title: Serum iron levels and the risk of Parkinson disease: a Mendelian randomization study.
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.
  
  
  RESULTS
  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.
authors.affiliation: Center for Biomedicine, European Academy Bozen/Bolzano (EURAC), Bolzano, Italy. irene.pichler@eurac.edu
authors.forename: Irene
authors.initials: I
authors.lastname: Pichler
authors.forename: Fabiola
authors.initials: F
authors.lastname: Del Greco M
authors.forename: Martin
authors.initials: M
authors.lastname: Gögele
authors.forename: Christina M
authors.initials: CM
authors.lastname: Lill
authors.forename: Lars
authors.initials: L
authors.lastname: Bertram
authors.forename: Chuong B
authors.initials: CB
authors.lastname: Do
authors.forename: Nicholas
authors.initials: N
authors.lastname: Eriksson
authors.forename: Tatiana
authors.initials: T
authors.lastname: Foroud
authors.forename: Richard H
authors.initials: RH
authors.lastname: Myers
authors.forename: Michael
authors.initials: M
authors.lastname: Nalls
authors.forename: Margaux F
authors.initials: MF
authors.lastname: Keller
authors.forename: Beben
authors.initials: B
authors.lastname: Benyamin
authors.forename: John B
authors.initials: JB
authors.lastname: Whitfield
authors.forename: Peter P
authors.initials: PP
authors.lastname: Pramstaller
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Hicks
authors.forename: John R
authors.initials: JR
authors.lastname: Thompson
authors.forename: Cosetta
authors.initials: C
authors.lastname: Minelli
mesh_terms: D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D007501:Iron / Q000097:blood*; D057182:Mendelian Randomization Analysis; D010300:Parkinson Disease / Q000097:blood* / Q000235:genetics*; D012307:Risk Factors
chemical_list: D007501:Iron