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The role of genetic variation in predisposition to alcohol-related chronic pancreatitis

Background Chronic pancreatitis (CP) is a disease of fibrosis of the pancreas for which alcohol is the main causative agent. However, only a small proportion of alcoholics develop chronic pancreatitis. Genetic polymorphism may affect pancreatitis risk. Aim To determine the factors required to classify a chronic pancreatic population and identify genetic variations that may explain why only some alcoholics develop chronic pancreatitis. Methods The most appropriate method of diagnosing CP was assessed using a systematic review. Genetics of different populations of alcohol-related chronic pancreatitics (ACP) were explored using four different techniques: genome-wide association study (GWAS); custom arrays; PCR of variable nucleotide tandem repeats (VNTR) and next generation sequencing (NGS) of selected genes. Results EUS and sMR were identified as giving the overall best sensitivity and specificity for diagnosing CP. GWAS revealed two associations with CP (identified and replicated) at PRSS1-PRSS2_rs10273639 (OR 0.73, 95% CI 0.68-0.79) and X-linked CLDN2_rs12688220 (OR 1.39, 1.28-1.49) and the association was more pronounced in the ACP group (OR 0.56, 0.48-0.64)and OR 2.11, 1.84-2.42). The previously identified VNTR in CEL was shown to have a lower frequency of the normal repeat in ACP than alcoholic liver disease (ALD; OR 0.61, 0.41-0.93). Homozygosity of the normal variant was more common in ALD than ACP (OR 0.53, 0.3-0.96) or Healthy Controls (OR 0.55, 0.3-1.00)). The NGS discovery phase lead on to validation of the 21 most significant SNPs with Sequenom array. This showed significance difference between ACP and ALD in allele frequency of the synonymous SNP, PRSS1_rs6666, (OR 1.99, 1.46-2.72) Conclusion A range of potential exonic and intronic sites have been identified that have association with a predisposition to developing chronic pancreatitis. These findings show that further work is justified to fully assess the interaction of the different polymorphisms and their phenotypic significance in development of the disease.

Identiferoai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:677592
Date January 2015
CreatorsJohnstone, Marianne
PublisherUniversity of Liverpool
Source SetsEthos UK
Detected LanguageEnglish
TypeElectronic Thesis or Dissertation
Sourcehttp://livrepository.liverpool.ac.uk/2037520/

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