期刊
PLOS MEDICINE
卷 10, 期 6, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pmed.1001462
关键词
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资金
- Ministry of Health and Department of Educational Assistance, University and Research of the Autonomous Province of Bolzano
- South Tyrolean Sparkasse Foundation
- Cure Alzheimer's Fund (CAF)
- Fidelity Biosciences Research Initiative
- Prize4Life
- National Alliance for Research on Schizophrenia and Depression (NARSAD)
- EMD Serono
- Robert P. & Judith N. Goldberg Foundation
- Cogan Family Foundation [R01-NS076843]
- Karyopharm Therapuetics Inc.
- NIH
- MJFF for Parkinson's Research
- Susan G. Komen Foundation
- Intramural Research Programs of the National Institute on Aging, National Institute of Neurological Disorders and Stroke, National Institute of Environmental Health Sciences
- National Human Genome Research Institute of the US National Institutes of Health (NIH), Department of Health and Human Services [Z01-AG000949-02, Z01-ES101986, 2003-077]
- US Department of Defense [W81XWH-09-2-0128]
- NIH [NS057105, RR024992]
- American Parkinson Disease Association (APDA)
- Barnes Jewish Hospital Foundation
- Greater St. Louis Chapter of the APDA
- Hersenstichting Nederland
- Neuroscience Campus Amsterdam
- section of medical genomics, the Prinses Beatrix Fonds
- Forschungszentrum fur Umwelt und Gesundheit
- German Federal Ministry of Education, Science, Research, and Technology
- State of Bavaria
- German National Genome Network (NGFNplus) [01GS08134]
- German Federal Ministry of Education and Research [NGFN 01GR0468]
- ERA-NET NEURON [01EW0908]
- Helmholtz Alliance Mental Health in an Ageing Society [HA-215]
- Initiative and Networking Fund of the Helmholtz Association
- French National Agency of Research [ANR-08-MNP-012]
- European Community
- IAPP on novel genetic and phenotypic markers of Parkinson's disease and Essential Tremor (MarkMD) [PIAP-GA-2008-230596 MarkMD]
- Wellcome Trust [083948/Z/07/Z]
- Medical Research Council
- Wellcome Trust disease centre [WT089698/Z/09/Z]
- Parkinson's UK [8047, J-0804]
- Medical Research Council [G0700943]
- Department of Health's National Institute for Health Research Biomedical Research Centres
- Wellcome Trust/Medical Research Council [WT089698]
- MRC [G0802462, MR/K01417X/1, G1100479, G0700943] Funding Source: UKRI
- Medical Research Council [G0802462, MR/K01417X/1, G0700943, G1100479] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0507-10376] Funding Source: researchfish
- Parkinson's UK [F-1202, G-0909, J-0901, J-0804] Funding Source: researchfish
Background: Although levels of iron are known to be increased in the brains of patients with Parkinson disease (PD), epidemiological evidence on a possible effect of iron blood levels on PD risk is inconclusive, with effects reported in opposite directions. Epidemiological studies suffer from problems of confounding and reverse causation, and mendelian randomization (MR) represents an alternative approach to provide unconfounded estimates of the effects of biomarkers on disease. We performed a MR study where genes known to modify iron levels were used as instruments to estimate the effect of iron on PD risk, based on estimates of the genetic effects on both iron and PD obtained from the largest sample meta-analyzed to date. Methods and Findings: We used as instrumental variables three genetic variants influencing iron levels, HFE rs1800562, HFE rs1799945, and TMPRSS6 rs855791. Estimates of their effect on serum iron were based on a recent genomewide meta-analysis of 21,567 individuals, while estimates of their effect on PD risk were obtained through meta-analysis of genome-wide and candidate gene studies with 20,809 PD cases and 88,892 controls. Separate MR estimates of the effect of iron on PD were obtained for each variant and pooled by meta-analysis. We investigated heterogeneity across the three estimates as an indication of possible pleiotropy and found no evidence of it. The combined MR estimate showed a statistically significant protective effect of iron, with a relative risk reduction for PD of 3% (95% CI 1%-6%; p=0.001) per 10 mu g/dl increase in serum iron. Conclusions: Our study suggests that increased iron levels are causally associated with a decreased risk of developing PD. Further studies are needed to understand the pathophysiological mechanism of action of serum iron on PD risk before recommendations can be made.
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