Cluster headache and the hypocretin receptor 2 reconsidered: a genetic association study and meta-analysis.
BACKGROUND
Cluster headache is a severe neurological disorder with a complex genetic background. A missense single nucleotide polymorphism (rs2653349; p.Ile308Val) in the HCRTR2 gene that encodes the hypocretin receptor 2 is the only genetic factor that is reported to be associated with cluster headache in different studies. However, as there are conflicting results between studies, we re-evaluated its role in cluster headache.


METHODS
We performed a genetic association analysis for rs2653349 in our large Leiden University Cluster headache Analysis (LUCA) program study population. Systematic selection of the literature yielded three additional studies comprising five study populations, which were included in our meta-analysis. Data were extracted according to predefined criteria.


RESULTS
A total of 575 cluster headache patients from our LUCA study and 874 controls were genotyped for HCRTR2 SNP rs2653349 but no significant association with cluster headache was found (odds ratio 0.91 (95% confidence intervals 0.75-1.10), p = 0.319). In contrast, the meta-analysis that included in total 1167 cluster headache cases and 1618 controls from the six study populations, which were part of four different studies, showed association of the single nucleotide polymorphism with cluster headache (random effect odds ratio 0.69 (95% confidence intervals 0.53-0.90), p = 0.006). The association became weaker, as the odds ratio increased to 0.80, when the meta-analysis was repeated without the initial single South European study with the largest effect size.


CONCLUSIONS
Although we did not find evidence for association of rs2653349 in our LUCA study, which is the largest investigated study population thus far, our meta-analysis provides genetic evidence for a role of HCRTR2 in cluster headache. Regardless, we feel that the association should be interpreted with caution as meta-analyses with individual populations that have limited power have diminished validity.
Department of Human Genetics, Leiden University Medical Centre, the Netherlands.
Claudia M
CM
Weller
Department of Neurology, Leiden University Medical Centre, the Netherlands.
Leopoldine A
LA
Wilbrink
Department of Medical Statistics and Bioinformatics, Leiden University Medical Centre, the Netherlands.
Jeanine J
JJ
Houwing-Duistermaat
Department of Human Genetics, Leiden University Medical Centre, the Netherlands.
Stephany C
SC
Koelewijn
Department of Human Genetics, Leiden University Medical Centre, the Netherlands.
Lisanne S
LS
Vijfhuizen
Department of Neurology, Leiden University Medical Centre, the Netherlands Department of Neurology, Rijnland Hospital, the Netherlands.
Joost
J
Haan
Department of Neurology, Leiden University Medical Centre, the Netherlands.
Michel D
MD
Ferrari
Department of Neurology, Leiden University Medical Centre, the Netherlands.
Gisela M
GM
Terwindt
Department of Human Genetics, Leiden University Medical Centre, the Netherlands Department of Neurology, Leiden University Medical Centre, the Netherlands maagdenberg@lumc.nl.
Arn M J M
AM
van den Maagdenberg
Department of Human Genetics, Leiden University Medical Centre, the Netherlands.
Boukje
B
de Vries
D003027:Cluster Headache / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D064446:Orexin Receptors / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
C578626:HCRTR2 protein, human; D064446:Orexin Receptors
G1246A polymorphism; HCRTR2 gene; Meta-analysis; cluster headache; genetic association; rs2653349