HFE genotype influences substantia nigra iron accumulation and Parkinson's disease progression

Increased iron in the substantia nigra has been thought to be a mechanism potentially related to the etiology and/or progression of Parkinson's disease (PD). We hypothesized that genetic variants of HFE, a major iron regulatory gene, would influence substantia nigra iron accumulation in PD. The HFE genotype was obtained from 195 subjects (102 PD and 83 Controls) who participated in the PD biomarker program (PDBP) in central Pennsylvania, United States. For this study, carriers of two SNPs (HFE H63D and/or C282Y) were considered as variants and the others as wildtype. Susceptibility MRI metrics (QSM, R2*) were assessed at baseline, 18, and 36 months. The primary region of interest was the substantia nigra, the key pathology focus of PD. Group differences in substantia nigra QSM and R2* between HFE variants carriers and wildtype were compared between PD patients and controls at baseline and in progression over time using linear mixed-effects model. We also used interaction analyses to explore if HFE genotype impacts clinical measures of PD progression. Of the 102 PD patients, 72 were wildtype, and 30 HFE variant. Of the 83 controls, 56 were wildtype and 27 were HFE variants. There was a total of 451 data points available for analysis. Compared to wildtype patients, patients with HFE variants showed higher baseline substantia nigra QSM (p=0.006), but not higher R2* (p=0.487). Controls had no HFE-dependent differences. Longitudinally, substantia nigra QSM and R2* increased significantly over both 18- and 36-months regardless of HFE status (p's<0.05). Compared to wildtype, PD subjects with HFE variants showed an overall faster increase in R2* (p=0.004) and QSM (p=0.003) over the total 36-month epoch, and this reached the statistical significance for R2* during the first 18-months (p=0.026) and for QSM in 36-months (p=0.005). HFE status showed a significant interaction with motor scales [MDS-UPDRS II (p=0.006), III (p=0.0002)], suggesting a faster symptomatic progression in PD patients with HFE variants compared to wildtype. Although HFE genotype has been shown not to associate with the occurrence of PD, these data demonstrate for the first time that in PD patients substantia nigra iron accumulation and disease progression are affected by HFE genotype. The underlying mechanisms may be important in the progression of PD and the development of personalized treatment.