Hemochromatosis Genotypes and Risk of Ischemic Stroke |
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Hemochromatosis, an autosomal recessive disorder of iron metabolism, is characterized by progressive accumulation of iron stores throughout the body that eventually compromise hepatic or cardiac function. The disease occurs in 0.2-0.5% of individuals of Northern European descent and is caused by point mutations in the hemochromatosis (HFE) gene. The unmutated and predominant form of the HFE gene is designated Wild Type (WT). Most patients with hemochromatosis are homozygous for a C282Y mutation. A second HFE mutation, H63D, is also associated with biochemical indicators of iron overload in homozygous or compound heterozygous (C282Y/H63D) form.
C282Y and H63D mutations are thought to influence iron metabolism via different molecular mechanisms. The HFE protein coded by an H63D mutation, unlike the C282Y mutation, forms stable complexes with the transferrin receptor and lowers its affinity for transferrin binding. Transferrin carries iron from blood into brain tissue via transferrin receptors located in the brain's microvasculature. Although HFE mutations have been linked in some studies with diseases of the brain, including Alzheimer and Parkinson diseases, ALS, MS and stroke, the relative association of C282Y and H63D mutations with brain disease has not been extensively studied.
A recent report in the journal Neurology (2007;68:1025-31) describes a well-controlled prospective study that investigated the association of HFE genotypes with ischemic cerebrovascular disease (ICVD) and ischemic stroke (IS) in 9,081 HFE genotyped individuals randomly selected to reflect the Danish adult population. Over a follow-up period of 24 years, 504 individuals developed ICVD, including IS (n=393), amaurosis fugax (n=7) and TIA (n=104). The remaining 8,577 individuals were not diagnosed with cerebrovascular disease. Outcome data is summarized in the table. Incident rates are listed as events per 1000 person-years; hazard ratios are multifactorially adjusted.
Cumulative incidence of ICVD as a function of age was increased in H63D homozygous individuals compared to WT/WT (log-rank, p = 0.003). A highly significant association was observed between H63D homozygotes and IS. Cumulative incidence of IS as a function of age was increased in H63D homozygous individuals compared to WT/WT (log-rank, p < 0.001). The hazard ratio for IS in H63D homozygotes was 2.8 (p < 0.001). Hazard ratios for all other HFE genotypes compared to WT/WT were not significant. Based on an H63D homozygote population frequency of 1.7% and the hazard ratio of 2.1 for ICVD and 2.8 for IS, the population attributable risk for ICVD was 2% and the risk for IS was 3%.
HFE Genotype |
Population Incidence (%) |
IS Incident
Rate |
IS Hazard Ratio
(95% CI) |
H63D/H63D |
1.7 |
5.4 |
2.8 (1.7-4.6) |
C282Y/C282Y |
0.25 |
2.5 |
1.5 (0.2-11) |
C282Y/H63D |
1.4 |
2.0 |
1.0 (0.4-2.5) |
H63D/WT |
20.5 |
2.3 |
1.0 (0.7-1.2) |
C282Y/WT |
9.2 |
2.2 |
1.0 (0.7-1.4) |
WT/WT |
66.9 |
2.3 |
1.0 |
The authors concluded that H63D/H63D genotype is strongly associated with ICVD and IS. The increased risk does not appear to correlate with development of atherosclerosis, since no association was observed in a previous case-controlled study. They also discount the intrinsic influence of iron overload because C282Y homozygosity or heterozygosity was not significantly associated with ICVD or IS. These well-controlled studies appear to provide further evidence that the C282Y and H63D hemochromatosis mutations affect the brain through different mechanisms.
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