Genomics
In an effort to identify genetic variants involved in migraine risk and influencing the appropriate pharmacological treatments, many genomic studies have been performed in the last years. Due to neurological origin of migraine, some researchers have studied receptors involved in mediation of neuronal activities. Chen et al. [2] characterized one polymorphism in GABRG2 gene encoding the GABAA receptor gamma-2-subunit (rs211037) on a migraine case–control population of 546 subjects. No significant correlation was found. Carreno et al. [3] studied the transient receptor potential (TRP) superfamily of non-selective cationic channels accountable of multimodal sensory and pain perception, central and peripheral sensitization, and regulation of calcium homeostasis, relevant steps of migraine physiopathology. They carried out a migraine-control genetic association study genotyping 149 SNPs covering 14 TRP genes. Consistent results were obtained for TRPV3 rs7217270 in the Migraine with aura group and TRPV1 rs222741 in the overall migraine group, suggesting the involvement of the vanilloid TRPV subfamily of receptors to the genetic susceptibility to migraine [4]. Another gene analyzed is the calcium-activated potassium ion channel gene (KCNN3) involved in neural excitability and in migraine susceptibility. Cox et al. [5] performed a gene-wide SNP genotyping in a high-risk genetic isolate from Norfolk Island, characterized by high percentage of migraineurs. A total of 85 SNPs spanning the KCNN3 gene were genotyped in a sub-sample of 285 related individuals. Only four intronic SNPs displayed gene-wide significance: rs4845663, rs7532286, rs6426929 and rs1218551, with the minor allele in each case conferring protection against migraine risk. Using the same population, Cox et al. [6] carried out another pedigree-based genome-wide association (GWA) study found a significant statistical association with SNP rs4807347 in ZNF555 gene, coding for a zing finger protein. This result has been confirmed in unrelated cohort with more than 500 patients affected by migraine. They also found 4 SNPs in neurotransmitter-related genes (ADARB2, GRM7 and HTR7 genes) suggesting an alteration in the serotoninergic pathway. Maher et al., characterized the entire X chromosome in an association study on the Norfolk population and provides evidence for the SNP rs102834 in the UTR of the HEPH gene, which is involved in iron homeostasis [7,8]. Ligthart et al. [9] performed a meta-analysis of GWA studies for migraine in six population-based European cohorts consisting of 2446 cases and 8534 controls. A total of 32 SNPs showed marginal evidence for association to migraine and the best result was obtained for SNP rs9908234 in the nerve growth factor receptor -NGFR- gene but those results were not replicated in other cohorts. Besides, they found a modest gene-based significant association between migraine and the rs1835740 near the metadherin gene, but further replication studies did not validated this association [10,11].
The opioid system plays an important role in various biological functions including analgesia, drug response and pain reduction. Menon et al. [12] studied the influence of polymorphism in gene coding for the μ-opioid receptor highlighting the association between the OPRM1 A118G SNP and head pain severity in a clinical cohort of 153 female migraineurs with aura. In particular, G118 allele carriers were more likely to be high pain sufferers compared to homozygous carriers of the A118 allele.
Migraine is a complex condition that may in part be related by endothelial and cerebrovascular disruption [13]. Some studies showed that supplementation of B vitamins lowered homocysteine levels and reduced the occurrence of migraine in women [14]. Besides, polymorphisms in genes coding for key player enzymes in the folate metabolic pathway have been investigated in order to define a relation with the pathology and its treatment. The C677T variant in the methylenetetrahydrofolate reductase (MTHFR) has been associated with increased risk of migraine with aura [15,16]. The C allele carrier is also related to higher reduction in homocysteine levels, severity of pain in migraine and percentage of high migraine disability in patient supplemented with B vitamins [14]. The same approach has been adopted for the polymorphism A66G in methionine synthase reductase gene (MTRR): the A allele carriers showed a better response to B vitamin administration [14]. Roecklein et al. [17] performed a haplotype analysis of migraine risk and MTHFR, MTRR and methionine synthase (MTR), including subjects with non-migraine headache (N = 367), migraine without aura (N = 85), migraine with aura (N = 167), and no headache (N = 1347). Haplotype analysis suggested an association between MTRR haplotypes and reduced risk of migraine with aura.
Miao J et al. [18] performed a meta-analysis to determine if polymorphisms in genes linked to the vascular system could be related to migraine. They focused their attention on the receptor for endothelin-1, (EDNRA) known as a potent vasoconstrictor investigating the EDNRA -231G > A SNP. Three studies were included in their meta-analysis for a total of 440 migraineurs, 222 subjects with tension-type headaches (TTHs) and 1323 controls. They found statistical difference between migraineurs and controls with AA genotype vs. AG + GG, suggesting a potential association of -231G > A SNP and migraine. These data suggest that individual SNPs will provide only a small piece of a much larger puzzle composed by a variety of (un) know clinical (phenotypic) information.
Gentile et al. [19] genotyped panel of SNPs involved in triptans pharmacokinetics and pharmacody-namics in a chronic migraine (CM) population. In particular they studied the 30 bp VNTR in MAO A (monoamine oxidase A) promoter, CYP 1A2 *1C and *1 F, CYP3A4 *1B and C825T SNP in the gene coding the G protein b3 subunit (GNB3). A significant association with CM was found for the long allele of monoamine oxidase A 30 bp VNTR and CYP1A2*1 F variant. The same authors performed an analysis of the association between genotypic and allelic frequencies of the analyzed SNPs and the grade of response to triptan administration: a significant correlation for MAOA uVNTR polymorphism was found. Further stratification of patients in abuser and non-abuser groups revealed a significant association with triptan overuse and, within the abusers, with drug response to the CYP1A2*1 F variant [20].