Look beyond Catechol-O-Methyltransferase genotype for cathecolamines derangement in migraine: the BioBIM rs4818 and rs4680 polymorphisms study

Non-physiological catecholamine levels play a major role in migraine aetiology [1]. Clinical, pharmacological and biochemical evidence point to a chronic dopaminergic and noradrenergic dysfunction in migraine. Of note, some patients show during the attack symptoms related to dopamine receptor stimulation such as yawning, somnolence and vomiting or to reduced sympathetic function such hypotension and, occasionally, syncope [2,3]. The deciphering of the biological basis (biotype) of these clinical phenotypes would allow a more precise comprehension of migraine mechanisms and a more tailored migraine treatment.

The Catechol-O-Methyltransferase (COMT) gene [OMIM:+116790], mapping on chromosome 22q11.21, encodes for the major enzyme that degrades catecholamines (dopamine, epinephrine, and norepinephrine). Two COMT transcripts isoforms are produced, leading to the synthesis of a soluble protein (S-COMT), localized in blood and peripheral tissues, and a membrane-bound protein (MB-COMT) concentrated in the brain, mainly in the prefrontal cortex [4,5]. The COMT gene contains several SNPs, some of which result in a marked clinical significance. The rs4680 causes a substitution of a Valine (Val: GTG) to Methionine (Met: ATG) at codon 158 for MB-COMT isoform, and at codon 108 for S-COMT isoform [4,5]. These functional amino acid changes lead to a higher dopamine-degrading activity (H: high) for the Val158 variant and to a lower thermostability and enzymatic activity (L: lower) for the Met158 variant [6-8]. COMT activity is 3 to 4 times higher in Val homozygous compared to Met homozygous genotype carriers [9]. The rs4680 has been related to human pain perception, cognitive phenotypes, psychiatric disorders and variations in brain activation and structure [4,10]. The synonymous polymorphism rs4818 causes a C/G substitution at codon 86 of S-COMT and 136 of MB-COMT, corresponding to a Leucine residue. This genetic variant is related to a haploblock comprising rs6269 (A/G), rs4633 (C/T), rs4818 (G/C) and rs4680 (A/G), which strongly affects the efficiency of protein synthesis based on the specific haplotype, leading to a huge variation in enzyme activity [11]. Three major haplotypes influencing COMT activity and pain sensitivity were identified: a “low pain sensitivity” haplotype (G-C-G-G), characterized by a 11.4 times higher COMT activity compared with the “high pain sensitivity” haplotype (A-C-C-G), and an “average pain sensitivity” haplotype (A-T-C-A), with intermediate COMT activity values [11]. Variability at the rs4818 has been correlated to cognitive functions: the G allele, corresponding to high COMT activity levels and low tonic prefrontal cortex dopamine signalling, has been associated to a less efficient planning and problem solving ability, lower prepulse inhibition levels and working memory performance [12].

The study of COMT polymorphism in migraine has been mainly focused on the rs4680 polymorphism (Table 1) however providing inconclusive results, mainly due to small sampling and poor patients’ clinical characterization [13-21]. Surprisingly, the rs4818 polymorphism, despite its strong influence on COMT activity, has still not been investigated. We also noticed that the combined assessment of rs4680 and rs4818 was sufficient to provide a high degree of informativeness relatively to the overmentioned haplotypes [11].

Therefore, in the present study we sought to study the relationship between COMT rs4818 polymorphism and migraine in a detailed clinical migraine Caucasian population, whose biological samples were stored in a specifically dedicated migraine biobank (Interinstitutional Multidisciplinary BioBank-BioBIM), providing also a replication study on rs4680 polymorphism [22].