News & Updates
Search Research Content
Resource Finder at Kennedy Krieger Institute
A free resource that provides access to information and support for individuals and families living with developmental disabilities.
Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis.
|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 FU, Wilcox MC, Zarnescu NO, Wisniewski SR, O'Connell MR, Kienholz ML, Roeder K, Barmada MM, Yadav D, Devlin B|
|Corporate Authors||Alzheimer's Disease Genetics Consortium|
|Date Published||2012 Dec|
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).
|Alternate Journal||Nat. Genet.|