Anthocyanin Supplementation Alleviates Antithrombotic Risk by Inhibiting Platelet Activity in Humans.

BACKGROUND: Platelet hyperactivity has a crucial role in initiating vascular thrombosis and subsequent cardiovascular disease (CVD). OBJECTIVE: This study aimed to assess the effect of anthocyanins (AC) on platelet aggregation and activation and lipid profile. STUDY DESIGN: A total of 26 healthy participants consumed 320 mg of AC/day in the form of Medox® capsules for 28 days. SETTING: This study was conducted in the laboratories of the School of Medical Sciences, Griffith University, Gold Coast, Australia. PARTICIPANTS: A total of 26 randomly recruited healthy 25- to 75-year-old participants completed this study. PRIMARY OUTCOME MEASURES: Fasting blood samples were collected pre- and post-the intervention period to perform platelet activation studies by measuring platelet surface marker expression of CD41a and P-selectin, and platelet-monocyte aggregates in adenosine diphosphate (ADP) stimulated platelets. Platelet aggregation studies were performed by stimulating platelets with various agonists such as ADP, collagen and arachidonic acid. Full blood examination, coagulation and biochemistry profile analyses were also performed pre- and post-intervention. Flow cytometric analysis showed a significant effect of AC on the expression of P-selectin as measured by the platelet surface expression of CD62p. RESULTS: There was a significant reduction of ADP-stimulated platelet aggregation. Hematologic analysis showed a significant reduction of mean platelet volume, mean cell hemoglobin, and mean cell hemoglobin concentration. Coagulation analysis demonstrated significant attenuation of fibrinogen level in the blood. CONCLUSION: This study showed inhibition of platelet activity, platelet aggregation and mean platelet volume (MPV). These results suggest that AC has a positive impact on attenuating platelet activity, which might minimize thrombotic risk.

Potential of anthocyanin as an anti-inflammatory agent: a human clinical trial on type 2 diabetic, diabetic at-risk and healthy adults.

OBJECTIVE: The present research aimed to investigate the anti-inflammatory potential of dietary anthocyanin (ACN) in type 2 diabetic (T2D), T2D-at-risk and healthy individuals. Furthermore, dietary inflammatory index (DII) was used to study the association of diet with biomarkers of inflammation. RESEARCH METHODS: An open-label clinical trial was conducted at Griffith University investigating the efficacy of 320 mg ACN supplementation per day over the course of 4 weeks. Diabetes-associated inflammatory biomarkers and relevant biochemical and physical parameters were tested pre-and post-intervention, and participants' dietary inflammatory potential was estimated. RESULTS: A significant reduction in the pro-inflammatory biomarkers' interleukin-6, interleukin-18, and tumour necrosis factor-α was observed in the T2D group. In addition, some, but not all, biochemical parameters including fasting blood glucose, low-density lipoprotein cholesterol and uric acid were significantly improved in T2D-at-risk group. Moreover, a significant difference was detected between the DII scores of the healthy and T2D groups. DII score for the T2D group was consistent with an anti-inflammatory diet. CONCLUSION: Anti-inflammatory potential of dietary ACN in T2D participants was evidenced in the present study. Although, anti-inflammatory dietary patterns of T2D participants may have accelerated the anti-inflammatory effect of the ACN capsules supplemented in this trial.

Sex Differences in the Expression of the α5 Subunit of the GABAA Receptor in Alcoholics with and without Cirrhosis of the Liver.

BACKGROUND: Alcohol exposure alters the expression of a large number of genes, resulting in neuronal adaptions and neuronal loss, but the underlying mechanisms are largely unknown. miRNAs are gene repressors that are abundant in the brain. A recent study identified ~ 35 miRNAs that are up-regulated in the prefrontal cortex of human alcoholics and predicted to target genes that are down-regulated in the same region. Although interactions between alcohol-responsive miRNAs and their target genes have been predicted, few studies have validated these predictions. METHODS: We measured the expression of GABAA α5 mRNA in the prefrontal and motor cortices of human alcoholics and matched controls using real-time PCR. The expression of miR-203 was measured in a subset of these cases. The predicted interaction of miR-203 and GABRA5 was validated for miR-203 using a luciferase reporter assay. RESULTS: In both frontal and motor cortices, the expression of GABAA α5 was significantly lower in cirrhotic alcoholics compared with controls. Further, the pattern of expression between the groups was significantly different between males and females. The expression of miR-203 was higher in the prefrontal cortex of cirrhotic alcoholics compared with controls and uncomplicated alcoholics. These differences were particularly marked in female cases. Cotransfection of GABRA5 with miR-203 in HEK293T cells reduced luciferase reporter activity. CONCLUSION: There are sex differences in the expression of GABAA α5 and miR-203 in the brain of human alcoholics which are particularly marked in alcoholics with cirrhosis of the liver. Further, miR-203 may mediate the changes in expression of this GABAA receptor isoform that is brought about by alcohol exposure.

Assessment of in vitro Effects of Anthocyanins on Platelet Function.

BACKGROUND: Increased platelet activity plays a significant role in the development of arterial thrombosis and cardiovascular disease (CVD). Natural antioxidants including anthocyanin (AC) have gained considerable interest due to their hypothesized antithrombotic potential. PRIMARY STUDY OBJECTIVE: Our study aimed to examine the in vitro effect of AC compounds on platelet activation and aggregation. METHODS: Fasting blood samples were collected from healthy volunteers (n = 13). A full blood examination was done to exclude any abnormal specimen. Flow cytometer assessed platelet activity by recording platelet surface markers expression of P-selectin (CD62P) and PAC-1. Platelet aggregation studies were performed by stimulating platelets using three different agonists adenosine diphosphate (ADP), collagen and arachidonic acid (AA). SETTING: The study was done in the school of Medical Sciences, Griffith University. PARTICIPANTS: Thirteen healthy adult participants were involved for blood collection. INTERVENTION: AC was prepared using hemicellulose capsules sourced from Bilberries and Black Currants. RESULTS: Anthocyanin (50 mg/L) significantly inhibited AA-induced platelet aggregation. Expression of P-selectin was significantly suppressed by 50 mg/L AC as measured by flow cytometer. CONCLUSIONS: AC attenuates platelet function by suppressing P-selectin expression and influencing Thromboxane A2 pathway (AA stimulation). These results provide further evidence for the effect of AC and the possible mechanism by which AC reduces platelet aggregation and activation. This study supports future human intervention trials to show that AC may act as a complement to other antiplatelet agents in reducing the risk of thrombosis.

Potential of Anthocyanin to Prevent Cardiovascular Disease in Diabetes.

Context • Type 2 diabetes mellitus is an independent precipitating factor for cardiovascular disease (CVD). Heart disease is one of the leading causes of mortality in patients with diabetes, mainly due to macrovascular complications, such as atherosclerosis. Although aspirin is a frequently used therapy for the inhibition of platelet hyperactivity, many studies suggest that aspirin resistance is rising. Objective • The study intended to investigate the benefits of anthocyanin (AC) as an antioxidant with inhibitory effects on platelets and, consequently, its potential usefulness as complementary antiplatelet therapy to attenuate the negative effects of atherosclerosis and CVD in patients with diabetes. Design • The research team performed a literature review. The team conducted a database search from 2007 to 2017 using Library of Congress, LISTA, PubMed, and Web of Science Core Collection databases, using the following keywords: anthocyanins, platelet, cardiovascular disease, and diabetes. Setting • The study took place at the School of Medical Sciences at Griffith University's Gold Coast campus (Southport, Australia). Results • Platelets have a major pathophysiological role of atherosclerosis and consequently CVD in diabetes. Antiplatelet drugs have a potent inhibitory effect of thrombotic and CVD risks in diabetes. Dietary antioxidants including ACs have a potential platelet inhibitory effect. Hence, ACs may act as complementary therapy to reduce CVD in diabetes. Conclusions • Although antiplatelet drugs such as aspirin provide significant action in the management of CVD, aspirin has limited benefits in diabetes. An AC antioxidant has a potential effect as an antiplatelet agent that subsequently can prevent atherosclerosis and CVD and, therefore, AC may be an alternative to other antiplatelet drugs such as aspirin. However, more interventional studies and large-scale clinical trials are necessary to prove the efficiency of AC as an alternative to other platelet-inhibitory drugs.

Effect of probiotics and synbiotics on blood glucose: a systematic review and meta-analysis of controlled trials.

PURPOSE: High fasting blood glucose (FBG) can lead to chronic diseases such as diabetes mellitus, cardiovascular and kidney diseases. Consuming probiotics or synbiotics may improve FBG. A systematic review and meta-analysis of controlled trials was conducted to clarify the effect of probiotic and synbiotic consumption on FBG levels. METHODS: PubMed, Scopus, Cochrane Library, and Cumulative Index to Nursing and Allied Health Literature databases were searched for relevant studies based on eligibility criteria. Randomized or non-randomized controlled trials which investigated the efficacy of probiotics or synbiotics on the FBG of adults were included. Studies were excluded if they were review articles and study protocols, or if the supplement dosage was not clearly mentioned. RESULTS: A total of fourteen studies (eighteen trials) were included in the analysis. Random-effects meta-analyses were conducted for the mean difference in FBG. Overall reduction in FBG observed from consumption of probiotics and synbiotics was borderline statistically significant (-0.18 mmol/L 95 % CI -0.37, 0.00; p = 0.05). Neither probiotic nor synbiotic subgroup analysis revealed a significant reduction in FBG. The result of subgroup analysis for baseline FBG level ≥7 mmol/L showed a reduction in FBG of 0.68 mmol/L (-1.07, -0.29; ρ < 0.01), while trials with multiple species of probiotics showed a more pronounced reduction of 0.31 mmol/L (-0.58, -0.03; ρ = 0.03) compared to single species trials. CONCLUSION: This meta-analysis suggests that probiotic and synbiotic supplementation may be beneficial in lowering FBG in adults with high baseline FBG (≥7 mmol/L) and that multispecies probiotics may have more impact on FBG than single species.

Thrombotic and cardiovascular risks in type two diabetes; Role of platelet hyperactivity.

One of the most commonly identified chronic illnesses in many countries is type 2 diabetes mellitus (T2DM). T2DM denotes an independent risk factor for cardiovascular disease (CVD). Heart disease is one of the causes of mortality in patients with diabetes, mainly due to the macrovascular complications. One of these macrovascular complications in diabetes is atherosclerosis, which involves a complicated pathophysiological process. Besides hyperglycemia, oxidative stress plays a significant role in the pathogenesis of diabetes and its associated risk of CVD. There are many other factors including molecular, metabolic, lipid, fibrinolytic, and platelet function disorders precipitate to thrombotic and CVD risks in T2DM. Also, Platelets have an increased response to procoagulants in patients with diabetes. Platelet hyperactivity, in the presence of oxidative stress, has a major effect on the progression of thrombotic and CVD events. This review will discuss the impact of the above factors and the potential effects of platelet hyperactivity on thrombotic and cardiovascular risks.

The impact of MTHFR 677 C/T genotypes on folate status markers: a meta-analysis of folic acid intervention studies.

PURPOSE: Methylenetetrahydrofolate reductase (MTHFR) is a key folate pathway enzyme with the T variant of the MTHFR gene increasing the risk of low folate status, particularly coupled with low folate intake. As genetic variability of MTHFR influences folate status, it is important to ensure an adequate intake that overrides genetic effects but minimises any adverse effects. Our aim was to assess the influence of MTHFR genotype on folate status followed by response to supplementation. METHODS: We performed a meta-analysis of ten folate intervention studies to assess the degree to which MTHFR C677T genotype influenced plasma homocysteine and serum folate levels as measures of folate status. We then examined response after supplementation at intake values up to the upper tolerable limit. RESULTS: The MTHFR 677TT genotype was associated with higher plasma homocysteine (2.7 µmol/L, TT vs. CT/CC; 2.8 µmol/L, TT vs. CC) and lower serum folate (2.5 nmol/L, TT vs. CT/CC; 3.6 nmol/L, TT vs. CC). In two studies, the TT groups had mean plasma Hcy >15 µmol/L. Serum folate levels were >7 nmol/L for all genotype groups. After supplementation of 400 up to 1670 µg DFEs of folic acid or folic acid + fortified foods and/or natural food folates for a minimum of 4 weeks, there were no significant differences in plasma homocysteine levels; however, individuals with the TT genotype had a lower serum folate response to supplementation (7.2 nmol/L, TT vs. CT/CC; 8.7 nmol/L, TT vs. CC). CONCLUSIONS: This meta-analysis confirms observations from observational and intervention studies that MTHFR TT genotype is associated with increased plasma homocysteine and lowered serum folate and less response to short-term supplementation. The results can be used for modelling and guiding personalised intake recommendations for the nutrient folate.

Probiotics and Subclinical Psychological Symptoms in Healthy Participants: A Systematic Review and Meta-Analysis.

INTRODUCTION/AIM: Interest in the gut-brain axis and emerging evidence that the intestinal microbiota can influence central nervous system function has led to the hypothesis that probiotic supplementation can have a positive effect on mood and psychological symptoms such as depression and anxiety. Although several human clinical trials have investigated this, results have been inconsistent. Therefore, a systematic review and meta-analytic approach was chosen to examine if probiotic consumption has an effect on psychological symptoms. METHODS: The online databases PubMed, Scopus, and the Cochrane Library were searched for relevant studies up to July 2016. Those that were randomized and placebo controlled and measured preclinical psychological symptoms of depression, anxiety, and perceived stress in healthy volunteers pre and post supplementation with a probiotic were included. To control for differences in scales of measurement, data were converted to percentage change, and the standardized mean difference between the probiotic and control groups was investigated using Revman software. A random effects model was used for analysis. Heterogeneity was assessed using the I2 statistic. Quality assessment was undertaken using the Rosendal scale. RESULTS: Seven studies met the inclusion criteria and provided data for nine comparisons. All studies passed the quality analysis. The meta-analysis showed that supplementation with probiotics resulted in a statistically significant improvement in psychological symptoms (standardized mean difference 0.34; 95% confidence interval 0.07-0.61, Z = 2.49) compared with placebo. CONCLUSION: These results show that probiotic consumption may have a positive effect on psychological symptoms of depression, anxiety, and perceived stress in healthy human volunteers.

Occupational health and metabolic risk factors: A pilot intervention for transport workers.

OBJECTIVES: Heavy vehicle transport workers have a high risk of obesity and obesity-related disorders including cardiovascular disease and diabetes. Sedentary nature of their work makes a healthy work and lifestyle balance difficult to achieve. Educational interventions that promote behavioral changes have been shown to be effective in various group settings. The aims of this study were to determine the prevalence of metabolic risk factors among a population of urban bus drivers; to deliver a 3-month educational intervention specifically tailored for the workplace environment of transport workers; and to evaluate the efficacy of the intervention through quantitative measurements and qualitative feedback. MATERIAL AND METHODS: Thirty-three bus drivers from depots in south Queensland were recruited for the study. Baseline metabolic data were collected through anthropometric measurements, blood collection and diet/lifestyle questionnaires. Metabolic risk factors that were analyzed included: waist circumference, blood pressure, fasting glucose, blood triglycerides and high density lipoprotein cholesterol (HDL-C). Three interactive seminars were delivered over a 3-month period. At the end of the period, data collection was repeated. RESULTS: At the commencement of the study, 35% of the participants exhibited ≥ 3 of the metabolic risk factors that characterize metabolic syndrome. This is higher than the reported prevalence in the general Australian population (22.1%). A total 21 of the 33 participants remained committed to the intervention and provided pre and post intervention data. Of these, 28% (N = 6) showed a decrease in one or more of the risk factors associated with metabolic syndrome. There was a significant increase in the average HDL-C after the intervention. Qualitative feedback indicated that the workers benefited from the program, especially regarding their awareness of the risks associated with their profession. CONCLUSIONS: This pilot study demonstrates that lifestyle education seminars specifically tailored for the workplace can have an impact on the health behaviors of transport workers.

A refined high carbohydrate diet is associated with changes in the serotonin pathway and visceral obesity.

Consumption of palatable foods high in refined carbohydrate has been implicated as a contributing factor to the epidemic levels of obesity. Such foods may disrupt appetite regulation in the hypothalamus through alterations in hunger and satiety signalling. This investigation examined whether a palatable high refined carbohydrate (HRC) diet with the potential to induce obesity was linked to modulation of serotonin and dopamine signalling within the hypothalamus of rats. Male Wistar rats were allowed ad libitum access to either a palatable refined carbohydrate enriched (HRC) diet or standard chow (SC). Visceral fat percentage was used as a measure of the animals' weight gain during the trial. Real-time PCR was applied to determine any variation in levels of expression of the serotonin (Slc6A4 or Sert) and dopamine transporter (Slc6A3 or Dat) genes. After 29 weeks, the HRC group showed a significant increase in visceral fat percentage accompanied by increased expression of Sert. Higher levels of circulating triglycerides were also seen. This investigation determined that a refined high carbohydrate diet is associated with visceral obesity, increased circulating lipids in the blood and distorted serotonergic signalling, which possibly alters satiety and hunger signals.

Significant differences in gene expression of GABA receptors in peripheral blood leukocytes of migraineurs.

Migraine is a debilitating neurovascular disorder, with a substantial genetic component. The exact cause of a migraine attack is unknown; however cortical hyperexcitability is thought to play a role. As Gamma-aminobutyric Acid (GABA) is the major inhibitory neurotransmitter in the brain, malfunctioning of this system may be a cause of the hyperexcitability. To date, there has been limited research examining the gene expression or genetics of GABA receptors in relation to migraine. The aim of our study was to determine if GABA receptors play a role in migraine by investigating their gene expression using profile in migraine affected individuals and non-affected controls by Q-PCR. Gene expression of GABA(A) receptor subunit isoforms (GABRA3, GABRB3, GABRQ) and GABA(B) receptor 2 (GABBR2) was quantified in mRNA obtained from peripheral blood leukocytes from 28 migraine subjects and 22 healthy control subjects. Analysis of results showed that two of the tested genes, GABRA3 and GABBR2, were significantly down regulated in migraineurs (P=0.018; P=0.017), compared to controls. Results from the other tested genes did not show significant gene expression variation. The results indicate that there may be specific GABA receptor gene expression variation in migraine, particularly involving the GABRA3 and GABBR2 genes. This study also identifies GABRA3 and GABBR2 as potential biomarkers to select migraineurs that may be more responsive to GABA agonists with future investigations in this area warranted.

Promoting metacognition in first year anatomy laboratories using plasticine modeling and drawing activities: a pilot study of the "blank page" technique.

Many first year students of anatomy and physiology courses demonstrate an inability to self-regulate their learning. To help students increase their awareness of their own learning in a first year undergraduate anatomy course, we piloted an exercise that incorporated the processes of (1) active learning: drawing and plasticine modeling and (2) metacognition: planning, monitoring, reaction, and reflection. The activity was termed "blank page" because all learning cues were removed and students had to create models and diagrams from reflection and recall. Two hundred and eighty-two students responded to a questionnaire reporting qualitative feedback on the exercise. Based on student responses, the "blank page" activity was a positive learning experience and confirmed a need to teach metacognitive skills. From this pilot study, we established that drawing or plasticine modeling is an excellent vehicle for demonstration of the metacognitive processes that enable self-regulation: a known predictor of academic success.

Differential expression of 14-3-3 isoforms in human alcoholic brain.

BACKGROUND: Neuropathological damage as a result of chronic alcohol abuse often results in the impairment of cognitive function. The damage is particularly marked in the frontal cortex. The 14-3-3 protein family consists of 7 proteins, ß, γ, ε, ζ, η, θ, and σ, encoded by 7 distinct genes. They are highly conserved molecular chaperones with roles in the regulation of metabolism, signal transduction, cell-cycle control, protein trafficking, and apoptosis. They may also play an important role in neurodegeneration in chronic alcoholism. METHODS: We used real-time PCR to measure the expression of 14-3-3 mRNA transcripts in both the dorsolateral prefrontal cortex and motor cortex of human brains obtained at autopsy. RESULTS: We found significantly lower 14-3-3ß, γ, and θ expression in both cortical areas of alcoholics, but no difference in 14-3-3η expression, and higher expression of 14-3-3σ in both areas. Levels of 14-3-3ζ and ε transcripts were significantly lower only in alcoholic motor cortex. CONCLUSIONS: Altered 14-3-3 expression could contribute to synaptic dysfunction and altered neurotransmission in chronic alcohol misuse by human subjects.

Analysis of the MTHFR C677T variant with migraine phenotypes.

BACKGROUND: The methylenetetrahydrofolate reductase (MTHFR) gene variant C677T has been implicated as a genetic risk factor in migraine susceptibility, particularly in Migraine with Aura. Migraine, with and without aura (MA and MO) have many diagnostic characteristics in common. It is postulated that migraine symptomatic characteristics might themselves be influenced by MTHFR. Here we analysed the clinical profile, migraine symptoms, triggers and treatments of 267 migraineurs previously genotyped for the MTHFR C677T variant. The chi-square test was used to analyse all potential relationships between genotype and migraine clinical variables. Regression analyses were performed to assess the association of C677T with all migraine clinical variables after adjusting for gender. FINDINGS: The homozygous TT genotype was significantly associated with MA (P < 0.0001) and unilateral head pain (P = 0.002). While the CT genotype was significantly associated with physical activity discomfort (P < 0.001) and stress as a migraine trigger (P = 0.002). Females with the TT genotype were significantly associated with unilateral head pain (P < 0.001) and females with the CT genotype were significantly associated with nausea (P < 0.001), osmophobia (P = 0.002), and the use of natural remedy for migraine treatment (P = 0.003). Conversely, male migraineurs with the TT genotype experienced higher incidences of bilateral head pain (63% vs 34%) and were less likely to use a natural remedy as a migraine treatment compared to female migraineurs (5% vs 20%). CONCLUSIONS: MTHFR genotype is associated with specific clinical variables of migraine including unilateral head pain, physical activity discomfort and stress.

Genetics of menstrual migraine: the molecular evidence.

Migraine is considered to be a multifactorial disorder in which genetic, environmental, and, in the case of menstrual and menstrually related migraine, hormonal events influence the phenotype. Certainly, the role of female sex hormones in migraine has been well established, yet the mechanism behind this well-known relationship remains unclear. This review focuses on the potential role of hormonally related genes in migraine, summarizes results of candidate gene studies to date, and discusses challenges and issues involved in interpreting hormone-related gene results. In light of the molecular evidence presented, we discuss future approaches for analysis with the view to elucidate the complex genetic architecture that underlies the disorder.

The effects of vitamin supplementation and MTHFR (C677T) genotype on homocysteine-lowering and migraine disability.

BACKGROUND: Migraine is a prevalent and debilitating disease that may, in part, arise because of disruption in neurovascular endothelia caused by elevated homocysteine. This study examined the homocysteine-lowering effects of vitamin supplementation on migraine disability, frequency and severity and whether MTHFRC677T genotype influenced treatment response. METHODS: This was a randomized, double-blind placebo, controlled trial of 6 months of daily vitamin supplementation (i.e. 2 mg of folic acid, 25 mg vitamin B6, and 400 microg of vitamin B12) in 52 patients diagnosed with migraine with aura. FINDINGS: Vitamin supplementation reduced homocysteine by 39% (approximately 4 mumol/l) compared with baseline, a reduction that was greater then placebo (P=0.001). Vitamin supplementation also reduced the prevalence of migraine disability from 60% at baseline to 30% after 6 months (P=0.01), whereas no reduction was observed for the placebo group (P>0.1). Headache frequency and pain severity were also reduced (P<0.05), whereas there was no reduction in the placebo group (P>0.1). In this patient group the treatment effect on both homocysteine levels and migraine disability was associated with MTHFRC677T genotype whereby carriers of the C allele experienced a greater response compared with TT genotypes (P<0.05). INTERPRETATION: This study provides some early evidence that lowering homocysteine through vitamin supplementation reduces migraine disability in a subgroup of patients. Larger trials are now warranted to establish whether vitamin therapy is a safe, inexpensive and effective prophylactic option for treatment of migraine and whether efficacy is dependant on MTHFRC677T genotype.

Investigation of gamma-aminobutyric acid (GABA) A receptors genes and migraine susceptibility.

BACKGROUND: Migraine is a neurological disorder characterized by recurrent attacks of severe headache, affecting around 12% of Caucasian populations. It is well known that migraine has a strong genetic component, although the number and type of genes involved is still unclear. Prior linkage studies have reported mapping of a migraine gene to chromosome Xq 24-28, a region containing a cluster of genes for GABA A receptors (GABRE, GABRA3, GABRQ), which are potential candidate genes for migraine. The GABA neurotransmitter has been implicated in migraine pathophysiology previously; however its exact role has not yet been established, although GABA receptors agonists have been the target of therapeutic developments. The aim of the present research is to investigate the role of the potential candidate genes reported on chromosome Xq 24-28 region in migraine susceptibility. In this study, we have focused on the subunit GABA A receptors type epsilon (GABRE) and type theta (GABRQ) genes and their involvement in migraine. METHODS: We have performed an association analysis in a large population of case-controls (275 unrelated Caucasian migraineurs versus 275 controls) examining a set of 3 single nucleotide polymorphisms (SNPs) in the coding region (exons 3, 5 and 9) of the GABRE gene and also the I478F coding variant of the GABRQ gene. RESULTS: Our study did not show any association between the examined SNPs in our test population (P>0.05). CONCLUSION: Although these particular GABA receptor genes did not show positive association, further studies are necessary to consider the role of other GABA receptor genes in migraine susceptibility.

A pharmacogenomic evaluation of migraine therapy.

Migraine is a common idiopathic primary headache disorder with significant mental, physical and social health implications. Accompanying an intense unilateral pulsating head pain other characteristic migraine symptoms include nausea, emesis, phonophobia, photophobia and in approximately 20-30% of migraine cases, neurologic disturbances associated with the aura phase. Although selective serotonin (5-HT) receptor agonists (i.e., 5-HT(1B/1D)) are successful in alleviating migrainous symptoms in < or = 70% of known sufferers, for the remaining 30%, additional migraine abortive medications remain unsuccessful, not tested or yet to be identified. Genetic characterization of the migrainous disorder is making steady progress with an increasing number of genomic susceptibility loci now identified on chromosomes 1q, 4q, 5q, 6p, 11q, 14q, 15q, 17p, 18q, 19p and Xq. The 4q, 5q, 17p and 18q loci involve endophenotypic susceptibility regions for various migrainous symptoms. In an effort to develop individualized pharmacotherapeutics, the identification of these migraine endophenotypic loci may well be the catalyst needed to aid in this goal. In this review the authors discuss the present treatment of migraine, known genomic susceptibility regions and results from migraine (genetic) association studies. The authors also discuss pharmacogenomic considerations for more individualized migraine prophylactic treatments.

Association analysis of chromosome 1 migraine candidate genes.

BACKGROUND: Migraine with aura (MA) is a subtype of typical migraine. Migraine with aura (MA) also encompasses a rare severe subtype Familial Hemiplegic Migraine (FHM) with several known genetic loci. The type 2 FHM (FHM-2) susceptibility locus maps to chromosome 1q23 and mutations in the ATP1A2 gene at this site have recently been implicated. We have previously provided evidence of linkage of typical migraine (predominantly MA) to microsatellite markers on chromosome 1, in the 1q31 and 1q23 regions. In this study, we have undertaken a large genomic investigation involving candidate genes that lie within the chromosome 1q23 and 1q31 regions using an association analysis approach. METHODS: We have genotyped a large population of case-controls (243 unrelated Caucasian migraineurs versus 243 controls) examining a set of 5 single nucleotide polymorphisms (SNPs) and the Fas Ligand dinucleotide repeat marker, located within the chromosome 1q23 and 1q31 regions. RESULTS: Several genes have been studied including membrane protein (ATP 1 subtype A4 and FasL), cytoplasmic glycoprotein (CASQ 1) genes and potassium (KCN J9 and KCN J10) and calcium (CACNA1E) channel genes in 243 migraineurs (including 85% MA and 15% of migraine without aura (MO)) and 243 matched controls. After correction for multiple testing, chi-square results showed non-significant P values (P > 0.008) across all SNPs (and a CA repeat) tested in these different genes, however results with the KCN J10 marker gave interesting results (P = 0.02) that may be worth exploring further in other populations. CONCLUSION: These results do not show a significant role for the tested candidate gene variants and also do not support the hypothesis that a common chromosome 1 defective gene influences both FHM and the more common forms of migraine.