The mitochondrial superoxide dismutase A16V polymorphism in the cardiomyopathy associated with hereditary haemochromatosis
- 1 December 2004
- journal article
- research article
- Published by BMJ in Journal of Medical Genetics
- Vol. 41 (12), 946-950
- https://doi.org/10.1136/jmg.2004.019588
Abstract
The A16V mitochondrial targeting sequence polymorphism influences the antioxidant activity of MnSOD, an enzyme involved in neutralising iron induced oxidative stress. Patients with hereditary haemochromatosis develop parenchymal iron overload, which may lead to cirrhosis, diabetes, hypogonadism, and heart disease. The objective of this study was to determine in patients with haemochromatosis whether the presence of the Val MnSOD allele, associated with reduced enzymatic activity, affects tissue damage, and in particular heart disease, as MnSOD knockout mice develop lethal cardiomyopathy. We studied 217 consecutive unrelated probands with haemochromatosis, and 212 healthy controls. MnSOD polymorphism was evaluated by restriction analysis. The frequency distribution of the polymorphism did not differ between patients and controls. Patients carrying the Val allele had higher prevalence of cardiomyopathy (A/A 4%, A/V 11%, V/V 30%, p = 0.0006) but not of cirrhosis, diabetes, or hypogonadism, independently of age, sex, alcohol misuse, diabetes, and iron overload (odds ratio 10.1 for V/V, p = 0.006). The frequency of the Val allele was higher in patients with cardiomyopathy (0.67 v 0.45, p = 0.003). The association was significant in both C282Y+/+ (p = 0.02), and in non-C282Y+/+ patients (p = 0.003), and for both dilated (p = 0.01) and non-dilated stage (p = 0.04) cardiomyopathy, but not for ischaemic heart disease. In patients with hereditary haemochromatosis, the MnSOD genotype affects the risk of cardiomyopathy related to iron overload and possibly to other known and unknown risk factors and could represent an iron toxicity modifier gene.Keywords
This publication has 23 references indexed in Scilit:
- Adenovirus-mediated expression of Cu/Zn- or Mn-superoxide dismutase protects against CYP2E1-dependent toxicityHepatology, 2003
- Hfe deficiency increases susceptibility to cardiotoxicity and exacerbates changes in iron metabolism induced by doxorubicinBlood, 2003
- Penetrance in hereditary hemochromatosisBlood, 2003
- HFE Mutation and Dietary Iron Content Interact to Increase Ischemia/Reperfusion Injury of the Heart in MiceCirculation Research, 2003
- A Study of Genes That May Modulate the Expression of Hereditary Hemochromatosis: Transferrin Receptor-1, Ferroportin, Ceruloplasmin, Ferritin Light and Heavy Chains, Iron Regulatory Proteins (IRP)-1 and -2, and HepcidinBlood Cells, Molecules, and Diseases, 2001
- Overexpression of Manganese Superoxide Dismutase Prevents Alcohol-induced Liver Injury in the RatPublished by Elsevier BV ,2001
- A Population-Based Study of the Clinical Expression of the Hemochromatosis GeneNew England Journal of Medicine, 1999
- Polymorphisms in the SOD2 and HLA-DRB1 Genes Are Associated with Nonfamilial Idiopathic Dilated Cardiomyopathy in JapaneseBiochemical and Biophysical Research Communications, 1999
- Heterogeneity of hemochromatosis in ItalyGastroenterology, 1998
- A novel MHC class I–like gene is mutated in patients with hereditary haemochromatosisNature Genetics, 1996