title: Haemochromatosis gene mutations in idiopathic dilated cardiomyopathy.
abstract: BACKGROUND
  Two common mutations of the haemochromatosis associated gene (HFE) (cys282tyr (C282Y) and his63asp (H63D)) have been implicated in haemochromatosis and as modulators in cardiovascular disease.
  
  
  OBJECTIVE
  To investigate the role of these mutations in the pathogenesis of idiopathic dilated cardiomyopathy.
  
  
  METHODS
  Case-control and prospective cohort study of patients attending a cardiomyopathy unit in a tertiary referral cardiac centre.
  
  
  METHODS
  207 unrelated white patients with dilated cardiomyopathy, followed up for 259 patient years, and 200 controls were tested for HFE C282Y and H63D mutations by polymerase chain reaction and restriction digestion.
  
  
  RESULTS
  31/207 patients (15%) v 24/200 controls (12%) carried C282Y (adjusted odds ratio (OR) 1.2 (95% confidence interval 0.7 to 2.2)), 74/207 (36%) v 53/200 (27%) carried H63D (OR 1.6 (1.1 to 2.5)), and 10/207 (4.8%) v 4/200 (2%) were compound heterozygotes (OR 2.6 (0.8 to 8.5)). Four patients and six controls were H63D homozygous and one was C282Y homozygous. There was a progressive increase in mean serum iron ([Fe]) and transferrin saturations from patients with no mutation ([Fe] = 16.3 micromol/l, transferrin saturation = 23.7%) through H63D heterozygotes (17.5 micromol/l, 25.8%), C282Y heterozygotes (17.1 micromol/l, 26.6%), H63D homozygotes (20.0 micromol/l, 33.5%), compound heterozygotes (26.8 micromol/l, 41.7%), and C282Y homozygotes (34 micromol/l, 71%). At follow up (median 90 months) the rate of death or cardiac transplantation was 52/207 (25%). C282Y heterozygotes had less ventricular dilatation (mean (SD): 59.9 (1.7) mm v 64.9 (0.9) mm, p < 0.05), better fractional shortening (24 (1. 7)% v 18.8 (1.4)%, p < 0.01), and a trend towards improved survival without transplantation. [Fe] and transferrin saturation did not correlate with disease severity and were not associated with reduced survival.
  
  
  CONCLUSIONS
  The frequency of the H63D mutation is significantly increased in patients with idiopathic dilated cardiomyopathy. As H63D has a relatively minor effect on iron status, the mechanism of this association may be unrelated to iron metabolism.
authors.affiliation: Department of Cardiological Sciences, St George's Hospital Medical School, Cranmer Terrace, London SW17 0RE, UK. nmahon@sghms.ac.uk
authors.forename: N G
authors.initials: NG
authors.lastname: Mahon
authors.forename: A S
authors.initials: AS
authors.lastname: Coonar
authors.forename: S
authors.initials: S
authors.lastname: Jeffery
authors.forename: F
authors.initials: F
authors.lastname: Coccolo
authors.forename: J
authors.initials: J
authors.lastname: Akiyu
authors.forename: B
authors.initials: B
authors.lastname: Zal
authors.forename: R
authors.initials: R
authors.lastname: Houlston
authors.forename: G E
authors.initials: GE
authors.lastname: Levin
authors.forename: C
authors.initials: C
authors.lastname: Baboonian
authors.forename: W J
authors.initials: WJ
authors.lastname: McKenna
mesh_terms: D000328:Adult; D002311:Cardiomyopathy, Dilated / Q000097:blood / Q000235:genetics* / Q000601:surgery; D016022:Case-Control Studies; D005260:Female; D006680:HLA Antigens / Q000235:genetics*; D016027:Heart Transplantation; D006432:Hemochromatosis / Q000235:genetics*; D000071020:Hemochromatosis Protein; D006579:Heterozygote; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D007501:Iron / Q000097:blood; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D009154:Mutation; D011446:Prospective Studies; D015996:Survival Rate
chemical_list: C103673:HFE protein, human; D006680:HLA Antigens; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D007501:Iron