{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:14:13Z","timestamp":1785413653676,"version":"3.56.0"},"posted":{"date-parts":[[2026,6,3]]},"group-title":"Neurology","reference-count":48,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T00:00:00Z","timestamp":1780444800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nd\/4.0\/"}],"funder":[{"award":["NS067222"],"award-info":[{"award-number":["NS067222"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["NS082151"],"award-info":[{"award-number":["NS082151"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["TR000127"],"award-info":[{"award-number":["TR000127"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["18078"],"award-info":[{"award-number":["18078"]}],"id":[{"id":"https:\/\/ror.org\/03arq3225","id-type":"ROR","asserted-by":"publisher"}]},{"award":["Tobacco CURE Funds"],"award-info":[{"award-number":["Tobacco CURE Funds"]}],"id":[{"id":"https:\/\/ror.org\/00ra1fg11","id-type":"ROR","asserted-by":"publisher"}]},{"name":"University of Virginia Translational Research Development Funds"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,3]]},"abstract":"<jats:title>\n                  A\n                  <jats:sc>bstract<\/jats:sc>\n                <\/jats:title>\n                <jats:p>\n                  Increased iron in the substantia nigra has been thought to be a mechanism potentially related to the etiology and\/or progression of Parkinson\u2019s disease (PD). We hypothesized that genetic variants of\n                  <jats:italic>HFE<\/jats:italic>\n                  , a major iron regulatory gene, would influence substantia nigra iron accumulation in PD. The\n                  <jats:italic>HFE<\/jats:italic>\n                  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 (\n                  <jats:italic>HFE<\/jats:italic>\n                  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\n                  <jats:italic>HFE<\/jats:italic>\n                  genotype impacts clinical measures of PD progression. Of the 102 PD patients, 72 were wildtype, and 30\n                  <jats:italic>HFE<\/jats:italic>\n                  variant. Of the 83 controls, 56 were wildtype and 27 were\n                  <jats:italic>HFE<\/jats:italic>\n                  variants. There was a total of 451 data points available for analysis. Compared to wildtype patients, patients with\n                  <jats:italic>HFE<\/jats:italic>\n                  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\n                  <jats:italic>HFE<\/jats:italic>\n                  status (p\u2019s&lt;0.05). Compared to wildtype, PD subjects with\n                  <jats:italic>HFE<\/jats:italic>\n                  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).\n                  <jats:italic>HFE<\/jats:italic>\n                  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\n                  <jats:italic>HFE<\/jats:italic>\n                  variants compared to wildtype. Although\n                  <jats:italic>HFE<\/jats:italic>\n                  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\n                  <jats:italic>HFE<\/jats:italic>\n                  genotype. The underlying mechanisms may be important in the progression of PD and the development of personalized treatment.\n                <\/jats:p>","DOI":"10.64898\/2026.06.02.26354750","type":"posted-content","created":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T03:30:17Z","timestamp":1780543817000},"source":"Crossref","is-referenced-by-count":0,"title":["HFE genotype influences substantia nigra iron accumulation and Parkinson\u2019s disease progression"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8267-0301","authenticated-orcid":false,"given":"Guangwei","family":"Du","sequence":"first","affiliation":[{"name":"Department of Neurology, Penn State Milton S. Hershey Medical Center, Hershey PA 17033"},{"name":"Department of Radiology, Penn State Milton S. Hershey Medical Center, Hershey PA 17033"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ernest","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Penn State Milton S. Hershey Medical Center, Hershey PA 17033"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Sica","sequence":"additional","affiliation":[{"name":"Department of Radiology, Penn State Milton S. Hershey Medical Center, Hershey PA 17033"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachael","family":"Stone","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Virginia School of medicine, Charlottesville VA 22903"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sol","family":"De Jesus","sequence":"additional","affiliation":[{"name":"Department of Neurology, Penn State Milton S. Hershey Medical Center, Hershey PA 17033"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6098-9445","authenticated-orcid":false,"given":"Lan","family":"Kong","sequence":"additional","affiliation":[{"name":"School of Public Health Sciences, Pennsylvania State College of Medicine, Hershey, PA 17033"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1353-2738","authenticated-orcid":false,"given":"Richard B.","family":"Mailman","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Virginia School of Medicine, Charlottesville VA 22903"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3583-5502","authenticated-orcid":false,"given":"Xuemei","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Penn State Milton S. 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