Polymorphism in alcohol-metabolizing enzymes, glutathione S-transferases and apolipoprotein E and susceptibility to alcohol-induced cirrhosis and chronic pancreatitis.
OBJECTIVE
Susceptibility to organ damage induced by alcohol may be due to inherited variation (polymorphism) in ethanol-metabolizing enzymes, or to polymorphisms affecting free radical or lipid metabolism mediated by enzymes such as glutathione S-transferases and apolipoprotein E. The aim was to compare the genotype frequencies of alcohol dehydrogenase-2 (ADH2), ADH3, aldehyde dehydrogenase-2 (ALDH2), cytochrome P450-2E1 (CYP2E1), glutathione S-transferase-M1 (GSTM1), GSTT1, and apolipoprotein E in patients with alcoholic cirrhosis and alcoholic chronic pancreatitis to those in control groups.


METHODS
The case-control study was restricted to Caucasian adults: 57 with alcoholic cirrhosis, 71 with alcoholic chronic pancreatitis, 57 alcoholics without apparent organ damage and 200 healthy blood donors. Genotypes were determined by restriction fragment length polymorphism after amplification of genomic DNA by polymerase chain reaction.


RESULTS
The genotype ADH3*2/*2 was more frequent in patients with cirrhosis (40%) than blood donors (12%; OR 4.92, 95% CI 2.36-10.31) and patients with chronic pancreatitis (8%; OR 7.33, 95% CI 2.54-23.78) but was not significantly different from alcoholic controls (23%; OR 2.27, 95% CI 0.95-5.66). Patients with cirrhosis also had a higher frequency (P < 0.05) of ADH2*1/*1 (100%) than blood donors (92%) and those with chronic pancreatitis (93%). The frequencies of genotypes of ALDH2, CYP2E1, GSTM1, GSTT1 and apolipoprotein E were similar in all groups.


CONCLUSIONS
Alcoholic cirrhosis but not alcoholic chronic pancreatitis is associated with ADH3*2/*2 and perhaps with ADH2*1/*1. Both genes encode less active alcohol-metabolizing enzymes that may be associated with cirrhosis because of delayed formation of acetaldehyde (with higher intakes of alcohol), or diversion of alcohol metabolism through pathways other than ADH.
Frenzer
Andreas
A
Department of Gastroenterology, The Queen Elizabeth Hospital, Adelaide, SA, Australia.
Butler
Wendy J
WJ
Norton
Ian D
ID
Wilson
Jeremy S
JS
Apte
Minoti V
MV
Pirola
Romano C
RC
Ryan
Philip
P
Roberts-Thomson
Ian C
IC
D000328:Adult; D000426:Alcohol Dehydrogenase / Q000235:genetics / Q000378:metabolism; D000444:Aldehyde Dehydrogenase / Q000235:genetics / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics*; D016022:Case-Control Studies; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism; D000431:Ethanol / Q000378:metabolism; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D008104:Liver Cirrhosis, Alcoholic / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010088:Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D019512:Pancreatitis, Alcoholic / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length
D001057:Apolipoproteins E; D000431:Ethanol; D010088:Oxidoreductases; D000426:Alcohol Dehydrogenase; D019392:Cytochrome P-450 CYP2E1; D000444:Aldehyde Dehydrogenase; D005982:Glutathione Transferase