Serum Iron Levels and the Risk of Parkinson Disease: A Mendelian Randomization Study

Irene Pichler, M. Fabiola Del Greco, Martin Gögele, Christina M. Lill, Lars Bertram, Chuong B. Do, Nicholas Eriksson, Tatiana Foroud, Richard H. Myers, Michael Nalls, Margaux F. Keller, Beben Benyamin, John B. Whitfield, Peter P. Pramstaller, Andrew A. Hicks, John R. Thompson, Cosetta Minelli

Research output: Contribution to journalArticle

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Abstract

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 genome-wide 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 μg/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.Please see later in the article for the Editors' Summary.

Original languageEnglish
Article numbere1001462
JournalPLoS Medicine
Volume10
Issue number6
DOIs
StatePublished - Jun 2013

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Random Allocation
Parkinson Disease
Iron
Serum
Meta-Analysis
Genome
Risk Reduction Behavior
Causality
Genes
Epidemiologic Studies
Biomarkers

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Pichler, I., Del Greco, M. F., Gögele, M., Lill, C. M., Bertram, L., Do, C. B., ... Minelli, C. (2013). Serum Iron Levels and the Risk of Parkinson Disease: A Mendelian Randomization Study. PLoS Medicine, 10(6), [e1001462]. https://doi.org/10.1371/journal.pmed.1001462

Serum Iron Levels and the Risk of Parkinson Disease : A Mendelian Randomization Study. / Pichler, Irene; Del Greco, M. Fabiola; Gögele, Martin; Lill, Christina M.; Bertram, Lars; Do, Chuong B.; Eriksson, Nicholas; Foroud, Tatiana; Myers, Richard H.; Nalls, Michael; Keller, Margaux F.; Benyamin, Beben; Whitfield, John B.; Pramstaller, Peter P.; Hicks, Andrew A.; Thompson, John R.; Minelli, Cosetta.

In: PLoS Medicine, Vol. 10, No. 6, e1001462, 06.2013.

Research output: Contribution to journalArticle

Pichler, I, Del Greco, MF, Gögele, M, Lill, CM, Bertram, L, Do, CB, Eriksson, N, Foroud, T, Myers, RH, Nalls, M, Keller, MF, Benyamin, B, Whitfield, JB, Pramstaller, PP, Hicks, AA, Thompson, JR & Minelli, C 2013, 'Serum Iron Levels and the Risk of Parkinson Disease: A Mendelian Randomization Study', PLoS Medicine, vol. 10, no. 6, e1001462. https://doi.org/10.1371/journal.pmed.1001462
Pichler I, Del Greco MF, Gögele M, Lill CM, Bertram L, Do CB et al. Serum Iron Levels and the Risk of Parkinson Disease: A Mendelian Randomization Study. PLoS Medicine. 2013 Jun;10(6). e1001462. https://doi.org/10.1371/journal.pmed.1001462
Pichler, Irene ; Del Greco, M. Fabiola ; Gögele, Martin ; Lill, Christina M. ; Bertram, Lars ; Do, Chuong B. ; Eriksson, Nicholas ; Foroud, Tatiana ; Myers, Richard H. ; Nalls, Michael ; Keller, Margaux F. ; Benyamin, Beben ; Whitfield, John B. ; Pramstaller, Peter P. ; Hicks, Andrew A. ; Thompson, John R. ; Minelli, Cosetta. / Serum Iron Levels and the Risk of Parkinson Disease : A Mendelian Randomization Study. In: PLoS Medicine. 2013 ; Vol. 10, No. 6.
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abstract = "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 genome-wide 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 μg/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.Please see later in the article for the Editors' Summary.",
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AB - 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 genome-wide 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 μg/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.Please see later in the article for the Editors' Summary.

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