Polymorphism of the 5'-flanking region of the CYP2E1 gene: an association study with alcoholism.
BACKGROUND
Recently, a restriction fragment length polymorphism in the regulatory region of the CYP2E1 gene was identified. It has been suggested that the polymorphism is associated with the elevated activity of the cytochrome P-450 2E1 (CYP2E1) enzyme in obese or alcoholic subjects. However, significance of the polymorphism in connection with alcoholism has not been studied. In the present study, we have characterized these repeated sequences in the 5'-untranslated region of the CYP2E1 gene in Japanese subjects and North American white subjects and investigated whether these polymorphisms are associated with drinking habits and alcoholism.


METHODS
DNAs were isolated from blood samples of 192 Japanese nonalcoholics and 202 alcoholics as well as 125 North American white nonalcoholics. DNA samples were amplified by polymerase chain reaction and subjected to a fluorescent-based single-strand conformational change polymorphism analysis, DNA fragment analysis, and polymerase chain reaction-direct sequencing.


RESULTS
Four alleles (A1-A4) were found, which were differentiated by the six subunits (L1, L2, L3, L4, S1, S2) based on the size difference and nucleotide replacement. A2 and A4 alleles were observed in the two ethnic groups (A2: Japanese subjects, 0.752; white subjects, 0.976; A4: Japanese subjects, 0.227; white subjects, 0.016). However, A1 allele was found only in North American white subjects (0.008), and A3 allele was detected only in Japanese subjects (0.021). Allele frequencies were significantly different between the two ethnic groups (p < 0.0001). Distribution of genotypes between Japanese nonalcoholics and alcoholics were not significantly different. Also, no significant difference for the allele frequencies was observed between Japanese moderate drinkers and heavy drinkers.


CONCLUSIONS
Our data suggested no association among the polymorphic repeats, drinking behavior, and alcoholism. Allele frequencies were significantly different between Japanese subjects and North American white subjects.
Itoga
S
S
Department of Laboratory and Clinical Medicine, Chiba University School of Medicine, Chiba, Japan.
Harada
S
S
Nomura
F
F
D020121:5' Untranslated Regions; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000437:Alcoholism / Q000235:genetics*; D000483:Alleles; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics*; D004247:DNA / Q000097:blood; D005787:Gene Frequency; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D018807:Polymorphism, Single-Stranded Conformational; D020080:Tandem Repeat Sequences
D020121:5' Untranslated Regions; D004247:DNA; D019392:Cytochrome P-450 CYP2E1