Increased iron levels may be causally associated with a decreased risk of developing Parkinson’s disease, says a new paper published this week in PLOS Medicine. Irene Pichler from EURAC in Italy and a group of international colleagues investigated whether there was any evidence of an association between serum iron levels and the risk of Parkinson’s disease. While the causes of Parkinson’s disease are currently unknown, a combination of genetic and environmental factors are said to be attributed to the disease.
Because previous studies have shown a possible association between lower blood levels of iron in people with Parkinson’s disease compared with controls, the researchers used a Mendelian randomization approach to investigate this link. The researchers estimated the effect of blood iron levels on the risk of Parkinson´s disease using three polymorphisms in two genes, HFE and TMPRSS6. For each polymorphism, they performed a meta-analysis combining the results of studies investigating the genetic effect on iron levels, which included almost 22,000 people from Europe and Australia, and a meta-analysis of studies investigating the genetic effect on the risk of Parkinson´s disease, which included a total of 20,809 people with Parkinson’s disease and 88,892 controls from Europe and North America. They then performed three separate Mendelian randomization analyses to estimate the effect of iron on Parkinson disease for the three polymorphisms. By combining the three estimates, they obtained a statistically significant odds ratio of 0.97 for Parkinson´s disease per 10 μg/dl increase in iron, corresponding to a 3% reduction in the risk of Parkinson´s disease for every 10 μg/dl increase in blood iron. Since genotype influences on blood iron levels represent differences that generally persist throughout adult life, the combined Mendelian randomization estimate reflects an effect of iron over the course of a lifetime.
These findings suggest that increased iron levels in the blood are associated with a 3% relative reduction in the risk of Parkinson’s disease for every 10 μg/dL increase in iron. This finding is important as it suggests that increased blood iron levels may have a protective effect against Parkinson’s disease, say the authors, although the underlying mechanism remains unclear. Another limitation to this study is that there may be remaining sources of bias associated with the Mendelian randomization approach, which may influence the interpretation of this study. Further studies on the underlying mechanisms are needed before any specific treatment recommendations can be proposed, say the authors.
Funding: This study was supported by the Ministry of Health and Department of Educational Assistance, University and Research of the Autonomous Province of Bolzano and the South Tyrolean Sparkasse Foundation. The PDGene database has been made possible by the kind support of the Michael J. Fox Foundation (MJFF) for Parkinson’s Research, with additional support from Cure Alzheimer’s Fund (CAF), the Fidelity Biosciences Research Initiative, Prize4Life, the National Alliance for Research on Schizophrenia and Depression (NARSAD), and EMD Serono. RHM received grants from the Robert P. & Judith N. Goldberg Foundation, the Cogan Family Foundation and R01-NS076843, Characterization of the Role of cyclin G-Associated Kinase in Parkinson disease and an unrestricted grant from the Karyopharm Therapuetics Inc. TF has received research grants from NIH, MJFF for Parkinson’s Research, and the Susan G. Komen Foundation. IPDGC was supported by the Intramural Research Programs of the National Institute on Aging, National Institute of Neurological Disorders and Stroke, National Institute of Environmental Health Sciences, and National Human Genome Research Institute of the US National Institutes of Health (NIH), Department of Health and Human Services (project numbers Z01-AG000949-02 and Z01-ES101986), human subjects protocol 2003-077. IPDGC was also supported by the US Department of Defense (award number W81XWH-09-2-0128); NIH (grants NS057105 and RR024992); American Parkinson Disease Association (APDA); Barnes Jewish Hospital Foundation; Greater St. Louis Chapter of the APDA; Hersenstichting Nederland; Neuroscience Campus Amsterdam; and the section of medical genomics, the Prinses Beatrix Fonds. The KORA (Cooperative Research in the Region of Augsburg) research platform was started and financed by the Forschungszentrum fu¨ r Umwelt und Gesundheit, which is funded by the German Federal Ministry of Education, Science, Research, and Technology and by the State of Bavaria. It was also funded by the German National Genome Network (NGFNplus number 01GS08134, German Ministry for Education and Research); by the German Federal Ministry of Education and Research (NGFN 01GR0468, PopGen); and 01EW0908 in the frame of ERA-NET NEURON and Helmholtz Alliance Mental Health in an Ageing Society (HA-215), which was funded by the Initiative and Networking Fund of the Helmholtz Association. The French GWAS work was supported by the French National Agency of Research (ANR-08-MNP-012). It was also sponsored by the European Community Framework Programme 7, People Programme, and IAPP on novel genetic and phenotypic markers of Parkinson’s disease and Essential Tremor (MarkMD), contract number PIAP-GA-2008-230596 MarkMD (to HP and JHu). The WTCCC2 project was funded by the Wellcome Trust (083948/Z/07/Z). WTCCC1 study was supported by the Medical Research Council and Wellcome Trust disease centre (grant WT089698/Z/09/Z to NW, JHa, and ASc). This study was also supported by Parkinson’s UK (grants 8047 and J-0804) and the Medical Research Council (G0700943). DNA extraction work that was done in the UK at University College London Hospitals, University College London, which received a proportion of funding from the Department of Health’s National Institute for Health Research Biomedical Research Centres funding. This study was supported in part by the Wellcome Trust/Medical Research Council Joint Call in Neurodegeneration award (WT089698) to the Parkinson’s Disease Consortium (UKPDC), whose members are from the UCL Institute of Neurology, University of Sheffield, and the Medical Research Council Protein Phosphorylation Unit at the University of Dundee. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: CM is a member of the Editorial Board of PLOS Medicine. NE and CBD are or have been employed by 23andMe and own stock options in the company. TF serves on Research Competitiveness Program for the American Association for the Advancement of Science; Study Sections, Review Panels, Board of Scientific Counselors for NIH; Scientific Advisory Board for University of Colorado; and the NIA’s Long Life Family Study Observational Study Monitoring Board. All other authors have declared that no competing interests exist.
Citation: Pichler I, Del Greco M. F, Go¨ gele M, Lill CM, Bertram L, et al. (2013) Serum Iron Levels and the Risk of Parkinson Disease: A Mendelian Randomization Study. PLoS Med 10(6): e1001462. doi:10.1371/journal.pmed.1001462
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