Analysis of HCRTR2, GNB3, and ADH4 Gene Polymorphisms in a Southeastern European Caucasian Cluster Headache Population
- 29 Downloads
Studies point to an increased hereditary risk of cluster headache. HCRTR2 gene rs2653349 and ADH4 gene rs1800759 polymorphisms have been associated with cluster headache susceptibility. Also, GNB3 rs5443 polymorphism, associated with increased signal transduction via GPCRs, seems to influence triptan treatment response. DNA from 114 cluster headache patients and 570 non-related controls, representing a general Southeastern European Caucasian (SEC) population, was extracted from buccal swabs and genotyped using real-time PCR. Gene distribution for the rs2653349 was GG = 79.8%, GA = 18.4%, and AA = 1.8% for patients and GG = 79.1%, GA = 19.1%, and AA = 1.8% for controls. The frequency of the mutated A allele was 11.0% for patients and 11.3% for controls. The frequencies for rs5443 were CC = 44.7%, CT = 44.7%, and TT = 10.5% for patients and CC = 43.9%, CT = 42.6%, and TT = 13.5% for controls. The frequency of the mutated T allele was 32.9% for patients and 34.8% for controls. A 2.7-fold more frequent appearance of the mutated T allele was observed in patients with better triptan treatment response, although not statistically significant. For rs1800759, the frequencies were CC = 36.0%, CA = 43.0%, and AA = 21.0% for patients and CC = 34.0%, CA = 50.2%, and AA = 15.8% for controls. The frequency of the mutated A allele was 42.5% and 40.9% for patients and controls, respectively. The mutated T allele of GNB3 rs5443 polymorphism was more prevalent in patients with better triptan treatment response, indicating a possible trend of association between this polymorphism and triptan treatment response in SEC population. According to our observation, no association of HCRTR2 rs2653349 and ADH4 rs1800759 polymorphisms and cluster headache in SEC population could be documented.
KeywordsPharmacogenomics rs2653349 rs5443 rs1800759 Southeastern European Caucasians Genetic susceptibility
Southeastern European Caucasian
International Classification of Headache Disorders 3rd edition
Trigeminal autonomic cephalalgias
Episodic cluster headache
Chronic cluster headache
G protein-coupled receptors
Alcohol dehydrogenase enzyme
The authors would like to thank Georgia Kanelopoulos for helping to improve the manuscript.
Compliance with Ethical Standards
The study was approved by the Ethics Committee of Mediterraneo Hospital, Glyfada, Greece and Eginition University Hospital, Athens, Greece. Informed consent was obtained from all subjects.
Conflict of Interest
The authors declare that they have no conflict of interest.
- Baumber L, Sjostrand C, Leone M et al (2006) A genome-wide scan and HCRTR2 candidate gene analysis in a European cluster headache cohort. Neurology 66:1888–1893. https://doi.org/10.1212/01.wnl.0000219765.95038.d7 CrossRefPubMedGoogle Scholar
- Chieffi S, Carotenuto M, Monda V, Valenzano A, Villano I, Precenzano F, Tafuri D, Salerno M, Filippi N, Nuccio F, Ruberto M, de Luca V, Cipolloni L, Cibelli G, Mollica MP, Iacono D, Nigro E, Monda M, Messina G, Messina A (2017) Orexin system: the key for a healthy life. Front Physiol 8:357. https://doi.org/10.3389/fphys.2017.00357 CrossRefPubMedPubMedCentralGoogle Scholar
- Guo L, Zhang L-L, Zheng B, Liu Y, Cao XJ, Pi Y, Li BH, Li JC (2013) The C825T Polymorphism of the G-Protein β3 subunit gene and its association with hypertension and stroke: an updated meta-analysis. PLoS One 8:e65863. https://doi.org/10.1371/journal.pone.0065863 CrossRefPubMedPubMedCentralGoogle Scholar
- Katsarou M-S, Papasavva M, Latsi R, Toliza I, Gkaros AP, Papakonstantinou S, Gatzonis S, Mitsikostas DD, Kovatsi L, Izotov BN, Tsatsakis AM, Drakoulis N (2018) Population-based analysis of cluster headache-associated genetic polymorphisms. J Mol Neurosci 65:367–376. https://doi.org/10.1007/s12031-018-1103-5 CrossRefPubMedGoogle Scholar
- Katsarou M, Karakonstantis K, Demertzis N et al (2017b) Effect of single-nucleotide polymorphisms in ADH1B , ADH4 , ADH1C , OPRM1 , DRD2 , BDNF , and ALDH2 genes on alcohol dependence in a Caucasian population. Pharmacol Res Perspect 5:e00326. https://doi.org/10.1002/prp2.326 CrossRefPubMedCentralGoogle Scholar
- Luo X, Kranzler HR, Zuo L, Lappalainen J, Yang BZ, Gelernter J (2006) ADH4 gene variation is associated with alcohol dependence and drug dependence in European Americans: results from HWD tests and case–control association studies. Neuropsychopharmacology 31:1085–1095. https://doi.org/10.1038/sj.npp.1300925 CrossRefPubMedGoogle Scholar
- Rainero I, Gallone S, Valfre W et al (2004) A polymorphism of the hypocretin receptor 2 gene is associated with cluster headache. Neurology 63:1286–1288. https://doi.org/10.1212/01.WNL.0000142424.65251.DB CrossRefPubMedGoogle Scholar
- Rainero I, Rubino E, Valfrè W, Gallone S, de Martino P, Zampella E, Pinessi L (2007) Association between the G1246A polymorphism of the hypocretin receptor 2 gene and cluster headache: a meta-analysis. J Headache Pain 8:152–156. https://doi.org/10.1007/s10194-007-0383-x CrossRefPubMedPubMedCentralGoogle Scholar
- Schurks M, Kurth T, Geissler I et al (2006) Cluster headache is associated with the G1246A polymorphism in the hypocretin receptor 2 gene. Neurology 66:1917–1919. https://doi.org/10.1212/01.wnl.0000215852.35329.34 CrossRefPubMedGoogle Scholar
- Siffert W (2003) Effects of the G protein β3-subunit gene C825T polymorphism: should hypotheses regarding the molecular mechanisms underlying enhanced G protein activation be revised? Focus on A splice variant of the G protein β3-subunit implicated in disease states does. Physiol Genomics 13:81–84. https://doi.org/10.1152/physiolgenomics.00031.2003 CrossRefPubMedGoogle Scholar
- Weller CM, Wilbrink LA, Houwing-Duistermaat JJ, Koelewijn SC, Vijfhuizen LS, Haan J, Ferrari MD, Terwindt GM, van den Maagdenberg A, de Vries B (2015) Cluster headache and the hypocretin receptor 2 reconsidered: a genetic association study and meta-analysis. Cephalalgia 35:741–747. https://doi.org/10.1177/0333102414557839 CrossRefPubMedGoogle Scholar