(Circulation. 1999;100:1268-1273.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Heterozygosity for a Hereditary Hemochromatosis Gene Is Associated With Cardiovascular Death in Women
From the Julius Center for Patient Oriented Research, Utrecht University Medical School (M.R., Y.T.v.d.S.), and the Departments of Internal Medicine (M.R., B.d.V., J.J.M.M., J.D.B.) and Hematology (M.R., M.J.T., P.G.d.G., J.J.S.), University Hospital Utrecht, The Netherlands.
Correspondence to Yvonne T. van der Schouw, PhD, Julius Center for Patient Oriented Research, Utrecht University Medical School, Room D01.335, PO Box 85500, 3508 GA Utrecht, The Netherlands. E-mail Y.T.VanDerSchouw{at}jc.azu.nl
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Abstract |
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Background—The genetic background of hereditary hemochromatosis (HH) is homozygosity for a cysteine-to-tyrosine transition at position 282 in the HFE gene. Heterozygosity for HH is associated with moderately increased iron levels and could be a risk factor for cardiovascular death.
Methods and Results—We studied the relation between HH heterozygosity and cardiovascular death in a cohort study among 12 239 women 51 to 69 years of age residing in Utrecht, the Netherlands. Women were followed for 16 to 18 years (182 976 follow-up years). The allele prevalence of the HH gene in the reference group was 4.0 (95% CI 2.9 to 5.4). The mortality rate ratios for HH heterozygotes compared with wild types was 1.5 (95% CI 0.9 to 2.5) for myocardial infarction (n=242), 2.4 (95% CI 1.3 to 3.5) for cerebrovascular disease (n=118), and 1.6 (95% CI 1.1 to 2.4) for total cardiovascular disease (n=530). The population-attributable risks of HH heterozygosity for myocardial infarction and cerebrovascular and total cardiovascular death were 3.3%, 8.8%, and 4.0%, respectively. In addition, we found evidence for effect modification by hypertension and smoking.
Conclusions—We found important evidence that inherited variation in iron metabolism is involved in cardiovascular death in postmenopausal women, especially in women already carrying classic risk factors.
Key Words: atherosclerosis • genes • genetics • cardiovascular diseases • cerebrovascular disorders
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Introduction |
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Atherosclerosis is a multifactorial disease in which iron may play a role by promoting oxygen radical formation and lipid peroxidation.1 2 The evidence from epidemiological studies linking body iron status to development of cardiovascular disease is inconclusive. Some studies have found an association between high levels of serum ferritin,3 serum iron,4 and total iron-binding capacity5 with cardiovascular disease, whereas others have not found an association.6 7 8 9
Studies of levels of serum ferritin and serum iron and total iron-binding capacity in relation to cardiovascular disease have limitations as estimates of body iron load because they are influenced by short-term effects such as inflammation, iron intake, blood loss, and diurnal variation.9 10 Recently, a G-to-A transition was found in a nonclassic MHC class I gene, called HFE gene (also referred to as HLA-H gene), resulting in a cysteine-to-tyrosine substitution at amino acid 282 (HFE Cys282Tyr).11 Because homozygosity for HFE Cys282Tyr is the major cause of hereditary hemochromatosis (HH), we will refer to this mutation as HH polymorphism. HH is characterized by increased iron release from intestinal mucosal cells, resulting in iron deposition in the liver and several other organs. Biochemical parameters of HH are increased levels of serum ferritin and serum iron and increased iron saturation of serum transferrin. Heterozygotes do not express clinical signs of HH unless combined with disorders such as porphyria cutanea tarda12 13 or hereditary spherocytosis.14 Still, heterozygotes have slightly but significantly increased levels of serum ferritin and serum iron, whereas total iron-binding capacity is reduced.15 Heterozygosity for the HH polymorphism may therefore be a common genetic marker of lifelong moderate iron overload. This marker may be used to study the relation of iron overload and cardiovascular death.
We examined prospectively the association between HH heterozygosity and cardiovascular death among 12 239 women initially 51 to 69 years of age.
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Methods |
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Population
Between December 1974 and October 1980, all 20 555 women, born between 1911 and 1925 who lived in the city of Utrecht, The Netherlands, were invited for an experimental program for breast cancer screening, (the so-called DOM project16 ). The women were invited for repeat examination at 1- to 6-year intervals. The baseline population of our study consisted of 12 239 (60%) who visited the second examination (1976 to 1978) because the first examination did not include a questionnaire on smoking. All women gave oral consent to use their data and urine for future scientific research. The study was approved by the medical ethics committee of the University Hospital Utrecht, the Netherlands.
Risk Factors
At baseline, questionnaires on cardiovascular
risk factors, including medication use, prescribed diets, previous or
present cardiovascular disease, and smoking were
completed, and blood pressure, height (m), and weight (kg) were
measured. Women were classified as having diabetes mellitus if they
reported use of insulin or oral hypoglycemic drugs or were following a
diabetes diet. Women were defined as smokers if they reported that they
were current smokers. Body mass index (kg/m2) was
calculated as weight (kg) divided by height squared
(m2). Obesity was defined as body mass index 
30
kg/m2. Hypertension was defined as
systolic blood pressure >160 mm Hg and/or
diastolic blood pressure >95 mm Hg.
End Points
Municipal registries informed the Department of
Epidemiology (presently called the Julius
Center for Patient Oriented Research) about migration and death of
cohort members. Cause of death was inquired from the general
practitioners. The 9062 surviving women had a median
follow-up time of 17 years, with a maximum of 18 years. One thousand
four hundred sixty-three (12.0%) women had moved outside the
recruitment area and had a median follow-up of 10 years, with a maximum
of 18 years. During follow-up (182 976 women-years), 1714 women died:
608 of cardiovascular diseases (codes 390 to 459 of the
International Classification of Diseases, Ninth Revision; ICD), 601 of
neoplasms (ICD 140 to 239), 299 of other causes, and 206 of unknown
causes.
Design
Full cohort analysis on the effects of DNA
polymorphisms on cardiovascular death is both
expensive and labor intensive. We therefore quantified the effect of
HH heterozygosity on cardiovascular death by
using a nested case-referent approach, which is an alternative name for
a nested case-control approach.17 The cases were 608
women who died of cardiovascular disease and the
reference group was composed of a random sample of 618 of 11 631 women
who did not die of cardiovascular disease (sampling
fraction 1: 18.8). Urine samples of 77 cardiovascular
death cases and of 63 women of the reference group were not collected
at baseline or were not suitable for DNA analyses, and these
women were therefore excluded from the study. The final study group
comprised 531 cardiovascular death cases and 555 women
of the reference group.
DNA Isolation and Polymerase Chain Reaction
DNA was isolated from 50-mL urine samples with the use of a DNA
isolation kit (Puregene, Gentra Systems). DNA was stored in 40 mL of
10 mmol/L TRIS, 1 mmol/L EDTA (TE), pH 7.6. A 268-bp fragment
of the HFE gene, which contained nucleotide 845,
was amplified in 20 mmol/L TRIS/HCl, pH 8.0, 2.5 mmol/L
MgCl2, 50 mmol/L KCl, 0.1 mg/mL BSA, 0.4
pmol of 5'-primer (5'-CCTCCTTTGGTGAAGGTGACA-3') and 0.4 pmol 3'-primer
(5'-CACAATGAGGGGCTGATCCA-3'), 0.42 mmol/L of each
nucleotide (Pharmacia, Biotech), 0.075 U of super-TAQ
polymerase (HT Biotechnology Ltd), and 5 mL of DNA, with the use of an
MJ Research PTC200 multicycler. Temperature cycles were 4 minutes at
94°C, 33 cycles of 40 seconds at 94°C, 40 seconds at 55°C, and 2
minutes at 72°C. The reaction was terminated with 10 minutes of
incubation at 72°C.
Detection
The amplified 268-bp fragment of each polymerase chain
reaction was dotted on 2 separate blot membranes (Hybond N+
nylon transfer membranes, Amersham), following the manufacturer's
protocol. Antigen-specific oligonucleotides (ASO) were
labeled with 
-32P-ATP (Amersham) with the use
of a T4-polynucleotide kinase kit (New England Biolabs).
One set of dot blots was hybridized with
32P-labeled ASO for mutated DNA (MUTHLA;
3'-GATATACGTGCCAGGTGGA-5') and the set of dot blots were hybridized
with 32P-ATP–labeled ASO for wild-type DNA
(OLHLA: 3'-GATATACGTACCAGGTGGA-5'). Dot blots were washed twice for 30
minutes in 2x SSC, 0.1% SDS at room temperature. A specific binding
of MUTHLA to wild-type polymerase chain reaction products was
removed by washing the blots for 30 minutes at 51°C in 2x SSC, 0.1%
SDS; a specific binding of OLHLA to mutated DNA was removed at 55°C.
Dots were visualized on x-ray films (DuPont) after overnight radiation.
Mutation analyses were performed with samples blinded for case
or reference group status.
Data Analysis
Means and proportions of baseline cardiovascular
risk factors and presence of HH genotype were
computed for wild types, heterozygotes, and homozygotes. Difference in
means was tested by ANOVA, whereas differences in proportions were
tested by 
2 statistics. Allele frequencies
were calculated by the law of Hardy-Weinberg.18 19
The 2 goodness-of-fit test was used to
determine whether the observed number of genotypes were in
equilibrium.
The nested case-referent approach enabled us to study mortality rates and rate ratios (RR) of cardiovascular disease for HH heterozygosity compared with wild types.20 Because our reference group was a random sample of the total cohort of noncases, multiplication of the person-years in the reference group with 18.8 (the inverse of the sampling fraction) enabled us to analyze the nested case-referent approach exactly as a full cohort analysis, in which the person-years are unbiased estimates of the true person-years. Poisson regression was used to estimate mortality rates and risk ratios; 95% CIs were calculated with Huber's method.21 Similarly, crude relative risks, mortality rates, and RRs were estimated for women with myocardial infarction (ICD 410 to 414), cerebrovascular disease (ICD 430 to 438), and other cardiovascular disease (all remaining ICD codes between 390 to 459), separately.
Potential confounding by age, smoking, obesity, and hypertension was analyzed in a multivariate model. Effect modification of smoking was investigated by comparing the mortality rates in 4 subgroups: nonsmokers and non–HH carriers (reference group), smokers and non–HH carriers, nonsmokers and HH carriers, and smokers and HH carriers. Similarly, effect modification for age (above or below the median), obesity (yes/no), and hypertension (yes/no) was studied. Effect modification by smoking and hypertension was also studied in one model. Cardiovascular mortality rates were estimated for HH carriers and non-HH carriers classified in subgroups of nonsmokers and nonhypertensives, either smokers or hypertensives, and both smokers and hypertensives.
The proportion of all cases occurring in our population that is attributable to HH heterozygosity is expressed as population-attributable risk.22
Homozygous subjects were analyzed as separate groups; however, the number of homozygous subjects was too low to draw any conclusions.
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Results |
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Baseline Statistics
As expected, the mean age, the percentages of women with hypertension, history of cardiovascular disease, or diabetes mellitus, and women who were current smokers and obese did not differ between HH heterozygotes and women who were wild type (Table 1
). The number of
homozygotes (n=4) was too small for meaningful statistical
analysis.
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Allele Frequencies
The allele prevalence of the HH polymorphism in
the reference group of 555 women was 4.1% (95% CI 2.9 to 5.4). The
prevalence of HH heterozygotes in the reference group was 40
(7.2%) and the prevalence of HH homozygotes was 3 (0.5%).
The number of homozygotes was higher than expected from previously
reported data12 ; our population was therefore not in
Hardy-Weinberg equilibrium (2=4.56; 1
df, P=0.033). One woman, who was homozygous for
the HH polymorphism, died of unspecified heart
failure.
Mortality Rates
The mortality rate for cerebrovascular disease was significantly
higher in HH heterozygotes than in wild types (Table 2); the RR was 2.4 (95% CI 1.3 to 4.4),
whereas a borderline-significantly increased RR of 1.5 (95% CI 0.9 to
2.5; P=0.135) was found for death as the result of
myocardial infarction. The overall cardiovascular death
risk was significantly higher for HH heterozygotes than for
wild types: RR of 1.6 (95% CI 1.1 to 2.4; P=0.028).
Population-attributable risks of myocardial infarction,
cerebrovascular, other cardiovascular, and total
cardiovascular deaths were 3.3%, 8.8%, 1.4%, and
4.0%, respectively (Table 2). The RR of HH
heterozygosity for cardiovascular death compared with
wild types was not changed when age, smoking, obesity, and hypertension
were included in a multivariate model, suggestive of
heterozygosity for the HH polymorphism to be an
independent risk factor for cardiovascular death.
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Adjustment for age, smoking, and hypertension had minor effects on the cardiovascular death ratio. The age-, smoking-, and hypertension-adjusted cardiovascular death ratio between HH heterozygotes and HH wild types remained 1.6 (95% CI 1.0 to 2.5), for myocardial infarction 1.5 (0.9 to 2.7), for stroke 2.6 (1.4 to 4.9), and for other cardiovascular death 1.3 (0.7 to 2.7).
Effect modification by smoking is presented in Table 3. In the subgroup of nonsmokers, the
risk of cardiovascular death is similar for
HH carriers as for noncarriers. In smokers, however,
cardiovascular mortality rate was higher for
HH carriers than for noncarriers (Table 3).
Similarly, cardiovascular mortality rate was highest
when women were both an HH carrier and hypertensive. Women
who were either hypertensive and were not a carrier or HH
carrier and not hypertensive had a moderately higher risk of
cardiovascular death than did women who were not a
carrier and not hypertensive (Table 3). The risk of
cardiovascular death in subgroups of age and weight,
higher or lower than the median, were not different from population
risks.
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Further subgroup analysis is presented in Table 4. HH carriership was not
associated with cardiovascular death in women who were
nonsmokers and nonhypertensives (RR 1.41, 95% CI 0.67 to 2.95). In
women who were either smokers or hypertensives, HH carriers
had a moderately increased risk of cardiovascular death
(RR 1.78, 95% CI 0.95 to 3.32), whereas in women who were both smokers
and hypertensives, HH heterozygotes had a strongly increased
risk of cardiovascular death (RR 18.85, 95% CI 8.38 to
42.37). The findings of the highest risk associated with the
combination of HH carriership plus 2 conventional risk
factors was not confined to 1 particular subgroup of cardiovascular
death (Table 4). The Figure
illustrates the effect modification of smoking and hypertension on the
relation between HH carriership and
cardiovascular death.
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Discussion |
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We studied the relation between HH heterozygosity and cardiovascular death among 12 239 postmenopausal women living in the city of Utrecht who were prospectively followed for 15 to 18 years. The allele prevalence of the HH polymorphism was 4.0% (95% CI 2.9 to 5.4). Compared with wild types, HH heterozygotes had a statistically significant RR for total cardiovascular death of 1.6 (95% CI 1.1 to 2.4) and for cerebrovascular death of 2.4 (95% CI 1.3 to 4.3) and a borderline-significant RR of 1.5 (0.9 to 2.5) for myocardial infarction.
We found strong evidence for effect modification by both smoking and hypertension. The association between HH heterozygosity and cardiovascular death appeared to be stronger in women who were hypertensive or current smokers. Women who were smokers, hypertensive, and heterozygous for HH had an 18.85-fold increased risk of cardiovascular death compared with nonsmokers, nonhypertensives, and noncarriers. The RR (95% CI) for fatal myocardial infarction was 19.93 (5.55 to 71.52); for cerebrovascular death it was 35.35 (8.31 to 150.46), and for the rest of the group it was 33.38 (9.78 to 113.87). Smokers and hypertensives who did not carry the HH polymorphism had an RR (95% CI) of 2.06 (1.39 to 3.03) compared with the group of nonsmokers, nonhypertensives, and noncarriers. The RRs for fatal myocardial infarction, cerebrovascular death, and the rest group of cardiovascular deaths were in the same range.
Our findings suggest that HH heterozygosity is associated with an increased risk of cardiovascular death. This result provides support for the view that iron overload may play a role in cardiovascular disease.2 23 Moderately excessive iron may be involved in oxygen radical formation, which may initiate peroxidation of LDL. Oxidized LDL is recognized by the scavenger receptor and taken up by macrophages in the intima of the arterial wall, leading to transformation of tissue macrophages into foam cells, the most important cells of the fatty streak.1 The iron necessary for catalyzing lipid peroxidation can be derived from ferritin,24 heme,25 and plasma iron, either transferrin bound26 or not.27 Although the LDL-oxidation pathway appears to be very plausible, iron may be involved in several other processes that promote cardiovascular disease.
The recently discovered HFE gene may play a role in the iron
release from intestinal mucosal cells and macrophages to the
plasma. Homozygotes for the common HFE mutation show
clinical expression of HH. HFE has a disulfide
bridge in its 
3 domain, necessary for association of
ß2-microglobulin with MHC class I molecules. The Cys282Tyr mutation
in HFE probably interferes with the formation of the
disulfide bridge, thus impairing association with ß2-microglobulin
and eliminating cell-surface presentation. Results of a
study of mice lacking the gene coding for ß2-microglobulin, which
also develop hemochromatosis,28 support this
hypothesis. Heterozygotes for the HH mutation do not develop
hemochromatosis but have slightly increased levels of serum ferritin
and serum iron and a reduced iron-binding capacity. Heterozygosity for
the HH mutation may therefore be a genetic indicator of
lifelong exposure to a moderate excess of iron not sufficient to lead
to clinical signs and symptoms of iron overload.
From our data, we cannot explain the functional mechanism that explains the effect modification by smoking and/or hypertension on the relation between HH carriership and cardiovascular death. A possible explanation is the combined oxidative effect of increased body iron caused by HH carriership and increased oxidative stress from smoking, which may lead to an overexposure of oxygen radicals, which may be involved in lipid peroxidation and therefore increase the risk of cardiovascular death. An alternative explanation is that lifelong exposure to moderately increased iron levels in HH carriers may lower the threshold for cardiovascular disease. HH carriers may therefore be more sensitive to the effects of smoking and hypertension on cardiovascular disease than women who do not carry the mutation.29
This is the first large follow-up study to detect a significant association between a single genetic polymorphism and cardiovascular death in women. Similar to our findings, an increased risk of cardiovascular disease for HH carriers was found in a cohort study among Finnish men.30 The population-attributable risk represents the proportion of women who died of a cardiovascular event that was attributable to a specific risk factor. In our study, the population-attributable risk of HH heterozygosity for cerebrovascular death was 8.8%, which was comparable to the population-attributable risk of smoking (7.4%) and obesity (6.1%) but not as high as the population-attributable risk of hypertension (27.2%). The population-attributable risk of HH heterozygosity for total cardiovascular death (4.0%) was comparable to the population-attributable risk of obesity (4.4%) but not as high as population-attributable risks of smoking (7.9%) and hypertension (30.4%).
Epidemiological studies on genetic markers have the advantage of not being biased by storage and handling procedures of biological samples, seasonal variability, or intrasubject and intersubject variability. Data were analyzed with the use of a nested case-referent approach, which is an alternative term for a nested case-control-study. Nested analysis of prospectively collected material has several advantages compared with normal case-control studies. First of all, population-attributable risks can be calculated. Second, control subjects are not biased by selection because they are randomly selected from the entire cohort and are therefore representative for the entire cohort. Third, follow-up time can be included in the data analysis. Moreover, the prospective approach enabled us to study cardiovascular death because DNA was collected before the event occurred. In case-control studies, DNA will be collected after the event, precluding the study of acute cardiovascular death.
A limitation of our study is that no blood samples were collected at baseline. We were therefore not able to study whether HH heterozygotes indeed had increased iron parameters as intermediate steps in the association between HH genotype and cardiovascular death. For the same reason, we could not measure lipid peroxidation by moderately increased iron exposure or lipid levels to study effect modification in hyperlipidemic patients.
We measured HH genotype in cardiovascular death cases and a random sample of the rest of the cohort only and do not have genetic data of all noncardiovascular death cases such as cancer. If women died of a cause other than cardiovascular disease, then they were censored from the follow-up and treated similarly to the rest of the cohort. The HH gene may be associated with increased risk of cancer; therefore excluding cancer cases from the cohort may lead to an even stronger cardiovascular death ratio between HH heterozygotes and wild types.
Our subjects were members of a normal population, and causes of death were obtained from the general practitioner. We expect some misclassification between ischemic and hemorrhagic fatal stroke because the diagnosis was not routinely confirmed by computed tomographic scan or magnetic resonance imaging. Moreover, the number of subjects in both subgroups become very small when analyzed separately. It was not possible to obtain a reliable distinction between ischemic or hemorrhagic fatal stroke in this study.
HH genotyping may play an important role in predicting the risk of cardiovascular death in postmenopausal women, especially when women have increased risks of cardiovascular disease such as hypertension and smoking, whereas effect modification by lipid levels needs to be delineated. Recent data from a Finnish cohort study are suggestive of a similar role of HH genotype in men.30
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Acknowledgments |
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This study was supported by Netherlands Heart Foundation grant NHS 95-165.
Received December 31, 1998; revision received June 10, 1999; accepted June 17, 1999.
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 D. L. van der, D. E. Grobbee, M. Roest, J. J.M. Marx, H. A. Voorbij, and Y. T. van der Schouw Serum Ferritin Is a Risk Factor for Stroke in Postmenopausal Women Stroke, August 1, 2005; 36(8): 1637 - 1641. [Abstract] [Full Text] [PDF]
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 C. Ellervik, A. Tybjaerg-Hansen, P. Grande, M. Appleyard, and B. G. Nordestgaard Hereditary Hemochromatosis and Risk of Ischemic Heart Disease: A Prospective Study and a Case-Control Study Circulation, July 12, 2005; 112(2): 185 - 193. [Abstract] [Full Text] [PDF]
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 H. S. Kok, N. C. Onland-Moret, K. M. van Asselt, C. H. van Gils, Y. T. van der Schouw, D. E. Grobbee, and P. H.M. Peeters No association of estrogen receptor {alpha} and cytochrome P450c17{alpha} polymorphisms with age at menopause in a Dutch cohort Hum. Reprod., February 1, 2005; 20(2): 536 - 542. [Abstract] [Full Text] [PDF]
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 A. E.R. Kartikasari, N. A. Georgiou, F. L.J. Visseren, H. van Kats-Renaud, B. S. van Asbeck, and J. J.M. Marx Intracellular Labile Iron Modulates Adhesion of Human Monocytes to Human Endothelial Cells Arterioscler. Thromb. Vasc. Biol., December 1, 2004; 24(12): 2257 - 2262. [Abstract] [Full Text] [PDF]
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 J. R Hunt and H. Zeng Iron absorption by heterozygous carriers of the HFE C282Y mutation associated with hemochromatosis Am. J. Clinical Nutrition, October 1, 2004; 80(4): 924 - 931. [Abstract] [Full Text] [PDF]
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 K J H Robson, A T Merryweather-Clarke, E Cadet, V Viprakasit, M G Zaahl, J J Pointon, D J Weatherall, and J Rochette Recent advances in understanding haemochromatosis: a transition state J. Med. Genet., October 1, 2004; 41(10): 721 - 730. [Abstract] [Full Text] [PDF]
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 J L Chicharro, J Hoyos, F Gomez-Gallego, J G Villa, F Bandres, P Celaya, F Jimenez, J M Alonso, A Cordova, and A Lucia Mutations in the hereditary haemochromatosis gene HFE in professional endurance athletes Br. J. Sports Med., August 1, 2004; 38(4): 418 - 421. [Abstract] [Full Text] [PDF]
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 G P Feeney, P A L Ashfield-Watt, M L Burr, F D J Dunstan, I F W McDowell, and M Worwood Heterozygosity for the haemochromatosis mutation HFE C282Y is not a risk factor for angina Heart, August 1, 2004; 90(8): 939 - 940. [Full Text] [PDF]
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I R Gunn, F K Maxwell, D Gaffney, A D McMahon, and C J Packard Haemochromatosis gene mutations and risk of coronary heart disease: a west of Scotland coronary prevention study (WOSCOPS) substudy Heart, March 1, 2004; 90(3): 304 - 306. [Abstract] [Full Text] [PDF]
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 A. R. Kallianpur, L. D. Hall, M. Yadav, B. W. Christman, R. S. Dittus, J. L. Haines, F. F. Parl, and M. L. Summar Increased Prevalence of the HFE C282Y Hemochromatosis Allele in Women with Breast Cancer Cancer Epidemiol. Biomarkers Prev., February 1, 2004; 13(2): 205 - 212. [Abstract] [Full Text] [PDF]
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C. H. van Gils, N. C. Onland-Moret, M. Roest, P. A. H. van Noord, and P. H. M. Peeters The V89L Polymorphism in the 5-{alpha}-Reductase Type 2 Gene and Risk of Breast Cancer Cancer Epidemiol. Biomarkers Prev., November 1, 2003; 12(11): 1194 - 1199. [Abstract] [Full Text]
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J. R Hunt Bioavailability of iron, zinc, and other trace minerals from vegetarian diets Am. J. Clinical Nutrition, September 1, 2003; 78(3): 633S - 639. [Abstract] [Full Text] [PDF]
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S Campbell, D K George, S D Robb, R Spooner, T A McDonagh, H J Dargie, and P R Mills The prevalence of haemochromatosis gene mutations in the West of Scotland and their relation to ischaemic heart disease Heart, September 1, 2003; 89(9): 1023 - 1026. [Abstract] [Full Text] [PDF]
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S. M. Day, D. Duquaine, L. V. Mundada, R. G. Menon, B. V. Khan, S. Rajagopalan, and W. P. Fay Chronic Iron Administration Increases Vascular Oxidative Stress and Accelerates Arterial Thrombosis Circulation, May 27, 2003; 107(20): 2601 - 2606. [Abstract] [Full Text] [PDF]
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R Surber, H H Sigusch, H Kuehnert, and H R Figulla Haemochromatosis (HFE) gene C282Y mutation and the risk of coronary artery disease and myocardial infarction: a study in 1279 patients undergoing coronary angiography J. Med. Genet., May 1, 2003; 40(5): e58 - 58. [Full Text] [PDF]
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 E. Beutler, A. V. Hoffbrand, and J. D. Cook Iron Deficiency and Overload Hematology, January 1, 2003; 2003(1): 40 - 61. [Abstract] [Full Text] [PDF]
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 H. Gaenzer, P. Marschang, W. Sturm, G.u. Neumayr, W. Vogel, J. Patsch, and G.u. Weiss Association between increased iron stores and impaired endothelial function in patients with hereditary hemochromatosis J. Am. Coll. Cardiol., December 18, 2002; 40(12): 2189 - 2194. [Abstract] [Full Text] [PDF]
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Y.F. Cheung, G. C.F. Chan, and S.Y. Ha Arterial Stiffness and Endothelial Function in Patients With {beta}-Thalassemia Major Circulation, November 12, 2002; 106(20): 2561 - 2566. [Abstract] [Full Text] [PDF]
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O. T. Njajou, M. Hollander, P. J. Koudstaal, A. Hofman, J. C.M. Witteman, M. M.B. Breteler, and C. M. van Duijn Mutations in the Hemochromatosis Gene (HFE) and Stroke Stroke, October 1, 2002; 33(10): 2363 - 2366. [Abstract] [Full Text] [PDF]
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K. Schumann, B. Borch-Iohnsen, M. W Hentze, and J. J. Marx Tolerable upper intakes for dietary iron set by the US Food and Nutrition Board Am. J. Clinical Nutrition, September 1, 2002; 76(3): 499 - 500. [Full Text] [PDF]
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C. T Sempos Do body iron stores increase the risk of developing coronary heart disease? Am. J. Clinical Nutrition, September 1, 2002; 76(3): 501 - 503. [Full Text] [PDF]
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 A. G. Mainous III, J. M. Gill, and W. S. Pearson Should We Screen for Hemochromatosis?: An Examination of Evidence of Downstream Effects on Morbidity and Mortality< |