title: Association between calcium sensing receptor gene polymorphisms and chronic pancreatitis in a US population: role of serine protease inhibitor Kazal 1type and alcohol.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh PA 15213, USA.
authors.forename: Venkata
authors.initials: V
authors.lastname: Muddana
authors.forename: Janette
authors.initials: J
authors.lastname: Lamb
authors.forename: Julia-B
authors.initials: JB
authors.lastname: Greer
authors.forename: Beth
authors.initials: B
authors.lastname: Elinoff
authors.forename: Robert H
authors.initials: RH
authors.lastname: Hawes
authors.forename: Peter B
authors.initials: PB
authors.lastname: Cotton
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Anderson
authors.forename: Randall E
authors.initials: RE
authors.lastname: Brand
authors.forename: Adam
authors.initials: A
authors.lastname: Slivka
authors.forename: David C
authors.initials: DC
authors.lastname: Whitcomb
mesh_terms: D000328:Adult; D000368:Aged; D000428:Alcohol Drinking / Q000009:adverse effects*; D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D005091:Exons / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D050500:Pancreatitis, Chronic / Q000208:ethnology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D044169:Receptors, Calcium-Sensing / Q000235:genetics*; D012307:Risk Factors; D014359:Trypsin Inhibitor, Kazal Pancreatic; D014481:United States
chemical_list: C095550:CASR protein, human; D002352:Carrier Proteins; D044169:Receptors, Calcium-Sensing; C486642:SPINK1 protein, human; D014359:Trypsin Inhibitor, Kazal Pancreatic