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Diabetes 54:3567-3572, 2005
© 2005 by the American Diabetes Association, Inc.

HFE Genetic Variability, Body Iron Stores, and the Risk of Type 2 Diabetes in U.S. Women

Lu Qi1,2, James Meigs3, JoAnn E. Manson2,4,5, Jing Ma2,5, David Hunter1,2,4, Nader Rifai6, and Frank B. Hu1,2,4

1 Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts
2 Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
3 General Internal Medicine and Clinical Epidemiology Units, General Medicine Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
4 Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts
5 Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
6 Department of Laboratory Medicine, Children’s Hospital and Harvard Medical School, Boston, Massachusetts

To determine whether the HFE gene variants H63D and C282Y are associated with body iron stores and the risk of type 2 diabetes, we conducted a nested case-control study of 714 incident cases of type 2 diabetes and 1,120 matching control subjects in a prospective cohort, the Nurses’ Health Study. In both healthy control and diabetic case subjects, H63D homozygosity, C282Y, and the compound heterozygotes were associated with significantly higher levels of plasma ferritin and significantly lower ratios of transferrin receptors to ferritin. Such effects were independent of age, BMI, and lifestyle factors. Overall, there were no significant differences in genotypes of H63D and C282Y between the case and control subjects. A meta-analysis of 4,245 case and 5,982 control subjects indicated a null association of C282Y with diabetes risk, whereas carriers of H63D or the compound heterozygotes had marginally increased risk (odds ratio [OR] 1.11 [95% CI 1.00–1.25] and 1.60 [0.99–2.60], respectively). In addition, we found a significant interaction between HFE variants and heme iron intake (P for interaction = 0.029). The ORs of type 2 diabetes across increasing quartiles of heme iron were 1.00, 1.21 (0.72–2.01), 1.72 (1.03–2.88), and 1.49 (0.91–2.46) among the participants with either the H63D or C282Y variant, whereas the ORs were 1.00, 0.71 (0.49–1.05), 1.12 (0.76–1.66), and 0.96 (0.65–1.42) among those with wild-type genotypes. Our data indicate significant effects of H63D and C282Y on body iron stores and suggest a potential interaction between HFE genotypes and heme iron intake in relation to the risk of type 2 diabetes.

Address correspondence and reprint requests to Dr. Lu Qi, Department of Nutrition, Harvard School of Public Health, 665 Huntington Ave., Boston, MA 02115. E-mail: nhlqi{at}channing.harvard.edu

Abbreviations: ADA, American Diabetes Association; CRP, C-reactive protein; HH, hereditary hemochromatosis; NHS, Nurses’ Health Study


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