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

• Authors: David C. Whitcomb, University of Pittsburgh; Jessica LaRusch, University of Pittsburgh; Alyssa Krasinskas, Emory University; Lambertus Klei, University of Pittsburgh; Jill P. Smith, Pennsylvania State University; Randall E. Brand, University of Pittsburgh; John P. Neoptolemos, University of Liverpool; Markus M. Lerch, University Medical Greifswald; Matt Tector, St. Luke's Medical Center; Bimaljit S. Sandhu, Virginia Commonwealth University; Nalini M. Guda, St. Luke's Medical Center; Lidiya Orlichenko, University of Pittsburgh; Samer Alkaade, St. Louis University; Stephen T. Amann, North Mississippi Medical Center; Michelle A. Anderson, University of Michigan; Marla Gearing, Emory University; Jonathan D Glass, Emory University; Robert Green, Emory University; Allan I Levey, Emory University; James J Lah, Emory University
• Journal Title: Nature Genetics
• Volume: Volume 44, Number 12
• Publisher: Nature Research (part of Springer Nature) | 2012-12-01, Pages 1349-1354
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1038/ng.2466
• Subjects: Health Sciences, Medicine and Surgery; Biology, Genetics; Health Sciences, Pathology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Genetics & Heredity; HEREDITARY PANCREATITIS; CLAUDIN-2 EXPRESSION; RECURRENT ACUTE; ACTIVATION; DIAGNOSIS; PROMOTER

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).