Title

 

Authors

S. Terrazzino¹, C. Tassorelli², G. Sances², M. Viana³, G. Nappi², P.L. Canonico¹, A.A. Genazzani^1
1Universitàdel Piemonte Orientale “A. Avogadro”, DiSCAFF and Centro di Ricerca Interdipartimentale di Farmacogenetica e Farmacogenomica (CRIFF), Via Bovio, 6, 28100 Novara, Italy; ²Headache Science Centre, IRCCS “C. Mondino National Neurological Institute” Foundation and University Consortium Adaptive Disorders and Head Pain (UCADH), University of Pavia,  Italy ; ³Division of Neurology, Maggiore Hospital, Amedeo Avogadro University, Novara, Italy.

 

Abstract

Few data are currently available on the genetic basis of Medication Overuse Headache (MOH), a chronic daily headache, typically occurring in patients with migraine or tension-type headache, that is induced and maintained by the overuse of symptomatic headache drugs. In the present study we evaluated the role of 5-HTTLPR, STin2 VNTR and rs1042173T>G polymorphisms of the serotonin transporter gene (SLC6A4) as susceptibility factors for MOH and their value was assessed as predictors of the number of headache days per month, a potential marker of disease severity. Genomic DNA was extracted from peripheral blood of 227 MOH patients and 312 control subjects and genotyping was performed by PCR and PCR-RFLP. The association between the SL6A4 gene polymorphisms and MOH risk was evaluated by logistic regression analysis, while the association between candidate polymorphic variants and monthly headache days was evaluated by linear regression analysis. In the logistic regression analysis, adjusted for age and gender, a nominal association was found between rs1042173T>G and MOH risk (TT vs TG+GG, OR: 1.58 95% CI: 1.05-2.37, P=0.028). However, this association did not remain statistically significant after applying the Bonferroni correction (threshold P-valuerequired for Bonferroni correction=0.00625). As STin2 VNTR polymorphism has been reported to belong to the rs1042173-containing haplotype block, we examined the association of haplotype combination of STin2 VNTR and rs1042173T>G polymorphisms with MOH risk. In the logistic regression analysis, adjusted for age and gender, however the global test statistic for the haplotype comprising STin2 VNTR and rs1042173 polymorphisms failed to reach nominal significance (P=0.099). In the linear regression analysis adjusted for confounding factors (age, gender, primary headache diagnosis, acute drug overused and monthly drug number), STin2 VNTR was found nominally associated to monthly headache days (12/12 vs 10/12+ 10/10, difference: 1.55 days, 95% CI: 0.01-3.08, P=0.050). When STin2 VNTR and rs1042173T>G were analysed in haplotypic combination, a global haplotype association emerged with monthly headache days which remained significant after Bonferroni correction for multiple comparisons (global haplotype association P=0.0056). This difference was explained by a higher number of headache days per month conferred by the STin2.10–rs1042173G haplotype in comparison to the most frequent STin2.12–rs1042173G haplotype (difference: 3.98 days, 95% CI: 1.19- 6.77, P=0.0056). Although a minor contribution of SLC6A4 variants in the genetic liability of MOH cannot be excluded, haplotype-based analysis of STin2 VNTR and rs1042173T>G polymorphisms allowed to identify a subgroup of MOH patients with a higher number of monthly headacheand, possibly, with a more severe disease.