title: Haplotype analysis confirms the association between the HCRTR2 gene and cluster headache.
abstract: BACKGROUND
  Several studies suggested that genetic factors play a role in cluster headache (CH) susceptibility. We found a significant association between the 1246 G>A polymorphism of the hypocretin receptor-2 (HCRTR2) gene and the disease. This association was confirmed in a large study from Germany but was not replicated in a dataset of CH patients from Northern Europe.
  
  
  OBJECTIVE
  The purpose of this study was to further evaluate the association between CH and the HCRTR2 gene using new polymorphisms, estimating the frequency of different gene haplotypes, searching for gene mutations, and evaluating the effects of the examined polymorphisms on hypocretin binding sites.
  
  
  METHODS
  We genotyped 109 CH patients and 211 healthy controls for 5 new polymorphisms of the HCRTR2 gene and we inferred different gene haplotypes. Complete HCRTR2 sequencing was undertaken for 11 independent CH patients, 5 of whom had a positive family history. The effects of the 1246 G>A polymorphism on the hypocretin binding sites were evaluated using different computer-assisted analyses.
  
  
  RESULTS
  Three new polymorphisms of the HCRTR2 gene resulted significantly associated with CH. The GTAAGG haplotype resulted more frequent in cases than in controls (OR: 3.68; 95% CI: 1.85-7.67). No point mutation of the HCRTR2 gene was found. Binding analyses showed that the 1246 G>A polymorphism (substitution of valine at position 308 by isoleucine) has no effect on the hypocretin binding sites but could influence the dimerization process of the receptor.
  
  
  CONCLUSIONS
  Our data confirm previous studies suggesting that the HCRTR2 gene or a linked locus significantly modulates the risk for CH. In addition, we suggest that the V308I substitution of the HCRTR2 may interfere with the dimerization process of the receptor, thereby influencing its functional activity.
authors.affiliation: Neurology II-Headache Center, Department of Neuroscience, Turin, Italy.
authors.forename: Innocenzo
authors.initials: I
authors.lastname: Rainero
authors.forename: Salvatore
authors.initials: S
authors.lastname: Gallone
authors.forename: Elisa
authors.initials: E
authors.lastname: Rubino
authors.forename: Paola
authors.initials: P
authors.lastname: Ponzo
authors.forename: Walter
authors.initials: W
authors.lastname: Valfre
authors.forename: Eleonora
authors.initials: E
authors.lastname: Binello
authors.forename: Pierpaola
authors.initials: P
authors.lastname: Fenoglio
authors.forename: Salvatore
authors.initials: S
authors.lastname: Gentile
authors.forename: Mihaela
authors.initials: M
authors.lastname: Anoaica
authors.forename: Mauro
authors.initials: M
authors.lastname: Gasparini
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Pinessi
mesh_terms: D000328:Adult; D001665:Binding Sites / Q000235:genetics; D003027:Cluster Headache / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005838:Genotype; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D064446:Orexin Receptors; D011110:Polymorphism, Genetic / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism; D018013:Receptors, Neuropeptide / Q000235:genetics* / Q000378:metabolism
chemical_list: D064446:Orexin Receptors; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide