A prospective study of coronary heart disease and the hemochromatosis gene (HFE) C282Y mutation: the Atherosclerosis Risk in Communities (ARIC) study
Introduction
Coronary heart disease (CHD) has a multifactorial etiology with both genetic and nongenetic causes. Sullivan hypothesized that the sex difference in CHD is due to iron excess in men and postmenopausal women compared to premenopausal women [1]. A prospective study by Salonen and colleagues [2], [3] in Eastern Finnish men suggested high serum ferritin, a marker of iron excess, is associated with increased risk of CHD. However, the majority of prospective epidemiologic research found no association between serum ferritin [4], [5], [6], [7], or other measures of iron level [4], [8], [9], [10], [11], [12], [13], [14], and CHD. In the ARIC study, there was no association between serum ferritin levels and carotid wall thickness [15].
Iron is thought to catalyze the formation of free radicals [16], [17], [18], [19], [20] and convert poorly reactive radicals (e.g. hydrogen peroxide) into highly reactive ones (e.g. the hydroxyl radical). The hydroxyl radical can initiate lipid peroxidation, causing LDL to undergo an oxidative modification that targets it for uptake by macrophages [20], [21], [22]. These macrophages form lipid rich foam cells in the endothelium of arteries, leading to the development of fatty streaks, the precursor to atherosclerotic plaques. It is also believed that free radicals may damage arterial endothelium directly [23] and interfere with normal vasomotor regulation [24].
Hereditary hemochromatosis, a relatively common autosomal recessive condition, is a disease of disordered iron metabolism causing the body to absorb and store excess iron. In 1996, Feder and colleagues [25] identified and cloned a gene for hemochromatosis at the HLA locus termed HFE. Amino acid substitutions caused by two missense mutations Cys282Tyr (C282Y) and His63Asp (H63D) in the gene have been reported [25]. The C282Y mutation, which causes a substitution of a tyrosine for a cysteine, provides a more consistent association with the disease across studies [26], [27], [28], [29], [30], [31] and has a higher penetrance than H63D [32]. Compound heterozygosity for C282Y and H63D is associated with increased hemochromatosis risk. Depending on ethnic backgrounds, the frequencies of homozygosity and heterozygosity for the C282Y mutation are ≈0–1% and 2–14%, respectively [33].
Tissue damage from iron overload in homozygous hemochromatosis results in various clinical manifestations including cirrhosis, cardiomyopathy, diabetes, skin pigmentation and various cancers [33], [34]. Heterozygosity for the C282Y mutation could increase risk of CHD by increasing iron stores and lipid oxidation. To date, two studies have suggested that heterozygosity for the C282Y mutation is associated with CHD [35], [36], and four have not [30], [37], [38], [39]. The objective of this study was to determine if there is an association between the presence of the C282Y mutation of the HFE gene and incident CHD in a population-based cohort study.
Section snippets
Study population
Between 1987 and 1989, the ARIC Study recruited a cohort totalling 15 792 persons aged 45–64 years. Population samples were selected by probability sampling of Forsyth County, North Carolina; Jackson, Mississippi (black people only); the northwest suburbs of Minneapolis, Minnesota; and Washington County, Maryland. Participants underwent reexamination in 1990 through 1992 (93% return rate), in 1993 through 1995 (86% return rate), and in 1996 through 1998 (80% return rate).
Baseline measurements
After an 8-h fasting
Sample characteristics
The sample included 243 incident CHD cases (157 definite or probable MI, 20 silent MI, 26 definite fatal CHD, and 40 revascularization procedure) and a reference cohort sample of 535. Due to the case-cohort design, 10 individuals in the reference cohort sample eventually became CHD cases. Approximately 25% of the CHD cases were black, and 72% were men.
Based on the cohort random sample, we estimated that the frequency of homozygosity for the C282Y mutation in the entire ARIC population was 0.2%
Discussion
In this prospective study, we found that individuals who carried the HFE C282Y mutation may be at greater risk of developing CHD than those without the mutation. The crude association was positive but relatively weak (RR=1.60) and not statistically significant. After adjusting for confounding variables the association became very strong (RR=2.70). This was explained by the surprising fact that C282Y carriers had lower CHD risk factors than non-carriers: less diabetes, less smoking, lower LDL
Acknowledgements
The ARIC Study was funded by contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022 from the US National Heart, Lung, and Blood Institute. The authors thank the ARIC participants and staff for their valuable contributions over many years.
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