Abstract
Alcohol abuse is one of the most common risk factor for chronic pancreatitis, but the underlying pathophysiological mechanisms remain unclear. The aim of this study was to identify genes that contribute to susceptibility or resistance for alcoholic chronic pancreatitis by screening the whole genome. Sixty-five patients with alcoholic chronic pancreatitis (63 men and 2 women, mean age 55.2 years) and 99 healthy Japanese controls were enrolled in this study. This was an association study using 400 polymorphic microsatellite markers with an average spacing of 10.8 cM distributed throughout the whole genome. This search revealed 10 candidate susceptibility regions and 5 candidate resistant regions throughout the genome. No specific microsatellite markers were detected in association with previously reported susceptibility genes for chronic pancreatitis, such as PRSS1, PRSS2, CTRC, SPINK1, CFTR, ALDH2, and CYP2E1. Among the statistically significant markers, D15S1007 on chromosome 15q14 showed strong evidence for disease susceptibility (70.8% vs. 35.1%, Pc = 0.0001). Within 500 kb of D15S1007, several genes were candidate genes for susceptibility, including FMN1, DKFZP686C2281, LOC440268, RYR3, and AVEN, This study identified 10 candidate susceptibility and 5 candidate resistant regions that may contain genes involved in ACP pathogenesis.
Highlights
Chronic pancreatitis is clinically characterized by severe abdominal pain, exocrine and endocrine dysfunction, and pancreatic calcification [1]
Four hundred microsatellite markers were used in a genome-wide linkage search in alcoholic chronic pancreatitis (ACP) patients with age- and sex-matched controls to identify genetic intervals that contained ACP susceptibility or resistance loci
Microsatellite analysis is an effective tool for this type of study, and we recently used it to identify genes associated with autoimmune hepatitis [25]
Summary
Chronic pancreatitis is clinically characterized by severe abdominal pain, exocrine and endocrine dysfunction, and pancreatic calcification [1]. Alcohol abuse remains one of the highest-impact risk factors associated with chronic pancreatitis [2,3]. Alcohol abuse might not be sufficient alone pancreatitis, as there is a limited prevalence of chronic pancreatitis in alcoholics. The pathophysiological mechanisms responsible for alcoholic chronic pancreatitis (ACP) remain unknown [4]. It seems likely that ACP is a multifactorial disease, with both genetic and environmental factors contributing to pathogenesis. Several studies have reported a genetic predisposition to chronic pancreatitis. Mutations that appear to affect disease susceptibility have been identified in isoforms of trypsinogen (PRSS1, PRSS2, CTRC) [5,6,7,8,9], in the pancreatic secretory trypsin inhibitor (SPINK1) gene [10,11,12,13], and in the cystic fibrosis transmembrane conductance regulator (CFTR) gene [14,15]. Alcohol may be a cofactor in the development of alcoholic pancreatitis in susceptible humans [4], and the alcohol metabolizing enzymes ADH2 [16], ADH3 [17], ALDH2 [18,19], CYP2E1 [20], and the HLA
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