title: Association Analysis of PRSS1-PRSS2 and CLDN2-MORC4 Variants in Nonalcoholic Chronic Pancreatitis Using Tropical Calcific Pancreatitis as Model.
abstract: Association of PRSS1-PRSS2 (rs10273639) and CLDN2-MORC4 (rs12688220 and rs7057398) variants with alcohol-related chronic pancreatitis (CP) is established but with nonalcoholic CP is unclear. We addressed this inconsistency using tropical calcific pancreatitis (TCP) as model.
  
  
  
  We sequenced 5'-UTR of PRSS1 and genotyped CLDN2-MORC4 variants in 555 patients with TCP and 801 controls and performed association analysis. Gene-gene interaction between PRSS1 and CLDN2-MORC4 variants and with p.Asn34Ser SPINK1 and p.Leu26Val CTSB was also evaluated.
  
  
  
  We observed significant association of rs10273639/rs4726576 in PRSS1-PRSS2 (odds ratio [OR] = 0.72; P = 3.50 × 10) and CLDN2-MORC4 variants, rs12688220 (OR = 1.54; P = 1.22 × 10) and rs7057398 (OR = 1.50; P = 1.22 × 10) with TCP. Patients carrying p.Asn34Ser SPINK1 were significantly younger than those with rs4726576 risk genotype (30.0 vs 38.0 years; P = 0.015) and those carrying both were even younger (22.0 years; P = 0.001). Presence of risk allele at rs12688220 in patients carrying p.Asn34Ser SPINK1 delayed the age of onset (32.0 vs 24.0 years; P = 0.013).
  
  
  
  Our study establishes strong association of PRSS1-PRSS2 and CLDN2-MORC4 variants with TCP and thus with nonalcoholic CP. These variants independently interact with p.Asn34Ser SPINK1 and influence the age of onset in TCP. However, latter results need to be replicated in other cohorts.
authors.affiliation: From the *CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB); †Asian Healthcare Foundation, Asian Institute of Gastroenterology, Punjagutta, Hyderabad; ‡Department of Gastroenterology, Medical College, Calicut, Kerala; §Department of Gastroenterology, SCB Medical College, Cuttack, Odisha, India; ∥Centre for DNA Fingerprinting and Diagnostics, Hyderabad, India; and ¶Genome Institute of Singapore, Singapore.
authors.forename: Sumit
authors.initials: S
authors.lastname: Paliwal
authors.forename: Seema
authors.initials: S
authors.lastname: Bhaskar
authors.forename: D
authors.initials: D
authors.lastname: Nageshwar Reddy
authors.forename: G Venkat
authors.initials: GV
authors.lastname: Rao
authors.forename: Varghese
authors.initials: V
authors.lastname: Thomas
authors.forename: Shivaram Prasad
authors.initials: SP
authors.lastname: Singh
authors.forename: Giriraj Ratan
authors.initials: GR
authors.lastname: Chandak
mesh_terms: D000483:Alleles; D002114:Calcinosis; D057167:Claudins; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D009154:Mutation; D009687:Nuclear Proteins; D016017:Odds Ratio; D050500:Pancreatitis, Chronic; D014357:Trypsin; D014359:Trypsin Inhibitor, Kazal Pancreatic; D014362:Trypsinogen
chemical_list: C491875:CLDN2 protein, human; D057167:Claudins; C523050:MORC4 protein, human; D009687:Nuclear Proteins; C064831:PRSS2 protein, human; D014359:Trypsin Inhibitor, Kazal Pancreatic; D014362:Trypsinogen; C489303:PRSS1 protein, human; D014357:Trypsin