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Several studies indicate a potential link between iron homeostasis and the pathophysiology of primary headaches. The <jats:italic>HFE<\/jats:italic> gene encodes for a protein involved in iron metabolism, while genetic variants in <jats:italic>HFE<\/jats:italic> have been associated with hereditary hemochromatosis (HH), an iron overload disorder. The objective of the current study was to examine the association of the more common <jats:italic>HFE<\/jats:italic> H63D variant, with the susceptibility to develop CH and diverse clinical phenotypes in a population of Southeastern European Caucasian (SEC) origin. Genomic DNA samples from 128 CH patients and 294 neurologically healthy controls were genotyped for the <jats:italic>HFE<\/jats:italic> rs1799945 (H63D) variant. H63D genotypic and allelic frequency distribution did not differ significantly between patients and controls (<jats:italic>p<\/jats:italic>\u2009&gt;\u20090.05). Subgroup analysis revealed a significantly more frequent occurrence of the variant G allele in chronic compared to episodic CH patients, indicative for a possible correlation of the <jats:italic>HFE<\/jats:italic> gene with the susceptibility for disease chronification. Although homozygosity for the less prevalent H63D variant G allele was minimal in the CH cohort, the results of the present study are in accordance with previous studies in CH and migraine patients, suggesting that <jats:italic>HFE<\/jats:italic> H63D variant modifies the disease clinical characteristics. Hence, despite the absence of a per se association with CH susceptibility in the current SEC cohort, variability in <jats:italic>HFE<\/jats:italic> gene may be potentially regarded as a disease modifier genetic factor in CH.<\/jats:p>","DOI":"10.1007\/s12031-021-01913-8","type":"journal-article","created":{"date-parts":[[2021,9,27]],"date-time":"2021-09-27T08:39:16Z","timestamp":1632731956000},"page":"393-400","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Evidence That HFE H63D Variant Is a Potential Disease Modifier in Cluster Headache"],"prefix":"10.1007","volume":"72","author":[{"given":"Maria","family":"Papasavva","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michail","family":"Vikelis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martha-Spyridoula","family":"Katsarou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vasileios","family":"Siokas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanouil","family":"Dermitzakis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoforos","family":"Papademetriou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantinos","family":"Karakostis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Lazopoulos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Efthimios","family":"Dardiotis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7545-8089","authenticated-orcid":false,"given":"Nikolaos","family":"Drakoulis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,9,27]]},"reference":[{"key":"1913_CR1","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1016\/j.gene.2015.10.009","volume":"574","author":"JC Barton","year":"2015","unstructured":"Barton JC, Edwards CQ, Acton RT (2015) HFE gene: structure function mutations and associated iron abnormalities. 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