NIA NIH HHS / United States P30AG008017 / AG / NIA NIH HHS / United States P30AG010124 / AG / NIA NIH HHS / United States P30AG010129 / AG / NIA NIH HHS / United States P30AG010161 / AG / NIA NIH HHS / United States P30AG012300 / AG / NIA NIH HHS / United States P30AG013846 / AG / NIA NIH HHS / United States P30AG013854 / AG / NIA NIH HHS / United States P30AG019610 / AG / NIA NIH HHS / United States P30AG028377 / AG / NIA NIH HHS / United States P30AG028383 / AG / NIA NIH HHS / United States P30AG08051 / AG / NIA NIH HHS / United States P30AG10133 / AG / NIA NIH HHS / United States P30CA047904 / CA / NCI NIH HHS / United States P50 AG016574 / AG / NIA NIH HHS / United States P50AG005131 / AG / NIA NIH HHS / United States P50AG005133 / AG / NIA NIH HHS / United States P50AG005134 / AG / NIA NIH HHS / United States P50AG005136 / AG / NIA NIH HHS / United States P50AG005138 / AG / NIA NIH HHS / United States P50AG005142 / AG / NIA NIH HHS / United States P50AG005146 / AG / NIA NIH HHS / United States P50AG005681 / AG / NIA NIH HHS / United States P50AG008671 / AG / NIA NIH HHS / United States P50AG008702 / AG / NIA NIH HHS / United States P50AG016570 / AG / NIA NIH HHS / United States P50AG016573 / AG / NIA NIH HHS / United States P50AG016574 / AG / NIA NIH HHS / United States P50AG016575 / AG / NIA NIH HHS / United States P50AG016576 / AG / NIA NIH HHS / United States P50AG016577 / AG / NIA NIH HHS / United States P50AG016582 / AG / NIA NIH HHS / United States P50AG023501 / AG / NIA NIH HHS / United States R01 AG015819 / AG / NIA NIH HHS / United States R01 AG022018 / AG / NIA NIH HHS / United States R01 AG032990 / AG / NIA NIH HHS / United States R01 MH057881 / MH / NIMH NIH HHS / United States R01AG017173 / AG / NIA NIH HHS / United States R01AG019085 / AG / NIA NIH HHS / United States R01AG020688 / AG / NIA NIH HHS / United States R01AG025259 / AG / NIA NIH HHS / United States R01AG026916 / AG / NIA NIH HHS / United States R01AG027944 / AG / NIA NIH HHS / United States R01AG031581 / AG / NIA NIH HHS / United States R01AG15819 / AG / NIA NIH HHS / United States R01AG17917 / AG / NIA NIH HHS / United States R01AG30146 / AG / NIA NIH HHS / United States R01AG33193 / AG / NIA NIH HHS / United States R01CA117926 / CA / NCI NIH HHS / United States R01CA129769 / CA / NCI NIH HHS / United States R01DK054709 / DK / NIDDK NIH HHS / United States R01DK077906 / DK / NIDDK NIH HHS / United States R01MH057881 / MH / NIMH NIH HHS / United States R01MH080295 / MH / NIMH NIH HHS / United States R01NS36960 / NS / NINDS NIH HHS / United States R37AG015473 / AG / NIA NIH HHS / United States R56DK061451 / DK / NIDDK NIH HHS / United States RC2AG036528 / AG / NIA NIH HHS / United States T32DK063922 / DK / NIDDK NIH HHS / United States U01 AG016976 / AG / NIA NIH HHS / United States U01AG016976 / AG / NIA NIH HHS / United States U01AG032984 / AG / NIA NIH HHS / United States U01AG10483 / AG / NIA NIH HHS / United States U24AG021886 / AG / NIA NIH HHS / United States UL1 RR024153 / RR / NCRR NIH HHS / United States UL1 RR029893 / RR / NCRR NIH HHS / United States UL1 TR000005 / TR / NCATS NIH HHS / United States UL1RR024153 / RR / NCRR NIH HHS / United States UL1RR02777 / RR / NCRR NIH HHS / United States UL1RR029893 / RR / NCRR NIH HHS / United States UL1TR000005 / TR / NCATS NIH HHS / United States |