Epigenetic DNA methylation changes in episodic and chronic migraine

Excerpt

According to International Headache Classification (ICHD-3), migraine is classified in episodic migraine (EM) and chronic migraine (CM) based on the frequency of attacks. Medication overuse headache (MOH) is a secondary chronic headache disorder defined as a frequent headache (15 days per month or more) induced by the overuse of analgesics. Currently, the best treatment options include a detoxification programme based on the abrupt withdrawal of overused painkillers and eventually a preventive treatment. Despite these therapeutic efforts, the relapse rate of MOH is high, and no valid biomarkers are available to detect among patients who suffer from EM and CM those at greatest risk of develop MOH. According to available data, certain groups of people are more vulnerable to develop chronic pain conditions and poor adaptation to stress. Based on the scientific knowledge, a behavioural model of headache was proposed considering the strong association between pain, homeostatic imbalance, and affective behaviour. The pain and stress vulnerability is determined by genetic and non-genetic but heritable factors under the effect of environmental exposures as well as stochastic events during development. Differences between individuals’ DNA sequences can predispose toward maladaptive behaviours in many disorders comorbid with MOH, conferring a risk for chronic pain and by functioning as a type of molecular memory. Several evidences confirmed that pain vulnerability and attitude to chronic pain sensitivity are heritable via genetic but also epigenetic pathways though changes in DNA expression. A main epigenetic mechanism is DNA methylation, the covalent addition of a methyl group to the fifth carbon of cytosine residues, which is typically associated with gene silencing. Epigenetic mechanisms would have the potential to link early life events, neuro-inflammation, and brain plasticity in the aetiology of migraine chronification [1]. It has been hypothesised that frequent headache attacks may lower the threshold for subsequent headache attacks through epigenetic mechanisms. The suggested hypothesis is that neuronal activity can cause epigenetic changes altering synaptic plasticity, and the frequent migraine attacks in a feed-forward loop may promote stable epigenetic changes which altering synaptic plasticity supporting migraine chronification. Similarly, psychological acute and chronic stress and female sex hormones, which have been implicated in migraine genesis, are known to exert their physiological effects partly through epigenetic mechanisms [1]. Finally, drug addiction can be viewed as maladaptive neural plasticity that occurs in vulnerable individuals in response to repeated exposure to a drug of abuse. Evidences suggested that this vulnerability is partly determined by non-genetic factors which include environmental exposures as well as stochastic events during development which act through epigenetic mechanisms. However, there are no studies in MOH. The reduction of nucleic acid sequencing costs and the availability of cost-effective microarray solutions for the analysis of DNA methylation has favoured the implementation of epigenomic studies. DNA methylation, miRNA, and histone modifications have proven to be a potential source of powerful and robust biomarkers. Taken together, both the new genetic and epigenetic omic approaches have the potential to provide new molecular insight in the aetiology of migraine chronification, patient stratification, and therapy [2]. Recently, the first genome-wide study of DNA methylation in headache chronification was published. Several potentially implicated loci and processes were identified, but in the combined meta-analysis, the strongest associated CpG sites were related to SH2D5 and NPTX2, two brain-expressed genes involved in the regulation of synaptic plasticity. H2D5 gene encodes the SH2 domain-containing 5 protein which regulates synaptic plasticity through the control of Rac-GTP levels. The second strongest associated CpG site is 76 kb downstream from the nearest gene NPTX2, which encodes the neuronal pentraxin II protein, an inhibitor of excitatory synapses, through binding and clustering of glutamatergic AMPA receptors. Both proteins are highly expressed in the adult human brain [3]. Based on this evidence, the aim of this pilot study was to identify changes in DNA methylation associated with headache chronification comparing controls without headache (HC), episodic migraineurs (EM), and patients suffering from chronic migraine with medication overuse headache (MOH), before and after detox programme. In all selected subjects, genome-wide DNA methylation levels were characterised longitudinally at baseline and during follow-up using the Infinium Human MethylationEPIC Bead-Chip (Illumina). …