Neurology
Gene-Environment Interactions between Cumulative Lead Exposures and Genetic Risk Factors for Iron Burden on Parkinson’s Disease Kanghong Shao* Kanghong Shao Cynthia Kusters Jeff Bronstein Adrienne Keener Danielle Thordarson Kimberly C Paul Beate Ritz
Background
Parkinson’s disease (PD) has been linked to cumulative lead exposure. While the role of iron in PD remains unclear, considering iron accumulates in the substantia nigra and may contribute to PD etiology via oxidative stress, it has been suggested to interact with lead metabolism in PD development. However, few epidemiologic studies have investigated this interaction.
Methods
Tibia, patella, and blood lead levels were estimated using blood DNA methylation biomarkers among 523 PD patients and 236 population controls in the Parkinson’s Environment and Gene (PEG) study, while polygenic risk scores (PRSs) for iron handling including total iron binding capacity [TIBC] and transferrin saturation [TSAT] were calculated based on single-nucleotide polymorphisms (SNPs) linked to iron metabolism and accumulation. We selected 11 SNPs associated with iron homeostasis. Logistic regressions were conducted to estimate effect sizes between lead biomarkers and PD stratified by each PRS’s percentiles and each SNP’s genotypes. The analyses were further stratified by gender.
Results
A low TSAT PRS ( 50th percentile) (OR = 1.11; 95% CI: 0.85, 1.45). A genetic profile of larger iron binding capacity also attenuates the effect size of cumulative lead exposure on PD (TIBC PRS Q4 vs Q1-Q3: OR = 1.11; 95% CI: 0.74, 1,66). The modifying effect of the TSAT but not the TIBC PRS was most pronounced and restricted to women (OR = 3.37; 95%CI: 1.53, 8.84).
Conclusion
Genetic susceptibility to iron deficiency may exacerbate the effect of cumulative lead exposure on PD development, while genetic predilection to high iron load and total iron binding capacity reduces the harmful effect of lead. We saw evidence for larger modifying effects from a genetic predisposition to iron deficiency among women and none for men. Our findings suggested a protective role of iron against neurotoxicity of lead in PD.
