Ibuprofen and Other Arylpropionics: The Relevance in Immediate Hypersensitivity Drug Reactions.

BACKGROUND: Ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), is the most frequent medication to be involved in hypersensitivity drug reactions (HDRs). Other analgesic/anti-inflammatory drugs in the arylpropionic group are also relevant, albeit to a lesser extent. Ibuprofen is widely consumed by people of all ages, both on medical prescription and over the counter; moreover, it is an organic contaminant of surface waters and foods. While numerous drugs cause HDR, ibuprofen's underlying mechanisms are more intricate and involve both specific immunological and non-immunological mediated reactions. SUMMARY: we concentrate on immediate responses, including urticaria with or without angioedema, anaphylaxis, and angioedema, classifying reactions according to whether they are caused by single or multiple NSAIDs and based on the mechanisms at play. Both groups may experience anaphylaxis, defined as an immediate, severe systemic reaction involving at least two organs, though the frequency and severity can vary. Following this classification, more clinical manifestations can be identified. Diagnosis is partly based on a detailed clinical history, including information about ibuprofen and/or other arylpropionic derivatives involved, the interval between drug intake and symptoms onset, clinical manifestations, number of episodes, and the patient's tolerance or response to other medications - mainly non-chemically related NSAID - both before and after reactions to ibuprofen and/or other arylpropionic drugs. A drug provocation test is frequently necessary to make a diagnosis. KEY MESSAGE: Because ibuprofen is the most widely prescribed NSAID, it is reasonable to assume its role as the leading cause of HDR will only become more important.

Developments in pharmacogenetics, pharmacogenomics, and personalized medicine.

The development of Pharmacogenetics and Pharmacogenomics in Western Europe is highly relevant in the worldwide scenario. Despite the usually low institutional support, many research groups, composed of basic and clinical researchers, have been actively working for decades in this field. Their contributions made an international impact and paved the way for further studies and pharmacogenomics implementation in clinical practice. In this manuscript, that makes part of the Special Issue entitled Spanish Pharmacology, we present an analysis of the state of the art of Pharmacogenetics and Pharmacogenomics research in Europe, we compare it with the developments in Spain, and we summarize the most salient contributions since 1988 to the present, as well as recent developments in the clinical application of pharmacogenomics knowledge. Finally, we present some considerations on how we could improve translation to clinical practice in this specific scenario.

Oxidative Stress Markers in Multiple Sclerosis.

The pathogenesis of multiple sclerosis (MS) is not completely understood, but genetic factors, autoimmunity, inflammation, demyelination, and neurodegeneration seem to play a significant role. Data from analyses of central nervous system autopsy material from patients diagnosed with multiple sclerosis, as well as from studies in the main experimental model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), suggest the possibility of a role of oxidative stress as well. In this narrative review, we summarize the main data from studies reported on oxidative stress markers in patients diagnosed with MS and in experimental models of MS (mainly EAE), and case-control association studies on the possible association of candidate genes related to oxidative stress with risk for MS. Most studies have shown an increase in markers of oxidative stress, a decrease in antioxidant substances, or both, with cerebrospinal fluid and serum/plasma malonyl-dialdehyde being the most reliable markers. This topic requires further prospective, multicenter studies with a long-term follow-up period involving a large number of patients with MS and controls.

Sleep Disorders in Patients with Choreic Syndromes.

PURPOSE OF REVIEW: Patients with different types of choreic syndromes, specially those with Huntington's (HD) and Wilson's (WD) diseases, report frequent sleep complaints. This review focuses on the main findings of studies addressing the sleep features in these diseases, and other less frequent causes of chorea associated with sleep disorders, including a new syndrome described in the last decade associated with IgLON5 antibodies. RECENT FINDINGS: Patients with HD and WD showed a bad quality of sleep and high frequency of insomnia and excessive daytime somnolence. WD patients also showed high scores on a specific scale for rapid eye movement sleep behavior disorders. HD and WD share decreased sleep efficiency and increased REM sleep latencies, percentage of sleep stage N1, and wake after sleep onset (WASO) among their polysomnographic features. Patients with HD and WD showed a high prevalence of different sleep disorders. Patients with other causes of chorea, including neuroacanthocytosis, parasomnia with sleep breathing disorder associated with antibodies to IgLON5, Sydenham's chorea, and choreic syndromes associated to certain genetic mutations show sleep disorders as well.

Lack of Association between Common LAG3/CD4 Variants and Risk of Migraine.

Several papers have been published suggesting a probable role of inflammatory factors in the etiopathogenesis of migraine. In this study, we investigated the possible association between common variants in the LAG3/CD4 genes (both genes, which are closely related, encode proteins involved in inflammatory and autoimmune responses) in the risk of migraine in a cohort of Caucasian Spanish participants. For this purpose, the frequencies of CD4 rs1922452, CD4 rs951818, and LAG3 rs870849 genotypes and allelic variants, using a specific TaqMan-based qPCR assay, were assessed in 290 patients diagnosed with migraine and in 300 healthy controls. The relationship of these variables with several clinical features of migraine was also analyzed. The frequencies of the analyzed LAG3/CD4 genotypes did not differ significantly between the two study groups and were not related to the sex, age at onset of migraine, family history of migraine, presence or absence of aura, or the triggering effect of ethanol on migraine episodes. These results suggest a lack of association between common variants in the LAG3/CD4 genes and the risk of developing migraine in the Caucasian Spanish population.

Association between LAG3/CD4 gene variants and risk of Parkinson's disease.

BACKGROUND/OBJECTIVES: Several recent studies suggest a possible role of lymphocyte activation 3 (LAG3) protein. LAG3 can behave as an α-synuclein ligand, and serum and cerebrospinal fluid-soluble LAG3 levels have been proposed as a marker of Parkinson's disease (PD). In this study, we aimed to investigate whether there is an association between 3 common single-nucleotide variations (SNVs) in the LAG3 gene and its closely related CD4 molecule gene and the risk of PD in a Caucasian Spanish population. Two of them have been previously associated with the risk of PD in Chinese females. METHODS: We analysed genotypes and allele frequencies for CD4 rs1922452, CD4 951818 and LAG3 rs870849 SNVs, by using specifically designed TaqMan assays, in a cohort composed of 629 PD patients and 865 age- and gender-matched healthy controls. RESULTS: The frequencies of the CD4 rs1922452 A/A genotype, according to the dominant and recessive genetic models, and of the CD4 rs1922452/A allelic variant were significantly lower, and the frequencies of the CD4 rs951818 A/A genotype, according to the dominant genetic model, and of the CD4 rs951818/A allele, were significantly higher in PD patients than in controls. The differences were not significant after stratifying by sex. These two SNVs showed strong linkage. Regression models showed a lack of relation between the 3 SNVs studied and the age at onset of PD. CONCLUSIONS: These data suggest a possible role of CD4 rs1922452 and CD4 rs951818 polymorphisms in the risk of PD.

Increased serum diamine oxidase activity in nonallergic patients with migraine.

BACKGROUND/OBJECTIVES: Histamine has shown a possible role in the etiopathogenesis of migraine. It has been reported an association between some polymorphisms in the diamine oxidase (DAO) gene and migraine, especially in women. Two studies addressing DAO activity in migraine patients showed conflicting results. We investigated the possible relationship of serum DAO activity and histamine levels and 3 polymorphisms in the DAO gene with the risk for migraine. METHODS: We studied the frequencies of DAO rs10156191, rs1049742 and rs1049793 genotypes and allelic variants in 298 migraine patients and 360 healthy controls (using a TaqMan-based qPCR assay), and serum DAO activity and histamine levels in a subset of 99 migraine patients and 115 controls with strict exclusion criteria, and analysed the relationship of these variables with several clinical features of migraine. RESULTS: The frequencies of the DAO genotypes and allelic variants analysed were similar in migraine patients and controls. Serum DAO activity was significantly higher in migraine patients (Vmax/Km 4.24 ± 2.93 vs. 3.60 ± 7.64, p < 0.001), especially in females (Vmax/Km 4.63 ± 2.96 vs. 3.18 ± 2.32, p < 0.0001), while serum histamine was similar in both study groups. CONCLUSION: Serum DAO activity was increased in patients with migraine, especially in females, while serum histamine levels were normal. None of the studied polymorphisms was associated with the risk for migraine.

LAG3/CD4 Genes Variants and the Risk for Restless Legs Syndrome.

According to several studies, inflammatory factors could be related to the pathogenesis of idiopathic restless legs syndrome (RLS). In addition, RLS and Parkinson's disease (PD) have shown a possible relationship, and recent studies have shown an association between CD4 rs1922452 and CD4 rs951818 single nucleotide variants (SNVs) and the risk for PD. For these reasons, we investigated the possible association between common variants in the LAG3/CD4 genes (which encoded proteins involved in inflammatory and autoimmune responses) and the risk for RLS in a Caucasian Spanish population. We assessed the frequencies of CD4 rs1922452, CD4 rs951818, and LAG3 rs870849 genotypes and allelic variants in 285 patients with idiopathic RLS and 350 healthy controls using a specific TaqMan-based qPCR assay. We also analyzed the possible influence of the genotypes' frequencies on several variables, including age at onset of RLS, gender, family history of RLS, and response to drugs commonly used in the treatment of RLS. We found a lack of association between the frequencies of genotypes and allelic variants of the 3 SNVs studied and the risk of RLS, and a weak though significant association between the CD4 rs1922452 GG genotype and an older age at onset of RLS. With the exception of this association, our findings suggest that common SNVs in the CD4/LAG3 genes are not associated with the risk of developing idiopathic RLS in Caucasian Spanish people.

Association between LAG3/CD4 Genes Variants and Risk for Multiple Sclerosis.

Several recent works have raised the possibility of the contribution of the lymphocyte activation gene 3 (LAG3) protein in the inflammatory processes of multiple sclerosis (MS). Results of studies on the possible association between LAG3 gene variants and the risk of MS have been inconclusive. In this study, we tried to show the possible association between the most common single nucleotide variants (SNVs) in the CD4 and LAG3 genes (these two genes are closely related) and the risk of MS in the Caucasian Spanish population. We studied the genotypes and allelic variants CD4 rs1922452, CD4 rs951818, and LAG3 rs870849 in 300 patients diagnosed with MS and 400 healthy patients using specific TaqMan-based qPCR assays. We analyzed the possible influence of the genotype frequency on age at the onset of MS, the severity of MS, clinical evolutive subtypes of MS, and the HLADRB1*1501 genotype. The frequencies of the CD4 rs1922452, CD4 rs951818, and LAG3 rs870849 genotypes and allelic variants were not associated with the risk of MS and were unrelated to gender, age at onset and severity of MS, the clinical subtype of MS, and HLADRB1*1501 genotype. The results of the current study showed a lack of association between the CD4 rs1922452, CD4 rs951818, and LAG3 rs870849 SNVs and the risk of developing MS in the Caucasian Spanish population.

Association between restless legs syndrome and peripheral neuropathy: A systematic review and meta-analysis.

BACKGROUND AND PURPOSE: The coexistence of peripheral neuropathy (PN) and restless legs syndrome (RLS) or Willis-Ekbom disease is relatively frequent, but its prevalence has shown a high variability across studies. In addition, several reports have shown data suggesting the presence of PN in patients with idiopathic RLS. METHODS: A search was undertaken using the PubMed, Embase and Web of Science Databases, from 1966 to 6 December 2020, crossing the search term 'restless legs syndrome' with 'neuropathy', 'polyneuropathy' (PNP) and 'peripheral neuropathy', and the references of interest for this topic were identified; a meta-analysis was performed, according to PRISMA guidelines, and a calculation of pooled prevalences, where appropriate, was made using standard methods. RESULTS: Restless legs syndrome has been reported in 5.2%-53.7% of patients with PN (average 21.5%; 95% confidence interval 18.6%-24.5%), and PN has been reported in 0%-87.5% of patients with RLS (average 41.8%; 95% confidence interval 39.9%-43.6%), both being significantly more frequent than in controls. The heterogeneity across studies could be due to differences in the diagnostic criteria used for both RLS and PN. RLS is a frequent clinical complaint in patients with PN of different aetiologies, mainly diabetic PN, uraemic PNP, familial amyloid PNP, Charcot-Marie-Tooth disease and chronic dysimmune inflammatory PNP. Recent neurophysiological findings suggest the presence of small sensory fibre loss in patients diagnosed with idiopathic RLS, but it remains to be determined whether RLS associated with small sensory fibre loss and idiopathic RLS are different clinical entities. CONCLUSIONS: Future studies including clinical and neurophysiological assessment and skin biopsy involving a large series of patients with PN and RLS are needed for a better understanding of the association between these two entities.

Biological fluid levels of iron and iron-related proteins in Parkinson's disease: Review and meta-analysis.

BACKGROUND AND PURPOSE: Several studies suggested a role or iron in the pathogenesis or Parkinson's disease (PD), and substantia nigra iron concentrarions have been found increased in PD. However, the results on cerebrospinal (CSF) and serum/plasma iron levels in PD patients have been controversial. The aim of this systematic review and meta-analysis was to establish the CSF and serum/plasma levels of iron and iron-related proteins (ferritin, transferrin, lactoferrin, haptoglobin, and hepcidine) levels, and the urine levels of iron, in patients with PD. METHODS: Four databases (PubMed, EMBASE, MedLine, and Web of Science - Core Collection) were reviewed for studies published from 1966 to October 5, 2020. References of interest were identified. A meta-analysis of eligible studies was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines, using the R software package meta. RESULTS: A non-significant trend towards higher CSF iron levels and marginally significantly lower serum/plasma iron levels was observed in patients with PD compared with age- and sex-matched controls. CSF and serum/plasma ferritin and transferrin concentrations, and serum/plasma lactoferrin and haptoglobin concentrations did not differ significantly between PD patients and controls. CONCLUSION: The findings of this study suggest an association between decreased serum/plasma iron levels and, possibly, higher CSF iron levels with risk of PD.

Sleep Disorders in Patients with Essential Tremor.

PURPOSE OF THE REVIEW: Patients diagnosed with essential tremor (ET) report frequent sleep complaints. This review focuses on the main findings of studies addressing sleep features in patients diagnosed with ET, updating previously reported information. Bad quality of sleep and excessive daytime somnolence are very frequent in patients with ET, although the effects of the drugs used for the therapy of ET could contribute to these complaints. REM sleep behavior disorder, restless legs, insomnia, and nocturia are frequent complaints as well. There is a lack of studies addressing polysomnographic features of ET.

Association between endothelial nitric oxide synthase (NOS3) rs2070744 and the risk for migraine.

Because nitric oxide could play an important role in the pathogenesis of migraine (suggested by experimental, neuropathological, biochemical, and pharmacological data), and a recent meta-analysis showed an association between the single-nucleotide polymorphism (SNP) rs2070744 in the endothelial nitric oxide synthase (eNOS or NOS3) gene (chromosome 7q36.1) and the risk for migraine in Caucasians, we attempted to replicate the possible association between this SNP and the and the risk for migraine in the Caucasian Spanish population. The frequencies for the NOS3 rs2070744 genotypes and allelic variants were assessed in 283 migraine patients and 287 healthy controls with a TaqMan-based qPCR Assay. The putative influence on genotype frequency of age at onset of migraine attacks, gender, family history of migraine, absence or presence of aura, and triggering of migraine attacks by ethanol, were also analyzed. The frequencies of NOS3 rs2070744 genotypes and allelic variants were not associated with the risk for migraine (OR [95%] CI for the minor allele = 0.91 [0.72-1.15]) and were not influenced by age at onset of migraine, gender, presence of aura, or triggering of migraine attacks by ethanol. NOS3 rs2070744CC genotypes were significantly more frequent in patients with a family history of migraine. NOS3 rs2070744 SNP is not associated with the risk for migraine in Caucasian Spanish people although it might be related to family history.

Endothelial nitric oxide synthase (NOS3) rs2070744 polymorphism and risk for multiple sclerosis.

The possible role of oxidative stress and nitric oxide (NO) in the pathogenesis of multiple sclerosis (MS) has been suggested by several neuropathological, biochemical, and experimental data. Because the single-nucleotide polymorphism (SNP) rs2070744 in the endothelial nitric oxide synthase (eNOS or NOS3) gene (chromosome 7q36.1) showed association with the risk for MS in Iranians, we attempted to replicate the possible association between this SNP and the risk for MS in the Caucasian Spanish population. The frequencies of NOS3rs2070744 genotypes and allelic variants in 300 patients diagnosed with MS and 380 healthy controls were assessed with a TaqMan-based qPCR assay. The possible influence of the genotype frequency on age at onset of MS, the severity of MS, clinical evolutive subtypes of MS, and HLA-DRB1*1501 genotype were also analyzed. The frequencies of rs2070744 genotypes and allelic variants were not associated with the risk of developing MS and were not influenced by gender, age at onset and severity of MS, the clinical subtype of MS or the HLA-DRB1*1501 genotype. This study found a lack of association between NOS3 rs2070744 SNP and the risk for MS in Caucasian Spanish people.

Gamma-aminobutyric acid (GABA) receptors genes polymorphisms and risk for restless legs syndrome.

The possible role of gammaaminobutyric acid (GABA) in the pathophysiology of restless legs syndrome (RLS) is suggested by the symptomatic improvement achieved with GABAergic drugs. Thalamic GABA levels have shown positive correlation with periodic limb movements indices and with RLS severity. We tried to investigate the possible association between the most common single nucleotide polymorphisms (SNPs) in the GABA receptors (GABR) genes rho1, 2, and 3 (GABRR1, GABRR2, GABRR3), alpha4 (GABRA4), epsilon (GABRE), and theta (GABRQ) with the risk of developing RLS. We studied the genotype and allelic variant frequencies of the most common SNPs in the GABRR1(rs12200969, rs1186902), GABRR2(rs282129), GABRR3(rs832032), GABRA4(rs2229940), GABRE(rs1139916), and GABRQ(rs3810651) genes in 205 RLS patients and 230 age- and gender-matched healthy controls using specific TaqMan assays. The frequencies of the GABRR3 rs832032TT genotype and the allelic variant GABRR3 rs832032T were significantly higher in RLS patients than in controls (odds ratio [95% confidence intervals] 7.08[1.48-46.44] and 1.66[1.16-2.37], respectively), although only the higher frequency of the rs832032T allele remained as significant after multiple comparison analysis, both in the whole series and in the female gender. The frequencies of the other genotypes of allelic variants did not differ significantly between RLS patients and controls. RLS patients carrying the GABRA4 rs2229940TT genotype showed a significantly younger age at onset of RLS symptoms than those with the other two genotypes. These results suggest association between GABRR3rs832032 polymorphism and the risk for RLS, and a modifier effect of GABRA4 rs2229940 on the age of onset of RLS.

Gamma-aminobutyric acid (GABA) receptors GABRA4, GABRE, and GABRQ gene polymorphisms and risk for migraine.

Several biochemical, pharmacological, neurophysiological and experimental data suggest a possible role of gamma-aminobutyric acid (GABA) in the pathogenesis of migraine. We investigated the possible association of the most common single nucleotide polymorphisms (SNPs) in the GABA receptor alpha4 (GABRA4), epsilon (GABRE), and theta (GABRQ) genes with the risk for migraine. A TaqMan-based qPCR assay designed to detect the most common SNPs in the GABRA4 (rs2229940), GABRE (rs1139916), and GABRQ (rs3810651) was performed in 197 migraine patients and 394 age- and gender-matched controls. The possible influence of gender, age at onset of migraine, positive family history of migraine, presence or absence of aura, and triggering of migraine by ethanol on the frequency of the genotypes was also studied. The frequency of GABRE rs1139916AA genotype was significantly lower in the migraine group only in the female gender, but the differences did not reach statistical significance after correction for multiple comparisons. The mean ± SD age at onset of migraine was significantly lower in patients with GABRQ rs3810651AA as compared with the other two genotypes. Positive family history of migraine and presence or absence of aura did not influence the frequencies of the genotypes of the three SNPs studied. Triggering of migraine by ethanol was significantly less frequent in patients with GABRA4 rs2229940GG and more frequent in patients with GABRQ 3810651TT genotype, but the differences lost statistical significance after correction for multiple comparisons. GABRQ rs3810651 could play a role in the modification of age at onset of migraine.

Missense mutations in TENM4, a regulator of axon guidance and central myelination, cause essential tremor.

Essential tremor (ET) is a common movement disorder with an estimated prevalence of 5% of the population aged over 65 years. In spite of intensive efforts, the genetic architecture of ET remains unknown. We used a combination of whole-exome sequencing and targeted resequencing in three ET families. In vitro and in vivo experiments in oligodendrocyte precursor cells and zebrafish were performed to test our findings. Whole-exome sequencing revealed a missense mutation in TENM4 segregating in an autosomal-dominant fashion in an ET family. Subsequent targeted resequencing of TENM4 led to the discovery of two novel missense mutations. Not only did these two mutations segregate with ET in two additional families, but we also observed significant over transmission of pathogenic TENM4 alleles across the three families. Consistent with a dominant mode of inheritance, in vitro analysis in oligodendrocyte precursor cells showed that mutant proteins mislocalize. Finally, expression of human mRNA harboring any of three patient mutations in zebrafish embryos induced defects in axon guidance, confirming a dominant-negative mode of action for these mutations. Our genetic and functional data, which is corroborated by the existence of a Tenm4 knockout mouse displaying an ET phenotype, implicates TENM4 in ET. Together with previous studies of TENM4 in model organisms, our studies intimate that processes regulating myelination in the central nervous system and axon guidance might be significant contributors to the genetic burden of this disorder.

Delta-amino-levulinic acid dehydratase gene and essential tremor.

BACKGROUND: Several reports found a relationship between increased serum lead levels and the risk for essential tremor (ET), especially in carriers of the minor allele of the single nucleotide polymorphism (SNP) rs1800435 in the aminolevulinate dehydratase (ALAD) gene, which is involved in the synthesis of haem groups. Our group reported decreased risk for ET in carriers of the minor alleles of the rs2071746 and rs1051308 SNPs in the haem-oxygenases 1 and 2 (HMOX1 and HMOX2), respectively, involved in haem metabolism. We analysed whether ALAD rs1800435 alone and their interactions with the four common SNPs in the HMOX1 and HMOX2 genes are associated with the risk for ET. MATERIALS AND METHODS: We analysed the genotype and allele variants frequencies of ALAD rs1800435 in 202 patients with familial ET and 218 healthy controls using a TaqMan method. We also analysed the role of the interaction between ALAD rs1800435 and the HMOX1 rs2071746, HMOX1 rs2071747, HMOX2 rs2270363 and HMOX2 rs1051308 with the risk of developing ET. RESULTS: The frequencies of genotype and allelic variants of ALAD rs1800435 did not differ significantly between patients with ET and controls, and were not influenced by gender. Subjects carrying the ALAD rs1800435CC genotype (wild-type) and the HMOX2 rs1051308GG genotype or the HMOX2 rs1051308G allele had significantly decreased risk for ET. CONCLUSIONS: These results suggest that the ALAD rs1800435 SNP is not related with the risk for ET, but its interaction with the HMOX2 rs1051308 SNP could be weakly associated with the risk for this disease.

Thr105Ile (rs11558538) polymorphism in the histamine-1-methyl-transferase (HNMT) gene and risk for restless legs syndrome.

A recent meta-analysis suggests an association between the rs11558538 single nucleotide polymorphism in the histamine-N-methyl-transferase (HNMT) gene and the risk for Parkinson's disease. Based on the possible relationship between PD and restless legs syndrome (RLS), we tried to establish whether rs11558538 SNP is associated with the risk for RLS. We studied the genotype and allelic variant frequencies of HNMT rs11558538 SNP 205 RLS patients and 410 healthy controls using a TaqMan assay. The frequencies of the HNMT rs11558538 genotypes allelic variants were similar between RLS patients and controls, and were not influenced by gender, family history of RLS, or RLS severity. RLS patients carrying the genotype rs11558538TT had an earlier age at onset, but this finding was based on three subjects only. These results suggest a lack of major association between HNMT rs11558538 SNP and the risk for RLS.

Gamma-Aminobutyric Acid (Gaba) Receptors Rho (Gabrr) Gene Polymorphisms and Risk for Migraine.

BACKGROUND/OBJECTIVES: The possible role of gammaaminobutyric acid (GABA) in the pathogenesis of migraine has been suggested by a number of biochemical, pharmacological, neurophysiological and experimental data. We investigated the possible association between the most common single nucleotide polymorphisms (SNPs) in the GABA receptor rho1, 2, and 3 genes (GABRR1, GABRR2, and GABRR3) and the risk of developing migraine. METHODS: The frequency of GABRR1 rs12200969, GABRR1 rs1186902, GABRR2 rs282129, and GABRR3 rs832032 genotypes and allelic variants were studied in a case-control association study involving 197 patients with migraine and 278 healthy controls by means of a TaqMan-based qPCR Assay. We also studied the possible influence of gender, age at onset of migraine, positive family history of migraine, presence or absence of aura, and triggering of migraine by ethanol on the frequency of the genotypes. RESULTS: The frequencies of the genotypes and allelic variants of the 4 SNPs were similar in migraine patients and controls. Gender, positive family history of migraine, presence or absence of aura, and triggering of migraine attacks by ethanol did not influence the frequency of these genotypes. Carriers of the minor allele of the rs1186902 SNP showed a trend towards later onset of migraine. CONCLUSION: The most common polymorphisms in the GABRR genes seemed to be not associated with the risk for migraine in Caucasian Spanish people, although one of them (GABRR1 rs1186902) shows a statistically significant association with the age of onset of migraine.