The New *G29A and G1222A of HCRTR1, 5-HTTLPR of SLC6A4 Polymorphisms and Hypocretin-1, Serotonin Concentrations in Migraine Patients

Abstract

Migraine is one of the most common primary headache disorders that affects 11% of the adult population. The disease is divided into two main clinical subtypes: migraine with aura (MA) and migraine without aura (MO). Both serotonergic and hypocretinergic systems are involved in the migraine pathomechanism. Polymorphisms in the serotonin transporter gene (SLC6A4) and the hypocretin receptor 1 gene (HCRTR1) may be risk factors for migraine development due to their ability to affect serotonin and hypocretin-1 (HCRT-1) concentrations. The aim of the study was to analyze, for the first time in the Polish population, the 5-HT transporter linked polymorphic region (5-HTTLPR) in SLC6A4, G1222A (rs2271933) and the never before studied *G29A (rs41263963) polymorphisms in the HCRTR1 gene, as well as the 5-HT and hypocretin-1 plasma concentrations in migraine patients (MA, MO) and control subjects. The study included 123 patients that were diagnosed with migraine and 123 control subjects. Methods such as PCR, HRMA and sequencing were used for genotyping, while 5-HT was determined by HPLC/EC and hypocretin-1 by ELISA. No significant differences were observed in 5-HTTLPR frequencies. The A allele of HCRTR1 G1222A occurred more often in MO, while the GA genotype of HCRTR1 *G29A was more frequent among MA when compared to control group (p < 0.05). The mean age of migraine onset in individuals with HCRTR1 *G29A was 18 years old for patients with MA and 26 years old for MO patients. The localization and type of HCRTR1 polymorphisms (G1222A—missense variant in exon 7, *G29A−3′UTR variant) may predispose patients to the clinical subtype of migraine: MO or MA, respectively. In control subjects, the short allele of 5-HTTLPR tended to decrease the 5-HT concentration, while the A allele of HCRTR1 G1222A decreased both 5-HT and hypocretin-1 levels. Serotonin concentrations differed in terms of clinical features of migraine. The relation between genotypes of 5-HTTLPR, HCRTR1 G1222A, and 5-HT concentrations may bedisturbed in migraine. It seems that HCRTR1 *G29A is more strongly associated with regulating the 5-HT in patients with MA than MO, and therefore may contribute to the early age of onset for migraine.

Serotonin and Neuropeptides in Blood From Episodic and Chronic Migraine and Cluster Headache Patients in Case‐Control and Case‐Crossover Settings: A Systematic Review and Meta‐Analysis

“…For comparison group f, ictal vs interictal also refers to the active cluster bout vs remission. In addition to the references from Table 3 with clear blood specimen descriptions (n = 30), 15 references were included 21,26,27,37,39,43,48,125‐132 . Abbreviations: chronic cluster headache (CCH); chronic migraine (CM); control (CTRL); episodic cluster headache (ECH); female/female‐dominated (F/FD); migraine (M); both sexes (M/F); male/male‐dominated (M/MD); migraine with aura (MWA); migraine without aura (MWoA).…”

“…Findings of abnormalities of the 5‐HT metabolism in migraine patients have varied extensively across studies 17,26,37 . All possible outcomes of 5‐HT were observed in the qualitative synthesis, even for the same stratum within a subgroup.…”

“…In the individual studies, detailed and precise reporting would be useful for future SR‐MAs, for example, including descriptive statistics of multiple factors for each subgroup and reporting the numeric value of estimates and corresponding precision, including units. An example of factors could be, but not limiting to, the following: Geographical origin, menstrual cycle, time point(s) of blood sampling (ie, from last ictal headache phase/ beginning of the ictal headache phase, local time range), site of blood sampling, nutrient state, body mass index, comorbidities, pain intensity, headache frequency, presence of symptoms and intake of medicine, and dietary supplements 26,37,47,48,86,98‐100 . These factors might affect the exposure‐outcome association, including others not mentioned.…”

“…The assessment was performed independently by 3 investigators (search1: SDF, MBND, AHS; search2: SDF, MBND), discussed and agreed upon. Authors of conference abstracts of interest were contacted which resulted in the inclusion of one additional study 26 . After assessment of full‐text eligibility, 64 eligible studies remained (n search1 = 56, n search2 = 8).…”

Correlation of 5‐HTR6 gene polymorphism with vestibular migraine

“…The result revealed that 5‐HT was significantly increased in VM patients compared to that in control group. Of note, partially different from our result, in a recent study by Kowalska et al, migraine patients were selected according to the ICHD‐3 criteria. MA patients (migraine with aura) and MO patients (migraine without aura) were further divided.…”