Haplotype Analysis Confirms the Association Between the HCRTR2 Gene and Cluster Headache
- 9 July 2008
- journal article
- research article
- Published by Wiley in Headache: The Journal of Head and Face Pain
- Vol. 48 (7), 1108-1114
- https://doi.org/10.1111/j.1526-4610.2008.01080.x
Abstract
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. 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. 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. 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. 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.Keywords
This publication has 32 references indexed in Scilit:
- Genetics of cluster headache: an updateThe Journal of Headache and Pain, 2005
- The study of G‐protein coupled receptor oligomerization with computational modeling and bioinformaticsThe FEBS Journal, 2005
- Spinal orexin-1 receptors mediate anti-hyperalgesic effects of intrathecally-administered orexins in diabetic neuropathic pain model ratsBrain Research, 2005
- Orexin-A Infusion in the Locus Ceruleus Triggers Norepinephrine (NE) Release and NE-Induced Long-Term Potentiation in the Dentate GyrusJournal of Neuroscience, 2004
- Hypocretin/Orexin Peptide Signaling in the Ascending Arousal System: Elevation of Intracellular Calcium in the Mouse Dorsal Raphe and Laterodorsal TegmentumJournal of Neurophysiology, 2004
- Antiallodynic Effects of Intrathecal Orexins in a Rat Model of Postoperative PainThe Journal of pharmacology and experimental therapeutics, 2003
- A New Statistical Method for Haplotype Reconstruction from Population DataAmerican Journal of Human Genetics, 2001
- Correlated mutations contain information about protein-protein interactionJournal of Molecular Biology, 1997
- Cluster headache is an autosomal dominantly inherited disorder in some families: a complex segregation analysis.Journal of Medical Genetics, 1995