Genetic Polymorphisms of Aldehyde Dehydrogenase 2, Cytochrome p450 2E1 for Liver Cancer Risk in HCV Antibody-Positive Japanese Patients and the Variations of CYP2E1 mRNA Expression Levels in the Liver due to its Polymorphism

Aug 28, 2003Scandinavian journal of gastroenterology

Liver cancer risk and liver gene activity linked to genetic differences in two enzymes in Japanese patients with hepatitis C

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Abstract

The allelic frequency of the homozygous ALDH2 2-2 genotype was significantly higher in patients with hepatocellular carcinoma (HCC) compared to non-cancer controls (OR = 5.4).

The homozygous ALDH2 2-2 genotype is associated with a higher risk of HCC in individuals with liver cirrhosis.
No significant differences were found in CYP2E1 genotype frequencies among HCC cases.
The combined presence of CYP2E1 C1/C1 homozygosity and ALDH2 2-2 homozygosity indicates a very high odds ratio of 23.0 for HCC occurrence.
Increased mRNA expression levels of CYP2E1 were observed in patients with C1/C1 homozygosity compared to other genotypes.
These findings suggest that polymorphisms in alcohol-metabolizing enzymes may influence HCC risk in the Japanese population.

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BACKGROUND: Hepatocellular carcinoma (HCC) in persons with liver cirrhosis (LC) arises following hepatitis virus infection. Alcohol may accelerate the risk of development of LC and HCC. Cytochrome p450 2E1 (CYP2E1) oxidizes ethanol to form acetaldehyde and aldehyde dehydrogenase 2 (ALDH2) detoxifies acetaldehyde, which is carcinogenic in humans, and both alcohol-metabolizing enzymes show the genetic polymorphisms in a Japanese population.

METHODS: Using polymorphism analysis, we studied the frequency of ALDH2 functional deletion due to the G to A single-bp mutation in exon 12 and CYP2E1 polymorphism in the transcriptional region, both associated with higher levels of acetaldehyde, in 135 patients with LC and/or HCC, including 99 with HCC, and 135 non-cancer controls. The mRNA expression levels of CYP2E1 in the liver were also examined in 55 surgical specimens.

RESULTS: The allelic frequency of the homozygous ALDH2 2-2 genotype, coding for the enzyme deletion, was significantly higher compared to that of the homozygous or heterozygous ALDH2 1-1 genotypes in cases with HCC (OR = 5.4, 95% CI 2.1-14.0). There were no differences in the frequencies of specific genotypes of CYP2E1 in cases of HCC, but combined analysis of ALDH2 and CYP2E1 revealed that the odds ratio of occurrence of the C1/C1 homozygosity of CYP2E1 and the ALDH2 2-2 homozygosity was as high as 23.0 (2.9-182). The mRNA levels of CYP2E1 were higher in the liver of patients with the C1/C1 homozygosity of CYP2E1 than in those with other genotypes (P < 0.05).

CONCLUSIONS: ALDH2 and CYP2E1 polymorphisms may modify the risk of development of HCC against the background of LC in the Japanese. Polymorphism analysis of alcohol-metabolizing enzymes using molecular techniques may be useful in the risk assessment of liver cancer in patients with hepatitis C virus infection.

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Genetic Polymorphisms of Aldehyde Dehydrogenase 2, Cytochrome p450 2E1 for Liver Cancer Risk in HCV Antibody-Positive Japanese Patients and the Variations of CYP2E1 mRNA Expression Levels in the Liver due to its Polymorphism

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