Research Submission Role of 2 Common Variants of 5HT2A Gene in Medication Overuse Headache Salvatore Terrazzino, PhD; Grazia Sances, MD; Francesca Balsamo, MD; Michele Viana, MD; Francesco Monaco, MD; Giorgio Bellomo, MD; Emilia Martignoni, MD; Cristina Tassorelli, MD; Giuseppe Nappi, MD; Pier Luigi Canonico, MD; Armando A. Genazzani, MD, PhD Objective.—The aim of the present study was to evaluate a possible involvement of 2 polymorphisms of the serotonin 5HT2A receptor gene (A-1438G and C516T) as risk factors for medication overuse headache (MOH) and whether the presence of these polymorphic variants might determine differences within MOH patients in monthly drug consumption. Background.—Despite a growing scientific interest in the mechanisms underlying the pathophysiology of MOH, few studies have focused on the role of genetics in the development of the disease, as well as on the genetic determinants of the inter-individual variability in the number of drug doses taken per month. Methods.—Our study was performed by polymerase chain reaction (PCR) and PCR-restriction fragment length polymor- phism on genomic DNA extracted from peripheral blood of 227 MOH patients and 312 control subjects. Genotype-specific risks were estimated as odds ratios with associated 95% confidence intervals by unconditional logistic regression and adjusted for age and gender. A stepwise multiple linear regression analysis was employed to identify significant predictors of the number of drug doses taken per month. Results.—No significant association was found between 5HT2A A and 1438G and C516T gene polymorphisms and MOH risk. In contrast, a higher consumption of monthly drug doses was observed among 516T 5HT2A carriers (median 50, range 13-120) compared to 516CC patients (median 30, range 12-128) (Mann–Whitney U-test, P = .018). In the stepwise multiple regression analysis, C516T 5HT2A polymorphism (P = .018) and class of overused drug (P = .047) emerged as significant, independent predictors of the monthly drug consumption in MOH patients. Conclusions.—Although our results do not support a major role of the A-1438G and C516T polymorphic variants of the 5HT2A gene in the susceptibility of MOH, our findings support an influence of the C516T polymorphism on the number of symptomatic drug doses taken and, possibly, on the drug-seeking behavior in these patients. Key words: medication overuse headache, 5HT2A, genetic polymorphism, susceptibility, drug overuse (Headache 2010;50:1587-1596) From the Università del Piemonte Orientale “A. Avogadro,” DiSCAFF and Centro di Ricerca Interdipartimentale di Farmacogenetica e Farmacogenomica (CRIFF), Novara, Italy (S.Terrazzino, P.L. Canonico, and A.A. Genazzani); Headache Science Center and Headache Unit, IRCCS “National Neurological Institute C. Mondino” Foundation—University Centre for Adaptive Disorders and Headache (UCADH), Pavia, Italy (G. Sances, F. Balsamo, C. Tassorelli, and G. Nappi); Division of Neurology, Maggiore Hospital, Amedeo Avogadro University, Novara, Italy (M. Viana and F. Monaco); Headache Group—Department of Neurology, University of California, San Francisco, CA, USA (M.Viana); Department of Medical Sciences, University of Eastern Piedmont Amedeo Avogadro, Novara, Italy (G. Bellomo); Department of Clinical Medicine, University of Insubria,Varese, Italy (E. Martignoni); University Centre for Adaptative Disorders and Headache (UCADH) Section of Novara, Italy (P.L. Canonico and A.A. Genazzani). Address all correspondence to S.Terrazzino, Università del Piemonte Orientale “A.Avogadro,” DiSCAFF and Centro di Ricerca Interdipartimentale di Farmacogenetica e Farmacogenomica (CRIFF), 28100 Novara, Italy. Accepted for publication April 29, 2010. Conflict of Interest: None ISSN 0017-8748 doi: 10.1111/j.1526-4610.2010.01757.x Published by Wiley Periodicals, Inc. Headache © 2010 American Headache Society 1587