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(Clinical Chemistry. 2002;48:622-628.)
© 2002 American Association for Clinical Chemistry, Inc.

Biochemical and Genetic Markers of Iron Status and the Risk of Coronary Artery Disease: An Angiography-based Study

Claudia Bozzini1, Domenico Girelli1a, Elisa Tinazzi1, Oliviero Olivieri1, Chiara Stranieri2, Antonella Bassi3, Elisabetta Trabetti2, Giovanni Faccini3, Pier Franco Pignatti2 and Roberto Corrocher1

1 Department of Clinical and Experimental Medicine,
2 Department of Mother and Child, Biology and Genetics, and
3 the Institute of Clinical Chemistry, University of Verona, 37134 Verona, Italy.

aAddress correspondence to this author at: Department of Clinical and Experimental Medicine, Policlinico G.B. Rossi, 37134 Verona, Italy. Fax 39-45-580111; e-mail domenico.girelli{at}univr.it.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Background: Iron may promote coronary atherosclerotic disease (CAD) by increasing lipid peroxidation. Studies on biochemical or genetic markers of body iron stores as risk factors for CAD have yielded conflicting results.

Methods: We studied 849 individuals with a clear-cut definition of the CAD phenotype, i.e., with (CAD; n = 546) or without (CAD-free; n = 303) angiographically documented disease. We determined serum ferritin, as a biochemical estimate of iron stores, and the C282Y mutation in the HFE gene, i.e., the main cause of hemochromatosis in Caucasians. The relationships of ferritin with serum markers of either inflammation [C-reactive protein (CRP)] or lipid peroxidation (malondialdehyde) were also investigated.

Results: Mean ferritin concentrations were slightly higher in CAD vs CAD-free individuals, but this difference disappeared after adjusting for sex and CRP. Ferritin was significantly correlated with CRP (Spearman’s test, {rho} = 0.129; P <0.001). Heterozygotes for Cys282Tyr were 4.8% among the CAD group and 6.6% among the CAD-free group (P = 0.26). The prevalence of high concentrations of stored iron, defined as ferritin concentrations above the sex-specific upper quintiles of the control distribution, was also similar in the two groups. There was a higher prevalence of "iron depletion" in CAD-free vs CAD females (20% vs 8.8%, respectively), but this difference disappeared after adjustment for age and other cardiovascular risk factors (odds ratio, 0.66; 95% confidence interval, 0.21–2.08). No differences in iron markers were found in CAD patients with or without myocardial infarction.

Conclusions: Our results do not support a role for biochemical or genetic markers of iron stores as predictors of the risk of CAD or its thrombotic complications.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
In 1981, Sullivan (1) first proposed iron depletion attributable to menstruation as a possible explanation for the sex difference in the risk of coronary atherosclerotic disease (CAD). 1 More recently, interest in the "iron hypothesis" has been renewed [for a review, see Ref. (2)]. Evidence has accumulated suggesting that iron may be involved in the events leading to atherosclerosis by promoting free-radical-induced lipid peroxidation (3)(4)(5)(6) and smooth-muscle cell proliferation (7). Early studies on the relationship between biochemical markers of body iron stores (serum ferritin and/or transferrin saturation) and CAD yielded inconsistent results (8).

In 1996, a G-to-A transition was found in the HFE gene on chromosome 6, leading to a cysteine-to-tyrosine substitution at amino acid 282 (C282Y). In Caucasian populations, homozygosity for this mutation is responsible for most cases of hereditary hemochromatosis, an autosomal recessive genetic disorder that causes excess iron accumulation in the body (9). Heterozygotes have been reported to have slight, but significant, increases of serum ferritin (10)(11). Thus, the C282Y mutation represents a potentially useful marker for testing whether a genetically determined lifelong iron overload may influence the risk of CAD. Two prospective studies (12)(13) published in 1999 analyzed the relationship between heterozygosity for C282Y mutation and cardiovascular risk. Roest et al. (12) followed 12 239 women for 16–18 years and found a risk of cardiovascular death significantly higher in C282Y heterozygotes compared with individuals with the wild-type genotype. Similarly, Toumainen et al. (13) found that male carriers of the mutation had a 2.3-fold risk of first acute myocardial infarction (MI) compared with noncarriers.

On the other hand, other case-control studies failed to demonstrate an association between the C282Y mutation and cardiovascular disease (14)(15)(16). In the present study, we tested the iron hypothesis in a large sample of Italian patients of both sexes with angiographically confirmed severe CAD, with or without a previous documented MI. We used a combined approach by examining both the prevalence of the C282Y mutation and serum ferritin concentrations. The relationships of serum ferritin with serum markers of either inflammation or lipid peroxidation were also investigated.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
study population
Criteria for selection of the study population have been described in detail elsewhere (17)(18). For the present investigation, we excluded only individuals with conditions known to influence serum ferritin concentrations (thus interfering with iron-stores evaluation and genotype/phenotype correlation analysis), such as any acute or chronic inflammatory disease (e.g., rheumatoid arthritis and inflammatory bowel disease), cancer, and viral or alcoholic liver disease. Briefly, we examined a total of 849 consecutive unrelated adult patients of both sexes recruited from those referred to the Institute of Cardiovascular Surgery and/or to the Department of Clinical and Experimental Medicine in Verona. Of these, 546 had angiographically confirmed severe CAD, the majority of whom were candidates for coronary bypass grafting. The disease severity was evaluated by counting the number of major epicardial coronary arteries (left anterior descending, circumflex, and right) affected with >=1 significant stenosis (>=50%).

As a control group, we considered 303 individuals with angiographically documented nondiseased coronary arteries (CAD-free), examined for reasons other than possible CAD, mainly valvular heart disease (90%). Because the primary aim of our selection was to provide an objective and clear-cut definition of the atherosclerotic phenotype, individuals with nonsignificant coronary stenosis (<50%) were not included in the present study. Controls were also required to have neither a history nor clinical or instrumental evidence of atherosclerosis in vascular districts other than the coronary bed. The angiograms were assessed by two cardiologists unaware that the patients were to be included in the study. Classification into MI and non-MI groups was made by combining data from history with a thorough review of medical records showing diagnostic electrocardiogram and enzyme changes, and/or the typical sequelae of MI on ventricular angiography. Appropriate documentation was obtained for 504 of 546 (92%) study participants. The entire population came from the same geographical area (Northern Italy), with a similar socioeconomic background. At the time of the blood sampling, a complete clinical history (including cardiovascular risk factors, such as smoking, hypertension and diabetes) was collected in all participants. The study was approved by our institutional review boards. Informed consent was obtained from every volunteer after a full explanation of the study.

biochemical analysis
Samples of venous blood were drawn from each volunteer in the free-living state, after an overnight fast, within 10 days from the angiographic procedure. Serum lipids, as well as other cardiovascular risk factors, including fibrinogen, were determined immediately after collection as described previously (17)(18). Serum ferritin and high-sensitivity C-reactive protein (HSCRP) were measured from frozen serum stored at -70 °C for a maximum of 18 months by particle-enhanced nephelometric immunoassay with commercially available methods and a BNII Behring Nephelometer Analyzer (Dade Behring Inc.). The within- and between-run CVs were 3% and 2% for ferritin (at a concentration of 103 µg/L) and 4% and 3.9% for HSCRP (at a concentration of 3 mg/L).

An adequate sample of serum for these measurements was available for 794 of 849 (93.5%) volunteers. We measured serum malondialdehyde (MDA) by an improved HPLC method as described previously by Carbonneau et al. (19) using a HPLC Gilson 305-805. The within- and between-run CVs for MDA were 4.9% and 7%, respectively (at a concentration of 0.6 µmol/L).

mutation analysis
DNA was extracted from peripheral lymphocytes by a phenol/chloroform protocol. The G-to-A transition at nucleotide 845 of the HFE-1 cDNA, leading to a substitution of tyrosine for cysteine at codon 282, was assayed by PCR amplification followed by RsaI restriction analysis and agarose gel electrophoresis (20).

Both biochemical and mutation analyses were conducted blind as to whether a sample came from a CAD or CAD-free study participant.

statistical analysis
All computations were performed by the SPSS 9.0 statistical package (SPSS Inc.). Distributions of continuous variables in groups were expressed as means ± SDs. Logarithmic transformation was performed on all skewed variables, including serum ferritin. These variables were expressed as geometric means (antilogarithm of the mean of log-transformed values) with 95% confidence intervals (CIs). Serum ferritin and HSCRP were also evaluated as categorical variables, by dividing them into quintile categories. "High" and "low" iron stores (iron overload or depletion) were defined as ferritin concentrations above or below the sex-specific upper or lower quintiles of the distribution in controls, respectively (upper, 237 µg/L in males and 120 µg/L in females; lower, 55 µg/L in males and 24 µg/L in females). Statistical significance for differences in quantitative variables was tested by Student unpaired t-test. Correlation coefficients were calculated by the Pearson or Spearman tests, depending on whether the variables were gaussian distributed. Qualitative data were analyzed by a {chi}2 test. Genotype frequencies of the C282Y mutation in different groups were compared, by {chi}2 analysis, with the values predicted on the basis of the assumption of the Hardy-Weinberg equilibrium. To assess the associations of the C282Y mutation and of high and low iron stores with coronary atherosclerosis and/or MI, odds ratios (ORs) with 95% CIs were first obtained by univariate logistic regression analysis. We performed adjustments for all the other cardiovascular risk factors by including covariates in a second set of multivariate logistic regression models.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
The prevalence of the C282Y mutation and the other characteristics of the 546 cases and 303 controls are summarized in Table 1 . As expected, the CAD patients had more conventional risk factors than CAD-free individuals. Fibrinogen, HSCRP, and MDA concentrations were also higher in CAD vs CAD-free individuals.


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  		Table 1. Clinical and biochemical data for CAD and CAD-free individuals.1

No homozygote for the C282Y mutation was found. Twenty-six CAD patients were heterozygous for the C282Y mutation (4.8%), but this frequency was not significantly different from that observed in CAD-free patients (6.6%; OR, 0.71; 95% CI, 0.39–1.3; P = 0.26). Mean ferritin concentrations were similar in heterozygotes for the C282Y mutation compared with individuals not carrying the mutation, either in males or in females. The corresponding geometric means (with 95% CIs) were as follows: 117 (84–162) vs 126 (117–135) µg/L in males (P = 0.64) and 58 (37–91) vs 56 (50–63) µg/L in females (P = 0.89). Moreover, only a minor proportion (5%) of C282Y heterozygotes had biochemical signs of iron overload, i.e., serum ferritin concentrations above the top quintile of the control distribution.

Ferritin concentrations were slightly higher in CAD vs CAD-free patients (Table 1Up ). Because the distribution of ferritin values was clearly different in the sexes, all subsequent analyses were conducted separately in males and females (Tables 2 and 3 ). After this procedure, the statistically significant difference in ferritin concentrations disappeared.


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  		Table 2. Biochemical and genetic markers of iron status in males and females with or without angiographically confirmed CAD.


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  		Table 3. Biochemical and genetic markers of iron status in CAD males and females with or without documented MI.

No correlation was found between serum ferritin concentrations and the severity of CAD. Geometric means (with 95% CIs) were 123.1 (98.5–153.8) µg/L in patients with single-vessel disease, 108.8 (92.4–128) µg/L in patients with double-vessel disease, and 105.6 (95.4–116.9) µg/L in patients with triple-vessel disease (P = 0.45 by ANOVA).

The prevalence of "mild to moderate iron overload", defined as mentioned above, was not significantly different between CAD and CAD-free groups (22% vs 19%, respectively; P = 0.36 by {chi}2), both in men and in women (Table 2Up ). On the other hand, there was a higher prevalence of iron depletion in CAD-free vs CAD females (Table 2Up ), but this difference disappeared after age-adjusted analysis (OR, 0.51; 95% CI, 0.21–1.19; P = 0.12), as well as after adjustment for all the other cardiovascular risk factors in a logistic regression model (OR, 0.66; 95% CI, 0.21–2.08; P = 0.48).

No statistically significant differences in serum ferritin concentrations, as well as in the prevalence of either iron overload/depletion or heterozygosity for C282Y mutation, were seen in CAD patients with or without MI (Table 3Up ).

To test the hypothesis of increased lipid peroxidation in individuals with mild to moderate iron overload, we evaluated the relationship between serum ferritin and MDA concentrations. Serum MDA was higher in CAD vs CAD-free individuals (Table 1Up ) and correlated positively with LDL-cholesterol (Spearman test, {rho} = 0.14; P <0.001). However, MDA was similar in individuals with ferritin concentrations in the top quintile compared with individuals with ferritin concentrations in the other quintiles (0.69 vs 0.68 µol/L).

Serum ferritin concentrations were significantly correlated with HSCRP (Spearman test, {rho} = 0.129; P <0.001). Moreover, we found a linear increase in the percentage of volunteers with high serum ferritin according to increasing quintiles of HSCRP (Fig. 1 ). Accordingly, in a multivariate logistic regression model including sex, age, HSCRP, and the C282Y mutation as covariates, HSCRP values in the top quintile were the strongest predictor of high ferritin concentrations (OR, 2.4; 95% CI, 1.23–4.52; P = 0.009).



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  		Figure 1. Shaded columns represent the proportion of study participants (n = 794) with ferritin concentrations above the top quintile as a function of increasing quintiles of CRP; {chi}2 = 11.7 with four degrees of freedom (P = 0.02).


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
Coronary atherosclerosis is a complex disease in which a myriad of genetic and environmental factors, some of them yet poorly understood, are involved. Recently, the iron hypothesis has generated an intense debate (1). Currently available clinical studies focused on either biochemical or, more recently, genetic markers of iron overload. In both cases, conflicting results have been reported [reviewed in Refs. (2)(21)(22)]. We used a combined approach by determining both the C282Y mutation in the HFE gene and serum ferritin concentrations. Serum ferritin concentrations were also used to categorize individuals with or without biochemical signs of either iron overload or depletion. In none of our analyses could we obtain any convincing evidence of an association between iron and either angiographically confirmed CAD or previous documented MI. A peculiarity that strengthens the relevance of our null findings lies in the fact that we included only individuals having objective angiographic information. The majority (66%) of our CAD patients had severe triple-vessel disease, whereas the controls were chosen to provide a contrasting population with an angiographically documented absence of CAD. This is a key point in studies aimed to evaluate the association between a putative risk factor (genetic or not) and coronary atherosclerosis. Such an approach reduces the chance of spurious results deriving from the inclusion of controls with substantial, although not yet clinically manifest, coronary atherosclerosis.

Nonetheless, several points have to be taken into account to set our study in the context of the currently available information on the iron hypothesis.

biochemical markers of iron stores and cad
Early epidemiologic investigations (23)(24)(25) that related body iron stores to CAD were criticized (8) because of the use of nonspecific markers, such as serum iron and/or transferrin. Studies that used serum ferritin have been considered more informative because ferritin is strongly correlated with body iron stores in healthy individuals (26). On the other hand, inflammation is now recognized to play an important role in atherosclerosis (27), and ferritin synthesis is known to be up-regulated by proinflammatory cytokines (26)(28). A frequently cited prospective study on Finnish men (29) reported that a serum ferritin concentration >200 µg/L was a risk factor for CAD. In our study, a high concentration of stored iron was not associated with the presence of CAD. Moreover, we considered the relationship between serum ferritin and HSCRP, which is now recognized as a very reliable marker of inflammation (30). We found not only a significant correlation between the two markers, but also a linear increase in the percentage of individuals with high serum ferritin according to increasing quintiles of HSCRP. The quintile approach to HSCRP has been demonstrated to provide a powerful and independent estimate of cardiovascular risk (30), with a linear increase across the spectrum of inflammation. Thus our data raise concern about the results from previous studies and, in general, on the use of high serum ferritin as a cardiovascular risk predictor, unless adjustment for HSCRP is made.

Because the original hypothesis of Sullivan (1) focused on the loss of iron with menstruation as an explanation for the sex difference in CAD risk, we also tested the protective effect of iron depletion. Under these circumstances, the reliability of ferritin is not lowered by the presence of inflammation; therefore, a low ferritin concentration can be considered an effective marker of iron deficiency. Although we found a higher prevalence of low iron stores in CAD-free compared with CAD women, the protective effect of iron depletion was no longer evident after adjustment for conventional risk factors, suggesting a spurious effect.

the lipid peroxidation hypothesis
The most plausible mechanism by which iron may promote the formation of the atherosclerotic plaque lies in its well-known ability to catalyze the production of reactive oxygen species and lipid peroxidation (31). Whereas some data in experimental animals support a potential adverse effect of iron overload (32), the relevance of such data to human atherosclerotic disease remains to be established. Previous studies suggested that the iron-mediated CAD risk might be increased in patients with high LDL-cholesterol concentrations, indicating a permissive effect of iron on LDL peroxidation (29). We tested this hypothesis by evaluating the relationship between serum ferritin and HPLC-measured plasma MDA, a validated marker of lipid peroxidation, although not the ideal one. Whereas there was indeed a positive correlation between LDL-cholesterol and MDA, MDA was not increased in patients with high serum ferritin. Thus, our results are not consistent with a major effect of iron in promoting peroxidation of circulating lipids in vivo. On the other hand, because we considered only serum markers, our data cannot exclude an iron-mediated oxidative stress occurring within the vessel wall.

genetic markers of iron stores and cad
Heterozygosity for the C282Y mutation in the HFE gene is a recently available adjunctive tool to study the relationship between iron stores and CAD risk. In contrast to single-point biochemical measurements (i.e., serum ferritin), which are influenced by several transient modifiers, this common mutation is theoretically a good marker of lifelong moderate iron overload. Our results are in contrast to those from two prospective studies in Northern European populations, in which C282Y heterozygosity was a risk factor for MI in Finnish men (13) and for cardiovascular mortality in Dutch postmenopausal women (12).

Discrepant results are quite common in studies attempting to relate any polymorphism in a candidate gene with the risk of CAD (33). Differences in the study design and/or in the ethnic background, with different gene-gene or gene-environment interactions, are common and reasonable explanations. A crucial point is the degree of iron overload in C282Y heterozygotes. A study involving 1058 obligate heterozygotes from the US found that only 20% of males and 8% of females actually had biochemical signs of increased body iron stores (10). In our series, an even lower percentage was found (5%). Because none of the prospective studies on Dutch and Finnish individuals gave details on the iron stores of C282Y heterozygotes, it is possible to speculate a higher impact of C282Y heterozygosity in determining the degree of iron overload in such populations as compared with other ones. Nonetheless, a major concern remains about the role of the C282Y mutation on CAD. As a matter of fact, whereas homozygosity confers a strong risk of developing hemochromatosis, this clinically relevant disease is not generally associated with an increased prevalence of CAD and/or an increased risk of cardiovascular events (22). Furthermore, it should be taken into account that positive findings in a given population do not necessarily imply a causal relationship. The HFE gene is in the major histocompatibility complex region of chromosome 6 (9), where many other highly polymorphic genes encode for proteins involved in immune and inflammatory responses. The associations reported in Northern Europe may be attributable to a linkage disequilibrium of the HFE gene with unknown mutations in other genes, specifically present in such populations.

A relative limitation of our study is that we did not assess another common polymorphism in the HFE gene, the H63D mutation (9). On the other hand, it is generally accepted that this polymorphism has only a minor influence on iron metabolism, and this has been shown to be particularly true in the Italian population (34). The North European prospective studies also did not consider the H63D mutation. Another limitation of this study lies in the case-control design because it evaluated association, not prospective prediction.

If validated, the iron hypothesis for CAD may influence public health policies, such as food fortification and/or encouraging blood donations. A recently published prospective study on 38 244 participants in the Health Professionals Follow-up Study failed to detect any association between regular blood donations and the risk of CAD (35). Accordingly, our results do not support the iron hypothesis or a role for either biochemical or genetic markers of body iron stores as useful predictors of the risk of coronary atherosclerosis and/or its thrombotic complications.


   Acknowledgments
 
We are indebted to Diego Minguzzi for excellent technical assistance and to Mirella Chesini for assistance in collecting data. Supported by Cariverona Foundation, Veneto Region, and Telethon Italy, Grant E.749 (to D.G. and R.C.), and by CNR target project biotechnologies (to P.F.F.)


   Footnotes
 
1 Nonstandard abbreviations: CAD, coronary atherosclerotic disease; MI, myocardial infarction; HSCRP, high-sensitivity C-reactive protein; MDA, malondialdehyde; CI, confidence interval; and OR, odds ratio.


   References
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 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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