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©2008 The WJG Press and Baishideng. All rights reserved.
World J Gastroenterol. Jul 28, 2008; 14(28): 4486-4491
Published online Jul 28, 2008. doi: 10.3748/wjg.14.4486
Association between calcium sensing receptor gene polymorphisms and chronic pancreatitis in a US population: Role of serine protease inhibitor Kazal 1type and alcohol
Venkata Muddana, Janette Lamb, Julia B Greer, Beth Elinoff, Robert H Hawes, Peter B Cotton, Michelle A Anderson, Randall E Brand, Adam Slivka, David C Whitcomb
Venkata Muddana, Janette Lamb, Julia B Greer, Beth Elinoff, Adam Slivka, David C Whitcomb, Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh PA 15213, United States
David C Whitcomb, Department of Human Genetics, University of Pittsburgh, Pittsburgh PA 15213, United States
Robert H Hawes, Peter B Cotton, Digestive Disorder Center, Medical University of South Carolina, Charleston SC 29403, United States
Michelle A Anderson, Department of Medicine, University of Michigan Medical Center, Ann Arbor MI 48109, United States
Randall E Brand, Department of medicine, Northwestern University, and Currently at University of Pittsburgh Medical Center, Pittsburgh PA 15213, United States
Author contributions: Muddana V: Study design, development of study methodology, data analysis, drafting the original manuscript and reviewing the final manuscript; Lamb J: Method development, data analysis, manuscript editing and review; Greer JB: Data analysis, reviewing, editing and writing of the final manuscript; Elinoff B: Study coordination, clinical data management and analysis, review of final manuscript; Hawes RH: Site PI, subject phenotyping, clinical data collection and analysis, review of final manuscript; Cotton PB: Subject phenotyping, clinical data collection and analysis, review of final manuscript; Anderson MA: Site PI, subject phenotyping, clinical data collection and analysis, review of final manuscript; Brand RE: Site PI, subject phenotyping, clinical data collection and analysis, review of final manuscript; Slivka A: Site PI, subject phenotyping, clinical data collection and analysis, review of final manuscript; Whitcomb DC: Study design, method development, data analysis, manuscript review and editing.
Correspondence to: David C Whitcomb, MD, PhD, Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh Medical Center, Mezzanine Level 2, C Wing, 200 Lothrop Street, Pittsburgh PA 15213, United
States.whitcomb@pitt.edu
Telephone: +1-412-6489604
Fax: +1-412-3837236
Received: April 11, 2008
Revised: July 15, 2008
Accepted: July 22, 2008
Published online: July 28, 2008
AIM: To test the hypothesis that calcium sensing receptor (CASR) polymorphisms are associated with chronic pancreatitis (CP), and to determine whether serine protease inhibitor Kazal 1type (SPINK1) N34S or alcohol are necessary co-factors in its etiology.
METHODS: Initially, 115 subjects with pancreatitis and 66 controls were evaluated, of whom 57 patients and 21 controls were predetermined to carry the high-risk SPINK1 N34S polymorphism. We sequenced CASR gene exons 2, 3, 4, 5 and 7, areas containing the majority of reported polymorphisms and novel mutations. Based on the initial results, we added 223 patients and 239 controls to analyze three common nonsynonymous single nucleotide polymorphisms (SNPs) in exon 7 (A986S, R990G, and Q1011E).
RESULTS: The CASR exon 7 R990G polymorphism was significantly associated with CP (OR, 2.01; 95% CI, 1.12-3.59; P = 0.015). The association between CASR R990G and CP was stronger in subjects who reported moderate or heavy alcohol consumption (OR, 3.12; 95% CI, 1.14-9.13; P = 0.018). There was no association between the various CASR genotypes and SPINK1 N34S in pancreatitis. None of the novel CASR polymorphisms reported from Germany and India was detected.
CONCLUSION: Our United States-based study confirmed an association of CASR and CP and for the first time demonstrated that CASR R990G is a significant risk factor for CP. We also conclude that the risk of CP with CASR R990G is increased in subjects with moderate to heavy alcohol consumption.
