Analysis of HCRTR2, GNB3, and ADH4 Gene Polymorphisms in a Southeastern European Caucasian Cluster Headache Population

  • Maria Papasavva
  • Martha-Spyridoula Katsarou
  • Michail Vikelis
  • Euthymia Mitropoulou
  • Emmanouil V. Dermitzakis
  • Stylianos Papakonstantinou
  • Chryssa Arvaniti
  • Dimos-Dimitrios Mitsikostas
  • Illana Gozes
  • Aristides M. Tsatsakis
  • Nikolaos DrakoulisEmail author


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.


Pharmacogenomics rs2653349 rs5443 rs1800759 Southeastern European Caucasians Genetic susceptibility 



Southeastern European Caucasian


Cluster headache


International Classification of Headache Disorders 3rd edition


Trigeminal autonomic cephalalgias


Episodic cluster headache


Chronic cluster headache


G protein-coupled receptors


Alcohol dehydrogenase enzyme


Hardy-Weinberg equilibrium



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.


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Maria Papasavva
    • 1
  • Martha-Spyridoula Katsarou
    • 1
  • Michail Vikelis
    • 2
  • Euthymia Mitropoulou
    • 3
  • Emmanouil V. Dermitzakis
    • 4
  • Stylianos Papakonstantinou
    • 1
  • Chryssa Arvaniti
    • 5
  • Dimos-Dimitrios Mitsikostas
    • 3
  • Illana Gozes
    • 6
  • Aristides M. Tsatsakis
    • 7
  • Nikolaos Drakoulis
    • 1
    Email author
  1. 1.Research Group of Clinical Pharmacology and Pharmacogenomics, Faculty of Pharmacy, School of Health SciencesNational and Kapodistrian University of AthensAthensGreece
  2. 2.Headache ClinicMediterraneo HospitalGlyfadaGreece
  3. 3.First Department of Neurology, Eginition Hospital, School of MedicineNational and Kapodistrian University of AthensAthensGreece
  4. 4.ThessalonikiGreece
  5. 5.B’ Neurological Clinic, Attikon Hospital, School of MedicineNational and Kapodistrian University of AthensAthensGreece
  6. 6.The Lily and Avraham Gildor Chair for the Investigation of Growth Factors, The Elton Laboratory for Molecular Neuroendocrinology, Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine Sagol School of Neuroscience and Adams Super Center for Brain StudiesTel Aviv UniversityTel AvivIsrael
  7. 7.Laboratory of Toxicology, School of MedicineUniversity of CreteHeraklionGreece

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