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Haemochromatosis gene mutations in idiopathic dilated cardiomyopathy
N G Mahon1, A S Coonar, S Jeffery
1Department of Cardiological Sciences, St George's Hospital Medical School, Cranmer Terrace, London SW17 0RE, UK. nmahon@sghms.ac.uk
Insights
The HFE H63D mutation is more common in idiopathic dilated cardiomyopathy patients, suggesting a link beyond iron metabolism. This finding may influence understanding of heart disease development.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Genetic Epidemiology
Background:
- Common HFE gene mutations (C282Y and H63D) are linked to hemochromatosis and cardiovascular disease.
- Investigating HFE mutations' role in idiopathic dilated cardiomyopathy (DCM) is crucial for understanding disease pathogenesis.
Purpose of the Study:
- To determine the association between HFE C282Y and H63D mutations and idiopathic dilated cardiomyopathy.
- To explore the potential impact of these mutations on disease progression and patient outcomes.
Main Methods:
- A case-control and prospective cohort study was conducted with 207 DCM patients and 200 controls.
- HFE C282Y and H63D mutations were genotyped using polymerase chain reaction and restriction digestion.
- Patients were followed for a median of 90 months to assess clinical outcomes.
Main Results:
- The H63D mutation was significantly more frequent in DCM patients (36%) compared to controls (27%).
- Compound heterozygotes for HFE mutations showed significantly elevated iron levels and transferrin saturation.
- C282Y heterozygotes exhibited reduced ventricular dilatation and improved fractional shortening, with a trend towards better survival.
Conclusions:
- The H63D mutation is significantly associated with idiopathic dilated cardiomyopathy.
- The mechanism underlying this association may not be directly related to iron metabolism due to H63D's minor effect on iron status.
- Further research is warranted to elucidate the non-iron-related pathways involved in HFE's influence on DCM.
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.
Design And Setting:
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.