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Serum iron levels and the risk of Parkinson disease: a Mendelian randomization study.

Pichler I, Del Greco M F, Gögele M, Lill CM, Bertram L, Do CB, Eriksson N, Foroud T, Myers RH, PD GWAS ConsortiumNalls M, Keller MF, International Parkinson's Disease Genomics ConsortiumWellcome Trust Case Control Consortium 2Benyamin B, Whitfield JB, Genetics of Iron Status ConsortiumPramstaller PP, Hicks AA, Thompson JR, Minelli C - PLoS Med. (2013)

Bottom Line: 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.We investigated heterogeneity across the three estimates as an indication of possible pleiotropy and found no evidence of it.Our study suggests that increased iron levels are causally associated with a decreased risk of developing PD.

View Article: PubMed Central - PubMed

Affiliation: Center for Biomedicine, European Academy Bozen/Bolzano (EURAC), Bolzano, Italy. irene.pichler@eurac.edu

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.

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Related in: MedlinePlus

Graphical representation of the MR approach, with all estimates used to derive the final MR estimate.*Reported is the allele that increases iron levels, together with its frequency (AF). **This corresponds approximately to an OR per unit µg/dl increase in iron of 0.997 (95%CI 0.994–0.999), that is 0.3% (0.1%–0.6%) relative reduction in PD risk per 1 µg/dl increase in iron.
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pmed-1001462-g001: Graphical representation of the MR approach, with all estimates used to derive the final MR estimate.*Reported is the allele that increases iron levels, together with its frequency (AF). **This corresponds approximately to an OR per unit µg/dl increase in iron of 0.997 (95%CI 0.994–0.999), that is 0.3% (0.1%–0.6%) relative reduction in PD risk per 1 µg/dl increase in iron.

Mentions: The selection of the genes modifying iron levels to be used as instruments in our MR study was based on published results showing that polymorphisms in the hemochromatosis (HFE, ENSG00000010704) gene and the transmembrane protease 6 (TMPRSS6, ENSG00000187045) gene have the strongest effects on serum iron in the general population of European ancestry [11]. The choice of the polymorphisms within these two genes was based on the findings of a recent large meta-analysis of genome-wide association (GWA) studies on iron levels in the general population (unpublished data). We selected the polymorphisms with the strongest statistical evidence, two for the HFE gene, rs1800562 (C282Y) and rs1799945 (H63D), which are not in linkage disequilibrium (HapMap CEU r2<0.01) and therefore represent independent signals of association, and one for the TMPRSS6 gene, rs855791 (V736A) (Figure 1).


Serum iron levels and the risk of Parkinson disease: a Mendelian randomization study.

Pichler I, Del Greco M F, Gögele M, Lill CM, Bertram L, Do CB, Eriksson N, Foroud T, Myers RH, PD GWAS ConsortiumNalls M, Keller MF, International Parkinson's Disease Genomics ConsortiumWellcome Trust Case Control Consortium 2Benyamin B, Whitfield JB, Genetics of Iron Status ConsortiumPramstaller PP, Hicks AA, Thompson JR, Minelli C - PLoS Med. (2013)

Graphical representation of the MR approach, with all estimates used to derive the final MR estimate.*Reported is the allele that increases iron levels, together with its frequency (AF). **This corresponds approximately to an OR per unit µg/dl increase in iron of 0.997 (95%CI 0.994–0.999), that is 0.3% (0.1%–0.6%) relative reduction in PD risk per 1 µg/dl increase in iron.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3672214&req=5

pmed-1001462-g001: Graphical representation of the MR approach, with all estimates used to derive the final MR estimate.*Reported is the allele that increases iron levels, together with its frequency (AF). **This corresponds approximately to an OR per unit µg/dl increase in iron of 0.997 (95%CI 0.994–0.999), that is 0.3% (0.1%–0.6%) relative reduction in PD risk per 1 µg/dl increase in iron.
Mentions: The selection of the genes modifying iron levels to be used as instruments in our MR study was based on published results showing that polymorphisms in the hemochromatosis (HFE, ENSG00000010704) gene and the transmembrane protease 6 (TMPRSS6, ENSG00000187045) gene have the strongest effects on serum iron in the general population of European ancestry [11]. The choice of the polymorphisms within these two genes was based on the findings of a recent large meta-analysis of genome-wide association (GWA) studies on iron levels in the general population (unpublished data). We selected the polymorphisms with the strongest statistical evidence, two for the HFE gene, rs1800562 (C282Y) and rs1799945 (H63D), which are not in linkage disequilibrium (HapMap CEU r2<0.01) and therefore represent independent signals of association, and one for the TMPRSS6 gene, rs855791 (V736A) (Figure 1).

Bottom Line: 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.We investigated heterogeneity across the three estimates as an indication of possible pleiotropy and found no evidence of it.Our study suggests that increased iron levels are causally associated with a decreased risk of developing PD.

View Article: PubMed Central - PubMed

Affiliation: Center for Biomedicine, European Academy Bozen/Bolzano (EURAC), Bolzano, Italy. irene.pichler@eurac.edu

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.

Show MeSH
Related in: MedlinePlus