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Original Articles

Mutations in the HFE Gene and Cardiovascular Disease Risk

An Individual Patient Data Meta-Analysis of 53 880 Subjects

Daphne L. van der A, PhD; Maroeska M. Rovers, PhD; Diederick E. Grobbee, MD, PhD; Joannes J.M. Marx, MD, PhD; Jill Waalen, MD, MPh; Christina Ellervik, MD, PhD; Børge G. Nordestgaard, MD, DMSc; John K. Olynyk, MD; Peter R. Mills, MD; James Shepherd, FRCP; Bernard Grandchamp, MD, PhD; Jolanda M.A. Boer, PhD; Calogero Caruso, MD; Marcello Arca, MD; Beat J. Meyer, MD and Yvonne T. van der Schouw, PhD

From the National Institute for Public Health and the Environment, Bilthoven, the Netherlands (D.L.v.d.A., J.M.A.B.); Julius Center for Health Sciences and Primary Care (D.L.v.d.A., M.M.R., D.E.G., Y.T.v.d.S.) and Eijkman Winkler Institute for Microbiology, Infectious Diseases, and Inflammation (J.J.M.M.), University Medical Center Utrecht, Utrecht, the Netherlands; Department of Molecular and Experimental Medicine, Scripps Research Institute, La Jolla, Calif (J.W.); Department of Clinical Biochemistry, Herlev University Hospital, University of Copenhagen, Herlev, Denmark (C.E., B.G.N.); Copenhagen City Heart Study, Bispebjerg University Hospital, University of Copenhagen, Copenhagen, Denmark (B.G.N.); School of Medicine and Pharmacology, Faculty of Medicine, University of Western Australia and the Department of Gastroenterology, Fremantle Hospital, Fremantle, Western Australia (J.K.O.); Gartnavel General Hospital, Glasgow, Scotland, UK (P.R.M.); Department of Vascular Biochemistry, University of Glasgow, Glasgow, Scotland, UK (J.S.); INSERM U773 and Université Denis Diderot, Paris, France, and AP-HP Service de Génétique et Biochimie Hormonale, Hôpital Xavier Bichat, Association Claude Bernard, Paris, France (B.G.); Department of Pathobiology and Biomedical Methodologies, University of Palermo, Palermo, Italy (C.C.); Department of Clinical and Applied Medical Therapy, University of Rome La Sapienza, Rome, Italy (M.A.); and Cardiovascular Center (CVC-Lindenhofspital), Bern University, Bern, Switzerland (B.J.M.).

Correspondence to Daphne L. van der A, PhD, Center for Nutrition and Health, Postbak 84, National Institute for Public Health and the Environment, PO Box 1, 3720 BA Bilthoven, The Netherlands. E-mail Daphne.van.der.A{at}rivm.nl

Received February 13, 2008; accepted July 28, 2008.

Background— Whether mutations in the hemochromatosis (HFE) gene increase cardiovascular disease risk is still undetermined. The main reason is the low frequency of the mutations, in particular of the compound C282Y/H63D genotype. We combined the data of 11 observational studies for an individual patient data meta-analysis.

Methods and Results— Individual patient data were obtained from published as well as unpublished studies that had information available on the C282Y mutation as well as the H63D mutation in relation to coronary heart disease risk. Individual records were provided on each of the 53 880 participants in 11 studies. In total, 10 541 patients with coronary events were documented, of whom 5724 had an acute myocardial infarction. The crude and adjusted association between HFE genotypes and coronary events was examined by logistic regression analysis. We explored potential effect modification of the association between traditional cardiovascular risk factors and coronary events by HFE genotypes. After full adjustment, the odds ratio for coronary heart disease was 1.12 (95% CI, 0.92 to 1.37) for subjects with the compound heterozygous (C282Y/H63D) genotype relative to those with the wild-type/wild-type genotype. The odds ratios for C282Y/C282Y, C282Y/wild-type, H63D/H63D, and H63D/wild-type were 0.78 (95% CI, 0.49 to 1.26), 0.98 (95% CI, 0.90 to 1.07), 1.16 (95% CI, 0.97 to 1.38), and 1.07 (95% CI, 1.00 to 1.14), respectively. There was no evidence for effect modification.

Conclusions— The results of this large individual patient data meta-analysis do not support the view that HFE gene mutations are associated with an increased risk of coronary heart disease or acute myocardial infarction.

Key Words: cardiovascular diseases • epidemiology • meta-analysis • myocardial infarction • risk factors

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The online-only Data Supplement is available with this article at http://circgenetics.ahajournals.org/cgi/content/full/1/1/43/DC1.

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