Valine-alanine manganese superoxide dismutase polymorphism is not associated with alcohol-induced oxidative stress or liver fibrosis

Abstract

The role of genetic factors in the pathogenesis of alcohol‐induced liver disease (ALD) is receiving increasing attention. Recently, it has been reported that homozygosity for a valine to alanine substitution in the mitochondrial targeting sequence of manganese superoxide dismutase (Mn‐SOD) represents a risk factor for severe ALD. Because this mutation is postulated to modify enzyme transport into mitochondria, we have sought confirmatory evidence of this association in a larger group of patients and investigated whether this polymorphism might influence alcohol‐induced oxidative stress. Genotyping for the valinealanine (Val‐Ala) polymorphism of the Mn‐SOD gene in 281 patients with advanced ALD (cirrhosis/fibrosis) and 218 drinkers without liver disease showed no differences in either the heterozygote (55% vs. 50%) or the homozygote (19% vs. 23%) frequency for the alanine allele. By measuring the titers of circulating antibodies against oxidized cardiolipin (OX‐CL) and malondialdehyde (MDA) or hydroxy‐ethyl radical (HER) adducts as markers of oxidative stress, we found a significant increase in ALD patients compared with healthy controls. However, the carriers of the alanine Mn‐SOD allele had titers of anti‐MDA, anti‐HER, and anti‐OX‐CL IgG comparable with heterozygotes and patients homozygous for the valine allele. Similarly, the frequency of subjects with antibody titers above the 95th percentile of controls was not increased among homozygotes for the alanine Mn‐SOD allele. In conclusion, in our population Val‐Ala polymorphism in Mn‐SOD influences neither susceptibility to alcohol‐induced liver fibrosis nor alcohol‐induced oxidative stress. (HEPATOLOGY2002;36:1355‐1360).

Genetic Polymorphisms in Antioxidant Enzymes Modulate Hepatic Iron Accumulation and Hepatocellular Carcinoma Development in Patients with Alcohol-Induced Cirrhosis

“…As the time of follow-up increased, the proportion of surviving patients with two Val-MnSOD alleles increased (27). This may explain why the genotypic repartition of alcoholic patients differed from control subjects when patients were studied at the time of the first liver biopsy showing cirrhosis (26,27), but not when blood samples were drawn at various times after diagnosis (40,41). In the present study, only patients with a documented HFE genotype were included.…”

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

“…Thus, an imbalance resulting in increased hydrogen peroxide formation and decreased detoxification may be a critical event for the initiation and progression of alcohol induced liver injury. With this said, however, studies performed in the UK with a larger cohort of alcoholic patients showed no association among the valine-alanine SOD2 polymorphism, alcohol-dependent markers of oxidative stress, and liver fibrosis [132]. Preliminary studies indicate that the SOD2 polymorphism may be correlated to fibrosis in NAFLD patients [133].…”

Genetic determinants of hepatic steatosis in man

“…The increased oxidative stress could lead to greater risk of the development of NASH. The 1183 polymorphism does not infl uence susceptibility to alcohol-induced liver fi brosis or alcohol-induced oxidative stress ( 248 ).…”

“…A single study by Namikawa et al found a higher frequency of SOD2 genotype 1183-TT in 63 biopsy-proven NASH patients (frequency 0.841) compared with 150 healthy controls (0.680) ( 178 ). The minor C allele results in a valine-to-alanine change that may alter the helical structure of the mitochondrial targeting sequence, enhancing transport of manganese SOD to the mitochondria ( 248 ). The increased oxidative stress could lead to greater risk of the development of NASH.…”