Gastroenterology

Gastroenterology

Volume 120, Issue 6, May 2001, Pages 1468-1474
Gastroenterology

Liver, Pancreas, and Biliary Tract
Homozygosity for alanine in the mitochondrial targeting sequence of superoxide dismutase and risk for severe alcoholic liver disease☆,☆☆

https://doi.org/10.1053/gast.2001.24051Get rights and content

Abstract

Background & Aims: For similar ethanol consumption, some subjects only develop macrovacuolar steatosis whereas others develop severe liver lesions. A genetic dimorphism encodes for either alanine or valine in the mitochondrial targeting sequence of manganese superoxide dismutase and could modulate its mitochondrial import. Methods: The DNA of 71 white patients with alcoholic liver disease and 79 white blood donors was amplified and genotyped. Results: The frequency of the alanine-encoding allele and the percentage of alanine homozygotes were higher in all patients than in controls and increased with the severity of liver lesions. The percentage of alanine homozygotes was 19% in controls, 17% in alcoholic patients with macrovacuolar steatosis, 43% in patients with microvesicular steatosis, 58% in patients with alcoholic hepatitis, and 69% in patients with cirrhosis. Alcohol consumption in alcoholics was similar whatever the genotype. Alanine homozygosity did not change the risk of developing macrovacuolar steatosis in alcoholics, but increased by 3-fold that of microvesicular steatosis, and 6- and 10-fold that of alcoholic hepatitis and cirrhosis. Conclusions: Homozygosity for alanine in the mitochondrial targeting sequence of manganese superoxide does not modify alcohol consumption and the risk of macrovacuolar steatosis in alcoholics but is a major risk factor for severe alcoholic liver disease.

GASTROENTEROLOGY 2001;120:1468-1474

Section snippets

Subjects

We determined the MnSOD mitochondrial targeting sequence genotype in a retrospective analysis of the liver DNA of 71 white patients with ALD and the blood cell DNA of 79 white blood donors from the same area. All these blood cell DNAs and most of the liver DNAs had been previously prepared to determine the prevalence of medium chain acyl-CoA dehydrogenase deficiency in a control white French population,16 and the prevalence of mitochondrial DNA deletions in white alcoholics, respectively.17, 18

Results

In blood donors, the frequency of the Ala allele (0.46) (Table 1) was similar to that (0.41–0.51) in other white populations.11, 13, 15In the entire ALD group, the frequency of the Ala allele (0.63) was higher than in controls (Table 1). The frequency increased with the severity of liver lesions: 0.47 (i.e., similar to controls) in patients with only macrovacuolar steatosis, 0.61 in patients with microvesicular steatosis, 0.75 in patients with alcoholic hepatitis, and 0.81 in patients with

Discussion

This is the first study to show that homozygotes for the alanine-encoding allele in the mitochondrial targeting sequence of MnSOD have an increased risk of developing severe ALD, compared with subjects with only one or no Ala-encoding alleles (Table 3). Similarly, prior studies have shown that Ala/Ala homozygotes have a higher risk of developing nonalcoholic diseases, such as sporadic motor neuron disease or breast cancer.14, 15

The genetic predisposition of Ala/Ala alcoholics is not caused by

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    ☆

    Address requests for reprints to: Françoise Degoul, Ph.D., INSERM U481, Hôpital Beaujon, 92118 Clichy, France. e-mail: [email protected]; fax: (33) 1-47-30-94-40.

    ☆☆

    Supported in part by a subvention from IREB (Institut de Recherches Scientifiques sur les Boissons).

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    Copyright © 2001 American Gastroenterological Association. Published by Elsevier Inc. All rights reserved.