|
|
||||||||
Original Research Communication |
1 From the Department of International Health, Rollins School of Public Health (UR and ADS) and the Doctoral Program in Nutrition and Health Sciences, Graduate Division of Biological and Biomedical Sciences (EK), Emory University, Atlanta.
2 Preliminary results presented in abstract form at the Experimental Biology Meeting, April 2000, San Diego. 3 Supported by grant HD-34531 from the National Institutes of Health. 4 Address reprint requests to U Ramakrishnan, Emory University, Rollins School of Public Health, 1518 Clifton Road, NE, Atlanta, GA 30322. E-mail: uramakr{at}sph.emory.edu.
| ABSTRACT |
|---|
|
|
|---|
Objective: This study examined the association between iron stores and a set of established CVD risk factors among nonpregnant women aged 2049 y.
Design: Data from the third National Health and Nutrition Examination Survey (19881994) were used to examine the relation between race-ethnicityspecific quartiles of serum ferritin (SF) and a set of CVD risk factors [body mass index (BMI), total cholesterol, triacylglycerol, HDL cholesterol, plasma glucose, and blood pressure (BP)]. Women with a history of CVD or liver disease were excluded. We controlled for age, session of measurement, prevalent infection, recent blood donation, and treatment with iron for anemia.
Results: Mean SF values were 53.22 ± 2.08 µg/L (n = 1178), 58.93 ± 2.39 µg/L (n = 1093), and 43.33 ± 1.39 µg/L (n = 1075) among non-Hispanic white, non-Hispanic black, and Mexican American women, respectively. Iron stores were positively associated with CVD risk factors only among non-Hispanic black and Mexican American women after adjustment for confounding variables. The strongest associations were seen among Mexican American women: compared with the middle 2 quartiles, the lowest and highest quartiles of SF had lower and higher values, respectively, for BMI, total cholesterol, triacylglycerol, glucose, and diastolic BP.
Conclusion: These findings suggest that CVD risk factors, especially those related to glucose and lipid metabolism, are positively associated with iron status in women.
Key Words: Cardiovascular disease heart disease women premenopausal women iron stores iron status anemia ferritin blood lipids lipid metabolism glucose metabolism NHANES III
| INTRODUCTION |
|---|
|
|
|---|
Hemochromatosis, an inherited genetic disorder in which iron absorption is impaired leading to excessive iron stores, represents the extreme case of iron overload (4). Population estimates of the hemochromatosis gene mutation were
0.4% for C282Y homozygosity and
9% for C282Y heterozygosity among subjects who were primarily of Caucasian descent (5, 6). The overall prevalence estimates in the United States are 0.26% and 5.4% for C282 homozygosity and heterozygosity, respectively, on the basis of data from phase 2 of the third National Health and Nutrition Examination Survey (NHANES III); rates were lower than expected among Mexican Americans (7).
A few epidemiologic studies in humans have examined the association between iron stores and increased risk of cardiovascular disease (CVD) (813). In Finnish men, for example, serum ferritin (SF) concentrations > 200 µg/L were associated with a 2.2-fold increase in the incidence of acute myocardial infarction compared with SF concentrations < 200 µg/L during a 3-y follow-up (8). However, other studies failed to confirm these findings (912). One plausible explanation is that elevated SF values do not reflect increased iron stores, but are rather the result of infections and other inflammatory processes associated with coronary heart disease; SF is an acute phase reactant protein (1417). However, more recently, Tuomainen et al (13) used the ratio of serum transferrin receptors to SF and found a 23-fold increased risk of acute myocardial infarction among Finnish men across tertiles, even after adjusting for inflammation and alcohol intake. Another possibility is that iron stores may interact with established CVD risk factors, such as LDL cholesterol and total cholesterol concentrations, in increasing the risk of CVD (18). Thus, current epidemiologic evidence of an increased risk for chronic disease as a result of high iron stores is far from conclusive.
In addition, most studies have been conducted in men, who typically have higher iron stores than women. For physiological reasons, women of reproductive age are at greater risk of iron deficiency and are therefore more likely to be adversely affected by policies that would reduce the dietary availability of iron, such as withdrawal of fortification of foods with iron or multivitamin and mineral supplements. On the other hand, if high iron stores are causally associated with increased CVD risk, a reduction in iron intakes would be warranted. The objective of this study was therefore to use nationally representative data from NHANES III to examine whether iron stores are positively associated with CVD risk factors in different race-ethnicity groups of women of reproductive age.
| SUBJECTS AND METHODS |
|---|
|
|
|---|
Blood lipid and glucose concentrations were measured in a venous blood sample by using standard techniques. Serum total cholesterol, HDL cholesterol, and triacylglycerol concentrations were determined at Johns Hopkins University Hospital Lipoprotein Analytic Laboratory by using spectrophotometry (21). Blood glucose was determined at the Diabetes Reference Laboratory, Columbia School of Medicine, University of Missouri by using the glucose-hexokinase method (21). SF concentration was measured with the Quantimune Ferritin IRMA kit (Bio-Rad Laboratories, Hercules, CA) (21). Blood tests were also used to evaluate subjects for liver disease. If any of the following 3 biochemical indexes were elevated, the subject was considered to have possible liver disease: alanine aminotransferase (EC 2.6.1.2) > 74 µmol/L or > 1.23 µkat/L, aspartate aminotransferase (EC 2.6.1.10) > 68 µmol/L or > 1.13 µkat/L, or alkaline phosphatase (EC 3.1.3.1) > 1.5 times normal. These enzyme concentrations were assayed at the White Sands Research Center by using spectrophotometric methods. C-reactive protein concentrations were determined by using latex-enhanced nephelometry at the University of Washington (21).
Study sample
NHANES III represents the total civilian noninstitutionalized population 2 mo of age or older in the United States. A stratified multistage probability design was used to select participants. The sample for the study described in this article consisted of non-pregnant women of reproductive age (2049 y) from the 3 largest race-ethnicity groups: non-Hispanic white (NHW), non-Hispanic black (NHB), and Mexican American (MA). Women were excluded if they were missing data on SF or any of 7 established CVD risk factors: body mass index (BMI), serum triacylglycerol, total cholesterol, HDL cholesterol, blood glucose, diastolic blood pressure (DBP), and systolic blood pressure (SBP). To minimize the potential for confounding of the primary relation of interest (SF and CVD risk factors), women with any of the following conditions were also excluded: possible liver disease, history of ischemic heart disease or stroke, current use of insulin, and use of oral medications for hypertension or diabetes. Women who had not fasted for
6 h at the time of blood collection were also excluded.
Data collection was approved by the National Institutes of Health. The secondary data analysis was approved by the Human Investigations Committee at Emory University.
Variable definition
The 25th and 75th percentile values of SF within each race-ethnicity group were used as threshold values to define 3 categories of iron stores: low (< 25th percentile), medium (25th to 75th percentile), and high (> 75th percentile). Ethnicity was self-reported. The CVD risk factors of interest were analyzed as continuous variables, and the triacylglycerol and glucose distributions were log transformed before analysis. Age was expressed in years as a continuous variable. The session of measurement was coded as either morning or afternoon and evening. Subjects reported whether they had been treated with iron for anemia in the past 3 mo or had donated blood in the past 3 mo; their answers were coded as yes, no, or missing. The presence of infection was determined on the basis of either elevated concentrations of C-reactive protein (> 6 mg/L) or an abnormal white blood cell count (> 11.0 or < 3.5 x 109/L). Women with missing data for infection, blood donation, and treatment with iron for anemia were included in the models as a separate stratum.
Statistical analysis
The relations between iron stores and the CVD risk factors were examined within each race-ethnicity group. Tests for linear trend were performed to compare unadjusted mean values for the CVD risk factors across the 3 categories of iron stores. General linear regression models were then used to examine the associations between individual CVD risk factors as the outcome and the categories of iron stores (low, medium, and high, with medium as the reference group). We adjusted for age, session, presence of infection, treatment with iron for anemia, and blood donation.
Because the CVD risk factors of interest represent a cluster of indicators that collectively predict risk and may be correlated, we used multivariate analysis of variance in which the entire set of CVD risk factors was considered as the dependent variable (22). A single P value was used to interpret the significance of the association between the set of CVD risk factors and SF concentration. This approach may be superior to consideration of each risk factor separately, because it adjusts for multiple comparisons and accounts for collinearity between the dependent variables. Because 2 comparisons were done (high versus medium and low versus medium SF), a Bonferroni correction was applied and P < 0.025 was considered statistically significant. In addition to race-ethnicityspecific models, a single model for the entire sample (ie, all race-ethnicity groups combined) was used to examine the overall relation between SF and CVD risk factors, along with main effects and interactions between SF and race-ethnicity groups. All statistical analyses were weighted appropriately and SUDAAN (release 5.5) was used to derive parameter estimates that took into account the complex sample design (23).
| RESULTS |
|---|
|
|
|---|
12% (n = 538) were subsequently excluded because of the presence of liver disease, history of CVD, or use of insulin or oral medications for diabetes or hypertension. An additional 383 women were excluded because they had not fasted for
6 h before blood sample collection. The final analytic sample (n = 3346) included 1178 NHW, 1093 NHB, and 1075 MA women. The sample of women who had been excluded (n = 1233) from the analytic sample was older and had a higher proportion of NHB women (18.3% compared with 12.5%). The prevalence of infections was also higher among those who were excluded (18.5 ± 0.8%) compared with those who were not (10.0 ± 2.8%), and the excluded group had significantly higher values for SF and all the CVD risk factors of interest (P < 0.05).
Mean values for SF, the CVD risk factors of interest, age, and prevalence of confounding factors (session, infection, treatment with iron for anemia, and recent blood donation) are shown by race-ethnicity groups in Table 1
. MA women had significantly higher triacylglycerol and glucose concentrations and lower HDL cholesterol and SF values than did NHB and NHW women (P < 0.001). NHB women had higher blood pressure than did NHW and MA women (P < 0.001). NHW women were older and less obese than were MA and NHB women and also had the highest prevalence of recent blood donation (P < 0.001). The proportion of women receiving iron as treatment for anemia was low overall but was highest among NHB women.
|
|
|
Age, session, and infections were significantly associated with the CVD risk factors in all 3 race-ethnicity groups, whereas blood donation and treatment with iron for anemia were associated with the outcomes for NHW women only. Examination of the relations with a single model that combined all 3 race-ethnicity groups confirmed the above results.
| DISCUSSION |
|---|
|
|
|---|
Few studies have examined the relation between iron stores and CVD risk factors in women of reproductive age. Milman and Kirchoff (25) found positive associations between SF and both BMI and serum triacylglycerol but no associations with serum total cholesterol, HDL cholesterol, or blood pressure among healthy white Danish women aged 4060 y who were not blood donors (25). In a much smaller sample of 159 healthy Nordic women (113 premenopausal and 46 postmenopausal), Berge et al (26) also reported significant associations between SF and serum total, LDL, and HDL cholesterol after adjusting for age. Interestingly, neither SF nor serum lipids were associated with female sex hormones.
The stronger association in MA women is intriguing because this group has the poorest iron status but increased prevalence of some CVD risk factors. Although serum cholesterol concentrations and blood pressure were similar among the 3 race-ethnicity groups in our sample, MA women had significantly higher concentrations of triacylglycerol and glucose and lower HDL cholesterol concentrations compared with NHW and NHB women. This raises important public health questions, because this subgroup was shown to be at increased risk of both iron deficiency and obesity in the United States (27, 28). More research is definitely needed to better understand the nature of this association before appropriate interventions can be developed. Dietary intakes do not explain the difference in the prevalence of iron deficiency between MA and NHW women, suggesting that the etiology of iron deficiency may depend on other factors (29). Prospective studies, especially intervention studies that ensure adequate iron status, are needed to compare 2 possible scenarios: 1) improved iron status increases the risk of CVD, or 2) women with a higher risk of CVD have higher iron stores, with both factors resulting from the same underlying cause.
| REFERENCES |
|---|
|
|
|---|
This article has been cited by other articles:
![]() |
S. Swaminathan, V. A. Fonseca, M. G. Alam, and S. V. Shah The Role of Iron in Diabetes and Its Complications Diabetes Care, July 1, 2007; 30(7): 1926 - 1933. [Full Text] [PDF] |
||||
![]() |
L. R. Zacharski, B. K. Chow, P. S. Howes, G. Shamayeva, J. A. Baron, R. L. Dalman, D. J. Malenka, C. K. Ozaki, and P. W. Lavori Reduction of Iron Stores and Cardiovascular Outcomes in Patients With Peripheral Arterial Disease: A Randomized Controlled Trial JAMA, February 14, 2007; 297(6): 603 - 610. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. Rajpathak, J. Ma, J. Manson, W. C. Willett, and F. B. Hu Iron Intake and the Risk of Type 2 Diabetes in Women: A prospective cohort study. Diabetes Care, June 1, 2006; 29(6): 1370 - 1376. [Abstract] [Full Text] [PDF] |
||||
![]() |
X. Chen, T. O. Scholl, and T. P. Stein Association of Elevated Serum Ferritin Levels and the Risk of Gestational Diabetes Mellitus in Pregnant Women: The Camden Study Diabetes Care, May 1, 2006; 29(5): 1077 - 1082. [Abstract] [Full Text] [PDF] |
||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |