Body iron stores and coronary heart disease.
Do increased body iron stores increase risk of CHD? Are individuals who are heterozygotes for the common C282Y mutation at especially high risk of CHD? Can iron depletion reduce the risk? These questions have important implications given the common practice of fortification of food and supplements with iron in industrialized countries and the high frequency of HFE C282Y carriers (~9% of them are of northern European descent) (11). Moreover, the "Oxidative Stress Theory" suggests that iron, as a potent catalytic agent, could promote formation of highly reactive oxygen species and lipid peroxidation, a crucial step in atherosclerosis (4). Thus, evaluation of the iron hypothesis for CHD will lead to advances in our understanding of its pathogenesis. To date, conflicting results have been reported from epidemiologic studies (4, 8, 9, 12-14) conducted in different countries and populations using different biochemical and genetic markers of body iron stores.
Among biochemical markers of iron stores, serum ferritin is generally considered the best measure that can be readily assessed in epidemiologic studies. Nine of the 11 cross-sectional or case-control studies (13) [including the study of Bozzini et al. (10)] reported no association between serum ferritin and CHD or atherosclerosis, with the exception of the Italian Bruneck Study (15) and a study of young Iranian male CHD patients (16). All of these studies evaluated serum ferritin among patients with CHD, but ferritin, an acute-phase protein, can be increased by myocardial damage and inflammation (17). A positive association could therefore be biased by post-myocardial infarction damage and inflammation. Chronic inflammation (as measured by fibrinogen, C-reactive protein, albumin, leukocytes, and erythrocyte sedimentation rate) has consistently been found to be associated with increased CHD risk (18). In the present Italian study of Bozzini et al. (10), serum C-reactive protein, but not ferritin, was significantly higher among CHD patients than the CHD-free controls, although the two markers were significantly correlated with each other. On the other hand, the lack of an association with serum ferritin in a case-control study could also reflect bias by factors related to treatment, such as aspirin, or behavioral changes, such as a healthy diet or increase in exercise.
Prospective cohort studies measure biomarkers using blood samples collected before the disease is diagnosed. Because CHD patients are prospectively ascertained and CHD-free controls arise from the same cohort, many potential biases can be avoided. Eight prospective cohort studies have reported results for the relationship of serum ferritin with risk of CHD or atherosclerosis (12, 13); only two found a significant positive association (12, 13, 19). The first positive finding was based on the Finnish Kuopio Ischemic Heart Disease Risk Factor Study (KIHD) (20, 21) in men, which reported a twofold increased risk of CHD (a total of 83 incident cases) among men with serum ferritin > 200 [micro]g/L. The other was based on the Italian Bruneck Study (19) and found a positive association between serum ferritin and ultrasound measures of progression of carotid atherosclerosis over a 5-year follow-up period. The Bruneck Study (11) presented results on the basis of a combined sample of men and women that is hard to interpret given the large gender difference in ferritin concentrations. Transferrin saturation percentage is the most widely used indicator for screening iron overload. However, none of the five cohort studies assessing transferrin saturation reported increased risk of CHD (12).
In addition to assessing the effect of iron overload, several recent studies have specifically addressed the hypothesis that "iron depletion" is associated with lower risk of CHD. In a recent prospective analysis of the second National Health and Nutrition Examination Study, Sempos et al. (13) observed either no association (in Caucasian men) or a possible nonsignificant increased risk (in Caucasian women) of cardiovascular or CHD death among individuals with low ferritin concentrations. In the current study (10), the observed higher prevalence of iron depletion in CHD-free vs CHD women was mainly explained by age and other CHD risk factors. In addition to the use of biomarkers, the comparison of blood donors with nondonors appears to provide a good test of the iron-depletion hypothesis because of the marked contrast in body iron stores of regular donors compared with those of nondonors (14). However, of three published studies on blood donation (14, 22, 23), only the Finnish KIHD study found a significant inverse relation with CHD (23).
Hereditary hemochromatosis causes progressive accumulation of iron in most tissues and has been used as a "human model" to evaluate the effect of marked iron overload on CHD (8). Autopsy or mortality studies have consistently shown that atherosclerosis, CHD, stroke, and peripheral artery disease are neither prominent clinical features nor frequent causes of death in clinically diagnosed hemochromatosis patients (8). Because most of these studies included patients with severe iron overload, individuals with moderate iron overload were not represented.
The recent discovery of the HFE gene mutation provides a new opportunity to address the iron hypothesis. Of the two common mutations of the HFE (C282Y and H63D), C282Y carrier status has recently been associated with significantly increased risk of CHD incidence or cardiovascular mortality in three cohort studies (5-7). The first study (5) was from a subgroup of the original Finnish KIHD cohort. Eight (11.8%) of 68 individuals diagnosed with acute myocardial infarction and 77 (6.7%) of 1150 non-CHD participants were carriers of C282Y. The crude relative risk of myocardial infarction was 2.0 [95% confidence interval (CI), 0.9-4.1), and the adjusted relative risk was 2.3 (95% CI, 1.1-4.8). In a cohort of 12 239 Dutch postmenopausal women, the C282Y carrier status was assessed among 531 (57 carriers; 10.7%) women who died of cardiovascular disease and 555 (43 carriers; 7.7%) randomly selected women who did not die of cardiovascular disease (6). This study reported a 1.5-fold increased risk of myocardial infarction death (95% CI, 0.9-2.5), a 2.4-fold increased risk of cerebrovascular death (95% CI, 1.3-4.4), and a relative risk of 1.6 (95% CI, 1.1-2.4) for total cardiovascular death. However, the numbers of C282Y carriers in the cause-specific subgroups were not given. In this study, a subgroup analysis suggested that C282Y heterozygotes who were both smokers and had hypertension had a strongly increased risk of cardiovascular death (relative risk, 18.9; 95% CI, 8.4-42.4). The wide CI reflects the small number of deaths in the smoker/hypertensive category; further study is needed to confirm or refute this finding. The third study, the United States Atherosclerosis Risk in Communities study (7), reported a C282Y carrier frequency of 9.9% among 243 CHD cases and 6.1% among 535 selected noncases. The crude relative risk of CHD associated with C282Y carrier status was 1.6 (95% CI, 0.9-3.0) and was 2.7 (95% CI, 1.2-6.0) after controlling for other risk factors, especially lipid concentrations. In addition to the current study by Bonzini et al. (10), all six previous case-control studies reported no association between atherosclerosis or cardiovascular events and heterozygosity for HFE C282Y (24-29). Although survival bias could not be ruled out in all these case-control studies, the three prospective studies did not specifically report a stronger impact of C282Y heterozygosity on fatal CHD.
It has been reported that heterozygotes for hereditary hemochromatosis have slightly but significantly increased serum ferritin and serum iron (30). However, it remains uncertain whether heterozygotes of C282Y indeed have increased iron stores because some studies, including the Finnish KIHD study and the study in this issue, found that serum ferritin concentrations were not correlated with C282Y carrier status (5, 10, 25). One recent study (31) suggested that non-transferrin-bound iron or low-molecular weight iron is increased in circulation of C282Y heterozygotes, leading to higher transferrin saturation. However, transferrin saturation was not associated with increased risk of CHD in epidemiologic studies as discussed previously (12). Moreover, in all three cohort studies (5-7) and seven case-control studies (10, 24-29) of HFE mutation and CHD risk, the numbers of individuals homozygous for C282Y were too small to evaluate a gene-dose effect, and a larger study is needed to address this issue.
In summary, the totality of available evidence from a variety of studies using different measures of body iron stores (ranging from blood donation, biochemical and genetic markers to hemochromatosis patients) do not provide persuasive evidence to support the iron hypothesis, although further studies are warranted. The majority of HFE heterozygotes have distributions of iron storage indicators that overlap substantially with controls. The potential influence of nongenetic factors (such as gender, chronic blood loss, regular blood donation, excessive iron intake, or other dietary modifiers that increase or decrease iron stores) on phenotype expression needs to be carefully evaluated. Previously published studies either lacked comprehensive nongenetic information or were too small to examine gene-environment interactions. A larger comprehensive prospective study or a pooled analysis of existing genetic studies might provide a more coherent picture before a large and expensive trial of genetic screening and iron depletion can be seriously entertained.
Supported by Research Grants CA 78293, CA 42182, CA 58684, CA 70817, and CA 90598 from NIH.
(1.) Sullivan JL. Iron and the sex difference in heart disease risk. Lancet 1981;1:1293-4.
(2.) Ascherio A, Willett WC. Are body iron stores related to the risk of coronary heart disease? N Engl J Med 1994;330:1152-4.
(3.) Gillum RF. Body iron stores and atherosclerosis. Circulation 1997;96: 3261-3.
(4.) de Valk B, Marx JJ. Iron, atherosclerosis, and ischemic heart disease. Arch Intern Med 1999;159:1542-8.
(5.) Tuomainen TP, Kontula K, Nyyssonen K, Lakka TA, Helio T, Salonen JT. Increased risk of acute myocardial infarction in carriers of the hemochromatosis gene Cys282Tyr mutation: a prospective cohort study in men in eastern Finland. Circulation 1999;100:1274-9.
(6.) Roest M, van der Schouw YT, de Valk B, Marx JJ, Tempelman MJ, de Groot PG, et al. Heterozygosity for a hereditary hemochromatosis gene is associated with cardiovascular death in women. Circulation 1999;100:1268-73.
(7.) Rasmussen ML, Folsom AR, Catellier DJ, Tsai MY, Garg U, Eckfeldt JH. A prospective study of coronary heart disease and the hemochromatosis gene (HFE) C282Y mutation: the Atherosclerosis Risk in Communities (ARIC) study. Atherosclerosis 2001;154:739-46.
(8.) Niederau C. Iron overload and atherosclerosis. Hepatology 2000;32:672-4.
(9.) Sullivan JL, Zacharski LR. Hereditary haemochromatosis and the hypothesis that iron depletion protects against ischemic heart disease. Eur J Clin Invest 2001;31:375-7.
(10.) Bozzini C, Girelli D, Yinazzi E, Olivieri O, Stranieri C, Bassi A, et al. Biochemical and genetic markers of iron status and the risk of coronary artery disease: an angiography-based study. Clin Chem 2002;48:622-8.
(11.) Hanson EH, Imperatore G, Burke W. HFE gene and hereditary hemochromatosis: a HuGE review. Human Genome Epidemiology. Am J Epidemiol 2001;154:193-206.
(12.) Danesh J, Appleby P. Coronary heart disease and iron status: meta-analyses of prospective studies. Circulation 1999;99:852-4.
(13.) Sempos CT, Looker AC, Gillum RE, McGee DL, Vuong CV, Johnson CL. Serum ferritin and death from all causes and cardiovascular disease: the NHANES II Mortality Study. National Health and Nutrition Examination Study. Ann Epidemiol 2000;10:441-8.
(14.) Ascherio A, Rimm EB, Giovannucci E, Willett WC, Stampfer MJ. Blood donations and risk of coronary heart disease in men. Circulation 2001;103: 52-7.
(15.) Kiechl S, Aichner F, Gerstenbrand F, Egger G, Mair A, Rungger G, et al. Body iron stores and presence of carotid atherosclerosis. Results from the Bruneck Study. Arterioscler Thromb 1994;14:1625-30.
(16.) Haidari M, Javadi E, Sanati A, Hajilooi M, Ghanbili J. Association of increased ferritin with premature coronary stenosis in men. Clin Chem 2001;47:1666-72.
(17.) Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med 1999;340:448-54.
(18.) Danesh J, Collins R, Appleby P, Peto R. Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies. JAMA 1998;279:1477-82.
(19.) Kiechl S, Willeit J, Egger G, Poewe W, Oberhollenzer F. Body iron stores and the risk of carotid atherosclerosis: prospective results from the Bruneck study. Circulation 1997;96:3300-7.
(20.) Salonen JT, Nyyssonen K, Korpela H, Tuomilehto J, Seppanen R, Salonen R. High stored iron levels are associated with excess risk of myocardial infarction in eastern Finnish men. Circulation 1992;86:803-11.
(21.) Salonen JT, Nyyssonen K, Salonen R. Body iron stores and the risk of coronary heart disease. N Engl J Med 1994;331:1159; discussion 1160.
(22.) Meyers DG, Strickland D, Maloley PA, Seburg JK, Wilson JE, McManus BF. Possible association of a reduction in cardiovascular events with blood donation. Heart 1997;78:188-93.
(23.) Salonen JT, Tuomainen TP, Salonen R, Lakka TA, Nyyssonen K. Donation of blood is associated with reduced risk of myocardial infarction. The Kuopio Ischaemic Heart Disease Risk Factor Study. Am J Epidemiol 1998;148: 445-51.
(24.) Franco RF, Zago MA, Trip MD, ten Cate H, van den Ende A, Prins MH, et al. Prevalence of hereditary haemochromatosis in premature atherosclerotic vascular disease. Br J Haematol 1998;102:1172-5.
(25.) Rossi E, McQuillan BM, Hung J, Thompson PL, Kuek C, Beilby JP. Serum ferritin and C282Y mutation of the hemochromatosis gene as predictors of asymptomatic carotid atherosclerosis in a community population. Stroke 2000;31:3015-20.
(26.) Annichino-Bizzacchi JM, Saad ST, Arruda VR, Ramires JA, Siqueira LH, Chiaparini LC, et al. C282Y mutation in the HLA-H gene is not a risk factor for patients with myocardial infarction. J Cardiovasc Risk 2000;7:37-40.
(27.) Battiloro E, Ombres D, Pascale E, D'Ambrosio E, Verna R, Arca M. Haemochromatosis gene mutations and risk of coronary artery disease. Eur J Hum Genet 2000;8:389-92.
(28.) Calado RT, Franco RF, Pazin-Filho A, Simoes MV, Marin-Neto JA, Zago MA. HFE gene mutations in coronary atherothrombotic disease. Braz J Med Biol Res 2000;33:301-6.
(29.) Hetet G, Elbaz A, Gariepy J, Nicaud V, Arveiler D, Morrison C, et al. Association studies between haemochromatosis gene mutations and the risk of cardiovascular diseases. Eur J Clin Invest 2001;31:382-8.
(30.) Bulaj ZJ, Griffen LM, Jorde LB, Edwards CQ, Kushner JP. Clinical and biochemical abnormalities in people heterozygous for hemochromatosis. N Engl J Med 1996;335:1799-805.
(31.) de Valk B, Addicks MA, Gosriwatana I, Lu S, Hider RC, Marx JJ. Non-transferrin-bound iron is present in serum of hereditary haemochromatosis heterozygotes. Eur J Clin Invest 2000;30:248-51.
Jing Ma  *
Meir J. Stampfer [1,2]
 Channing Laboratory
Department of Medicine
Brigham and Women's Hospital
Harvard Medical School
Boston, MA 02115
 Departments of Epidemiology and Nutrition
Harvard School of Public Health
Boston, MA 02115
* Author for correspondence. Fax 617-525-2008; e-mail email@example.com.
|Printer friendly Cite/link Email Feedback|
|Author:||Ma, Jing; Stampfer, Meir J.|
|Date:||Apr 1, 2002|
|Previous Article:||Announcements from our in box.|
|Next Article:||Erythrocyte galactose 1-phosphate quantified by isotope-dilution gas chromatography--mass spectrometry.|