Dataset Information

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

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).

SUBMITTER: Whitcomb DC

PROVIDER: S-EPMC3510344 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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

Whitcomb David C DC LaRusch Jessica J Krasinskas Alyssa M AM Klei Lambertus L Smith Jill P JP Brand Randall E RE Neoptolemos John P JP Lerch Markus M MM Tector Matt M Sandhu Bimaljit S BS Guda Nalini M NM Orlichenko Lidiya L Alkaade Samer S Amann Stephen T ST Anderson Michelle A MA Baillie John J Banks Peter A PA Conwell Darwin D Coté Gregory A GA Cotton Peter B PB DiSario James J Farrer Lindsay A LA Forsmark Chris E CE Johnstone Marianne M Gardner Timothy B TB Gelrud Andres A Greenhalf William W Haines Jonathan L JL Hartman Douglas J DJ Hawes Robert A RA Lawrence Christopher C Lewis Michele M Mayerle Julia J Mayeux Richard R Melhem Nadine M NM Money Mary E ME Muniraj Thiruvengadam T Papachristou Georgios I GI Pericak-Vance Margaret A MA Romagnuolo Joseph J Schellenberg Gerard D GD Sherman Stuart S Simon Peter P Singh Vijay P VP Slivka Adam A Stolz Donna D Sutton Robert R Weiss Frank Ulrich FU Wilcox C Mel CM Zarnescu Narcis Octavian NO Wisniewski Stephen R SR O'Connell Michael R MR Kienholz Michelle L ML Roeder Kathryn K Barmada M Michael MM Yadav Dhiraj D Devlin Bernie B

Nature genetics 20121111 12

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 a ...[more]

PMID: 23143602

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Project description:Background and Aim:The risks of post-ERCP pancreatitis (PEP) are identified as patient- and procedure-related factors. However, the genetic contribution for PEP is still unclear. Recent data show that the polymorphisms of PRSS1-PRSS2 (rs10273639) and MORC4 (rs12688220) are associated with recurrent acute pancreatitis and chronic pancreatitis. We aim to evaluate the association between these polymorphisms and post-ERCP pancreatitis in order to improve better prognosis and better care for these patients. Methods:This is a retrospective, case-control study which includes 49 cases and 97 controls that are age-, procedure-, and risk of PEP-matched with the cases in 1?:?2 fashion. The PEP was diagnosed and graded for severity according to the standard consensus, and the risk factors of PEP were identified according to the ESGE guideline. Polymorphisms at rs10273639 and rs12688220 were evaluated by TaqMan technique and were identified in 133 (40 cases and 93 controls) and 146 patients, respectively. Results:The demographic data between 2 groups are not significantly different. The genotype frequencies of PRSS1-PRSS2 (TT, TC, and CC) are 26, 13, and 1 vs. 67, 25, and 1 in cases and controls, respectively (p = 0.642). The genotype frequencies of MORC4 in female (TT, TC, and CC) are 8, 23, and 5 vs. 12, 26, and 21 in cases and controls, respectively (p = 0.071). The genotype frequencies of MORC4 in male (T and C) are 5 and 8 vs. 21 and 17 in cases and controls, respectively (p = 0.468). The allelic frequencies of MORC4 in combination of both genders (T, C) are 44 and 41 vs. 71 and 84 in cases and control, respectively (p = 0.431). In PEP cases, the allelic frequencies of PRSS1-PRSS2 (T and C) are 59 and 13 vs. 6 and 2 in mild and moderate/severe cases, respectively (p = 0.633). The allelic frequencies of MORC4 (T and C) are 38 and 39 vs. 4 and 4 in mild and moderate/severe cases, respectively (p = 0.972). Conclusion:Polymorphisms at PRSS1-PRSS2 and MORC4 are not associated with the risk or severity of post-ERCP pancreatitis.

Dataset Information

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

Publications

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

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