The serotonin transporter gene polymorphism STin2 VNTR confers an increased risk of inconsistent response to triptans in migraine patients Salvatore Terrazzino a,1 , Michele Viana b,1 , Elisa Floriddia a , Francesco Monaco b , Daniela Mittino b , Grazia Sances c , Cristina Tassorelli c , Giuseppe Nappi c , Maurizio Rinaldi a , Pier Luigi Canonico a,d , Armando A. Genazzani a,c,d, ⁎ a Università del Piemonte Orientale “A. Avogadro”, DiSCAFF and Centro di Ricerca Interdipartimentale di Farmacogenetica e Farmacogenomica (CRIFF), Via Bovio, 6, 28100 Novara, Italy b Division of Neurology, Maggiore Hospital, Amedeo Avogadro University, Novara, Italy c University Centre for Adaptive Disorders and Headache (UCADH) and Headache Unit, IRCCS Neurological Institute “C. Mondino Foundation”, Pavia, Italy d University Centre for Adaptive Disorders and Headache (UCADH) Section of Novara, Italy abstract article info Article history: Received 6 November 2009 Received in revised form 7 April 2010 Accepted 25 April 2010 Available online 18 May 2010 Keywords: Migraine Triptans Headache response Consistency Serotonin transporter STin2 polymorphism The aim of the present observational study was to assess the value of the C825T polymorphism of the β-3 subunit of G proteins (GNB3) as well as of variants in the SLC6A4 gene (5HTTLPR and STin2 VNTR) and DRD2 gene (TaqI A and NcoI) as predictive markers for consistency in headache response to triptans in migraine patients. Consistent responders to triptans were defined as the migraineurs who experienced a ≥ 2 point reduction in a 4-point scale intensity of pain from 3 (severe) to 0 (absent) 2 h after triptan administration, in at least two attacks out of the three. Genotyping was performed by PCR and PCR-RFLP on genomic DNA extracted from peripheral blood. The impact of clinical and biological variables on consistency status of headache response to triptans was evaluated by using a binary logistic regression model with stepwise selection. Forty-three (33%) of the 130 migraine patients included in the study did not consistently respond to triptan administration. In a binary logistic regression model, STin 2.12/12 genotype (OR = 3.363, 95% CI: 1.262–8.966, P = 0.005) and non-use of migraine prophylactic medications (OR = 2.848, 95% CI: 1.019–7.959, P = 0.010) were found as significant factors increasing the odds of achieving inconsistent response to triptans. The analysis of classificatory power of the model showed moderate values of sensitivity (0.56), high specificity (0.87), and an overall prediction correctness (0.77). These results support the role of STin2 VNTR polymorphism of serotonin transporter gene as a relevant genetic factor conferring a higher risk of inconsistent response to triptans in migraine patients. © 2010 Elsevier B.V. All rights reserved. 1. Introduction Selective serotonin 5-HT 1B/1D agonists (triptans) are recom- mended as first-line therapy for migraine patients with moderate- to-severe attacks and in those patients with mild-to-moderate attacks that are not adequately controlled by other agents (Silberstein, 2000; Dowson et al., 2006). In spite of the well-established efficacy and safety of triptans, up to 40% of migraine patients do not respond to triptan treatment (Diener and Limmroth, 2001; Ferrari et al., 2001). Few studies have addressed the genetic basis for the variability in the therapeutic effects of triptans. Among the most interesting findings are associations with the polymorphic variants in the GNB3 and DRD2 genes. The C825T polymorphism in the gene encoding the β-3 subunit of G proteins (GNB3) has been associated with a splice variant with increased biological activity that ultimately enhances G protein signaling (Siffert et al., 1998). Although this polymorphism has been recently associated to triptan response in cluster headache (Schürks et al., 2007b), it is not known whether it is also involved in the clinical response of migraine patients to triptan treatment. Furthermore, allele frequency and genotype distribution of the DRD2 NcoI polymorphism have been found significantly different in responders and non-responders to rizatriptan (Asuni et al., 2007), yet given the small number of migraine patients examined, these findings need to be replicated in larger studies. On the other hand, although the serotonin transporter (5HTT) is a key regulator of the level of serotonergic neurotransmission and being the most important factor in the inactivation of 5HT transmission (Lesch and Mössner, 1998), polymorphic variants of this gene have not been investigated in the clinical response to triptans. As variations in 5HTT expression or function may influence 5-HT levels at all serotonin synapses, functional 5HTT polymorphisms may affect the response to almost any agent affecting the serotonin system, including triptans. Two common polymorphic variants of the gene European Journal of Pharmacology 641 (2010) 82–87 ⁎ Corresponding author. DiSCAFF, Via Bovio, 6-28100, Novara, Italy. Tel.: +39 0321 375827; fax: +39 0321 375821. E-mail address: genazzani@pharm.unipmn.it (A.A. Genazzani). 1 These authors equally contributed to this work. 0014-2999/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2010.04.049 Contents lists available at ScienceDirect European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar