Correction: 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. 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 metaanalysis of 21,567 individuals, while estimates of their effect on PD risk were obtained through meta-analysis of genomewide 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 mg/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.

The Causal Effects of Blood Iron and Copper on Lipid Metabolism Diseases: Evidence from Phenome-Wide Mendelian Randomization Study

“…The random allocation of alleles at conception and the natural direction of causality from genetic variants to phenotypes protect MR estimates from confounding and reverse causality [15,16]. MR studies have been performed to evaluate the causality of specific mineral-outcome pairs, such as iron on stroke, coronary artery disease, and Parkinson's disease [17][18][19]; and copper on ischemic heart disease [20]. Compared to these hypothesis-driven MR studies with an obvious bias toward cardiovascular diseases, a phenome-wide association study coupled with MR (PheWAS-MR) enables an unbiased and hypothesis-free scan through a wide range of phenotypes (i.e., phenome) and prioritized candidate clinical outcomes for MR causal inferences.…”

Regional siderosis: a new challenge for iron chelation therapy

“…The treatment of regional siderosis demanded a novel modality of chelation, one that can be used for clearing siderotic regions comprised of labile (toxic) metal but without interfering with essential local functions, thus sparing the patient's systemic iron pools. That selectivity property is of cardinal importance, since increased serum iron levels have recently been suggested by genome-wide meta-analysis (GWAS) to be correlated with a decreased risk of developing PD (Pichler et al, 2013), although, as we referred earlier, a direct role of the implicated genes (HFE and TMPRSS) in brain iron metabolism in general and on neurodegeneration in specific, still need to be properly evaluated, particularly in the context of PD.…”

“…Iron maldistribution is also found in various neurodegenerative disorders(Zecca et al, 2004; Weinreb et al, 2010; Li et al, 2011; Pichler et al, 2013; Rouault, 2013). In the inherited movement disorder Friedreich's ataxia (FRDA), siderosis manifests itself first in the brain's dentate nuclei and ultimately in the heart (Rouault, 2013).…”

“…In the inherited movement disorder Friedreich's ataxia (FRDA), siderosis manifests itself first in the brain's dentate nuclei and ultimately in the heart (Rouault, 2013). In Parkinson's disease (PD), the dopaminergic neurons of the substantia nigra pars compacta progressively succumb to oxidative stress (Zecca et al, 2004; Halliwell, 2006; Li et al, 2011; Sian-Hulsmann et al, 2011; Pichler et al, 2013). …”

“…However, the contribution of brain siderosis to the etiology of PD is subject to debate—largely because opposing hypotheses have mostly relied on correlations between functional or biophysical indices of PD and indicators of systemic, rather than local and/or labile, iron levels (Zecca et al, 2004; Hider et al, 2011; Li et al, 2011) Those studies included trials of chelators that affect systemic iron but not necessarily brain iron, (Li et al, 2011; Mounsey and Teismann, 2012) or genetic factors that affect systemic iron levels [e.g., HFE and TMPRSS6 gene mutations (Camaschella, 2009, 2013; Pichler et al, 2013)] that in turn might be inversely correlated with PD severity (Pichler et al, 2013) and possibly with iron accumulated in the substantia nigra. Moreover, in regional siderosis (whether inherited or acquired), detection of iron agglomerates by T2 * MRI or histochemical staining is not necessarily indicative of an existing or impending disease state, just as failure to detect regional iron agglomerates does not rule out an existing or impending disease state.…”