147 ISSN 1462-2416 10.2217/PGS.13.186 © 2014 Future Medicine Ltd Pharmacogenomics (2014) 15(2), 147–155 ReseaRch aRticle Association between migraine and ACE gene (insertion/deletion) polymorphism: the BioBIM study Migraine is the third most common and the seventh most disabling disease in the world [1]. However, this disease appears to be considerably underestimated in regards to frequency, diagnosis and therapy [2]. The pathogenesis of migraine has seen, over time, a number of alternate theories including vascular, neuroactive and vasoactive substances, alteration of cortical electrical activ- ity or modulation of immune system involve- ment, refecting the fact that the problem is still far from being fully elucidated [3]. It is therefore evident that the identifcation of genetic factors related to headache offers the possibility of a broader understanding of the problem, regard- less of the pathogenic mechanisms responsible. Owing to the signifcant vascular involvement in migraine pathophysiology, some authors have considered genes that encode enzymes affecting the vascular system and causing changes in blood fow as candidates for genetic factors involved in migraine susceptibility. The angiotensin I-converting enzyme (ACE) (ENZYME entry: EC 3.4.15.1) is a dipeptidyl carboxypeptidase expressed in vascular endothe- lial cells and other tissues. It plays an important role in blood pressure regulation and electro- lyte balance by hydrolyzing angiotensin I into angiotensin II, a vasopressor and aldosterone- stimulating peptide [4]. ACE is also able to inac- tivate potent vasodilators such as bradykinin and substance P [5], thus modulating vascular tension and blood pressure [6,7]. The ACE gene (OMIM #106180) presents with an intron 16 insertion (I) or deletion (D) polymorphism of the 287 bp Alu repeat sequence, resulting in three genotypes (D/D, I/D and I/I) [7]. This polymorphism is directly related to serum ACE levels, resulting in higher, intermediary and lower levels in the subjects carrying D/D, I/D and I/I genotype, respectively [6,7]. Several studies have suggested a positive association between the ACE-D allele and cardiovascular diseases [8–10]. Owing to the signifcant vascular involvement in migraine, several authors have considered the ACE gene as a candidate genetic factor involved in migraine susceptibility; however, to date, the studies investigating the association between the ACE D/I polymorphism and migraine are contro- versial and contradictory (SUPPLEMENTARY TABLE 1; see www.futuremedicine.com/doi/suppl/10.2217/ pgs.13.186). Several studies showed that ACE D/D genotype increases the risk of migraine with aura (MwA) [6,11,12], migraine without aura (MwoA) [13,14], and/or their combination [4]. Other authors found a correlation between ACE D/D genotype and the frequency of migraine [9] or suggested a protective effect against migraine in male patients [7]. Additionally, one study dem- onstrated that subjects with the ACE I/I genotype may be protected from migraine development [5]. Aim: In the present case–control study, we investigated the correlation between the common ACE insertion/deletion (I/D) polymorphism and migraine. Materials & methods: Genotyping of the ACE I/D variant was performed in 502 Caucasian patients with migraine and 323 age-, sex- and race/ethnicity- matched healthy controls. We investigated associations between ACE genetic variants and sociodemographic and/or clinical features of migraineurs. Results: We found a significant association between ACE insertion/insertion (I/I) polymorphism and lower use of pharmacological prophylaxis in migraine patients with aura and in those with chronic migraine. Moreover, ACE I/I polymorphism was significantly more common in migraine patients with aura who had a negative family history of migraine. Conclusion: Our data suggest that although the ACE I/D polymorphism is not a direct risk factor for migraine, the ACE I/I genotype may influence the clinical feature of this disease being associated with reduced use of prophylactic agents in patients with migraine with aura and in those with chronic migraine. Original submitted 5 June 2013; Revision submitted 16 September 2013 KEYWORDS: ACE I/D polymorphism n genetics n migraine n pharmacological prophylaxis Rafaele Palmirota ‡1 , Piero Barbant ‡2 , Giorgia Ludovici 1 , Maria Laura De Marchis 1 , Cristano Ialongo 3 , Gabriella Egeo 2 , Cinzia Aurilia 2 , Luisa Fof 2 , Pasquale Abete 4 , Antonella Spila 1 , Patrizia Ferroni 1 , David Della-Morte* 1,5 & Fiorella Guadagni 1 1 Interinsttutonal Multdisciplinary BioBank (BioBIM), Department of Advanced Biotechnologies & Bioimaging, IRCCS San Rafaele Pisana, Rome, Italy 2 Headache & Pain Unit, Department of Neurological, Motor & Sensorial Sciences, IRCCS San Rafaele Pisana, Via Della Pisana 235, Rome 00163, Italy 3 Department of Internal Medicine, University of Rome ‘Tor Vergata’, Medicine & Surgery, Via Montpellier, 1, Rome 00133, Italy 4 Department of Translatonal Medical Sciences, University of Naples Federico II, Napoli 80131, Italy 5 Department of Systems Medicine, University of Rome ‘Tor Vergata’, Medicine & Surgery, Via Montpellier, 1, Rome 00133, Italy *Author for correspondence: david.dellamorte@sanrafaele.it ‡ Authors contributed equally part of For reprint orders, please contact: reprints@futuremedicine.com