Association study of calcitonin gene-related polypeptide-alpha (CALCA) gene polymorphism with migraine

Migraine is a neurological disorder that is associated with increased levels of calcitonin gene-related peptide (CGRP) in plasma. CGRP, being one of the mediators of neurogenic inflammation and a phenomenon implicated in the pathogenesis of migraine headache, is thus suggested to have an important role in migraine pathophysiology. Polymorphisms of the CALCA gene have been linked to Parkinson's disease, ovarian cancer and essential hypertension, suggesting a functional role for these polymorphisms. Given the strong evidence linking CGRP and migraine, it is hypothesised that polymorphisms in the CALCA gene may play a role in migraine pathogenesis. Seemingly non functional intronic polymorphisms are capable of disrupting normal RNA processing or introducing a splice site in the transcript. A 16 bp deletion in the first intron of the CALCA gene has been reported to be a good match for the binding site for a transcription factor expressed strongly in neural crest derived cells, AP-2. This deletion also eliminates an intron splicing enhancer (ISE) that may potentially cause exon skipping. This study investigated the role of the 16 bp intronic deletion in the CALCA gene in migraineurs and matched control individuals. Six hundred individuals were genotyped for the deletion by polymerase chain reaction followed by fragment analysis on the 3130 Genetic Analyser. The results of this study showed no significant association between the intronic 16 bp deletion in the CALCA gene and migraine in the tested Australian Caucasian population. However, given the evidence linking CGRP and migraine, further investigation of variants with this gene may be warranted.

Genome-wide association study reveals three susceptibility loci for common migraine in the general population

Migraine is a common, heterogeneous and heritable neurological disorder. Its pathophysiology is incompletely understood, and its genetic influences at the population level are unknown. In a population-based genome-wide analysis including 5,122 migraineurs and 18,108 non-migraineurs, rs2651899 (1p36.32, PRDM16), rs10166942 (2q37.1, TRPM8) and rs11172113 (12q13.3, LRP1) were among the top seven associations (P < 5 × 10(-6)) with migraine. These SNPs were significant in a meta-analysis among three replication cohorts and met genome-wide significance in a meta-analysis combining the discovery and replication cohorts (rs2651899, odds ratio (OR) = 1.11, P = 3.8 × 10(-9); rs10166942, OR = 0.85, P = 5.5 × 10(-12); and rs11172113, OR = 0.90, P = 4.3 × 10(-9)). The associations at rs2651899 and rs10166942 were specific for migraine compared with non-migraine headache. None of the three SNP associations was preferential for migraine with aura or without aura, nor were any associations specific for migraine features. TRPM8 has been the focus of neuropathic pain models, whereas LRP1 modulates neuronal glutamate signaling, plausibly linking both genes to migraine pathophysiology.

Identification of molecular genetic factors that influence migraine

Migraine is a common neurological disorder with a strong genetic basis. However, the complex nature of the disorder has meant that few genes or susceptibility loci have been identified and replicated consistently to confirm their involvement in migraine. Approaches to genetic studies of the disorder have included analysis of the rare migraine subtype, familial hemiplegic migraine with several causal genes identified for this severe subtype. However, the exact genetic contributors to the more common migraine subtypes are still to be deciphered. Genome-wide studies such as genome-wide association studies and linkage analysis as well as candidate genes studies have been employed to investigate genes involved in common migraine. Neurological, hormonal and vascular genes are all considered key factors in the pathophysiology of migraine and are a focus of many of these studies. It is clear that the influence of individual genes on the expression of this disorder will vary. Furthermore, the disorder may be dependent on gene–gene and gene–environment interactions that have not yet been considered. In addition, identifying susceptibility genes may require phenotyping methods outside of the International Classification of Headache Disorders II criteria, such as trait component analysis and latent class analysis to better define the ambit of migraine expression.

Communicating personal amnesty : a model for health promotion in an Australian disability context

Currently pathological and illness-centric policy surrounds the evaluation of the health status of a person experiencing disability. In this research partnerships were built between disability service providers, community development organizations and disability arts organizations to build a translational evaluative methodology prior to implementation of an arts-based workshop that was embedded in a strengths-based approach to health and well-being. The model consisted of three foci: participation in a pre-designed drama-based workshop program; individualized assessment and evaluation of changing health status; and longitudinal analysis of participants changing health status in their public lives following the culmination of the workshop series. Participants (n = 15) were recruited through disability service providers and disability arts organizations to complete a 13-week workshop series and public performance. The study developed accumulative qualitative analysis tools and member-checking methods specific to the communication systems used by individual participants. Principle findings included increased confidence for verbal and non-verbal communicators; increased personal drive, ambition and goal-setting; increased arts-based skills including professional engagements as artists; demonstrated skills in communicating perceptions of health status to private and public spheres. Tangential positive observations were evident in the changing recreational, vocational and educational activities participants engaged with pre- and post- the workshop series; participants advocating for autonomous accommodation and health provision and changes in the disability service staff's culture. The research is an example of translational health methodologies in disability studies.

A dominant-negative mutation in the TRESK potassium channel is linked to familial migraine with aura

Migraine with aura is a common, debilitating, recurrent headache disorder associated with transient and reversible focal neurological symptoms. A role has been suggested for the two-pore domain (K2P) potassium channel, TWIK-related spinal cord potassium channel (TRESK, encoded by KCNK18), in pain pathways and general anaesthesia. We therefore examined whether TRESK is involved in migraine by screening the KCNK18 gene in subjects diagnosed with migraine. Here we report a frameshift mutation, F139WfsX24, which segregates perfectly with typical migraine with aura in a large pedigree. We also identified prominent TRESK expression in migraine-salient areas such as the trigeminal ganglion. Functional characterization of this mutation demonstrates that it causes a complete loss of TRESK function and that the mutant subunit suppresses wild-type channel function through a dominant-negative effect, thus explaining the dominant penetrance of this allele. These results therefore support a role for TRESK in the pathogenesis of typical migraine with aura and further support the role of this channel as a potential therapeutic target.

Investigation of the [−/A]8 and C1236T genetic variations within the human toll-like receptor 3 gene for association with multiple sclerosis

Multiple sclerosis (MS) is a serious cause of neurological disability among young adults. The clinical course remains difficult to predict, and the pathogenesis of the disease is still modestly understood. Autoimmunity is thought to be a key aspect of the disease, with autoreactive T cells thought to mediate central nervous system (CNS) inflammation to some extent. Toll-like receptors are known to mediate cellular recognition of pathogens by way of patterns of molecular presentation. Toll-like receptor 3 is coded by the gene TLR3 and is recognized as an important factor in virus recognition and is known to be involved in the expression of neuroprotective mediators. We set out to investigate two variations within the TLR3 gene, an 8 bp insertion-deletion \[-/A](8) and a single base-pair variation C1236T, in subjects with MS and matched healthy controls to determine whether significant differences exist in these markers in an Australian population. We used capillary gel electrophoresis and TaqMan genotyping assay techniques to resolve genotypes for each marker, respectively. Our work found no significant difference between frequencies for TLR3 \[-/A](8) by genotype (chi(2)=1.03, p=0.60) or allele (chi(2)=1.09, p=0.30). Similarly, we found no evidence for the association of TLR3 C1236T by genotype (chi(2)=0.35, p=0.84) or allele frequency (chi(2)=0.31, p=0.58). This work reveals no evidence to suggest that these markers are associated with MS in the tested population. Although the role of TLR3 and the wider toll-like receptor family remain significant in neurological and CNS inflammatory disorders, our current work does not support a role for the two tested variants in this gene with regard to MS susceptibility.

An investigation of the C77G and C772T variations within the human protein tyrosine phosphatase receptor type C gene for association with multiple sclerosis in an Australian population

Multiple sclerosis (MS) is a common cause of neurological disability in young adults. The disease generally manifests in early to middle adulthood and causes various neurological deficits. Autoreactive T lymphocytes and their associated antigens have long been presumed important features of MS pathogenesis. The Protein tyrosine phosphatase receptor type C gene (PTPRC) encodes the T-cell receptor CD45. Variations within PTPRC have been previously associated with diseases of autoimmune origin such as type 1 diabetes mellitus and Graves' disease. We set out to investigate two variants within the PTPRC gene, C77G and C772T in subjects with MS and matched healthy controls to determine whether significant differences exist in these markers in an Australian population. We employed high resolution melt analysis (HRM) and restriction length polymorphism (RFLP) techniques to determine genotypic and allelic frequencies. Our study found no significant difference between frequencies for PTPRC C77G by either genotype (Χ2 = 0.65, P = 0.72) or allele (Χ2 = 0.48, P = 0.49). Similarly, we did not find evidence to suggest an association between PTPRC C772T by genotype (Χ2 = 1.06, P = 0.59) or allele (Χ2 = 0.20, P = 0.66). Linkage disequilibrium (LD) analysis showed strong linkage disequilibrium between the two tested markers (D' = 0.9970, SD = 0.0385). This study reveals no evidence to suggest that these markers are associated with MS in the tested Australian Caucasian population. Although the PTPRC gene has a significant role in regulating CD4+ and CD8+ autoreactive T-cells, interferon-beta responsiveness, and potentially other important processes, our study does not support a role for the two tested variants of this gene in MS susceptibility in the Australian population.

Association between migraine and a functional polymorphism at the dopamine β-hydroxylase locus

Migraine is a common neurological disorder with a significant genetic component. Although a number of linkage and association studies have been undertaken, the number and identity of all migraine susceptibility genes has yet to be defined. The existence of dopaminergic hypersensitivity in migraine has been recognised on a pharmacological basis and some studies have reported genetic association between migraine and dopamine-related gene variants. Our laboratory has previously reported association of migraine with a promoter STR marker in the dopamine beta hydroxylase (DBH) gene. In the present study, we analysed two additional DBH markers in two independent migraine case–control cohorts. These two markers are putative functional SNPs, one within the promoter (−1021C→T) and another SNP (+1603C→T) in exon 11 of the DBH gene. The results showed a significant association for allelic and genotypic frequency distribution between the DBH marker in the promoter and migraine in the first (P = 0.004 and P = 0.012, respectively) and the second (P = 0.013 and P = 0.031, respectively) tested cohorts. There was no association observed between either genotype and/or allelic frequencies for the DBH marker located in exon 11 and migraine (P ≥ 0.05). The promoter DBH marker, reported associated with migraine in this study, has been shown to affect up to 52% of plasma DBH activity. Varying DBH activity levels have been postulated to be involved in migraine process with an increase of dopamine, resulting from a lower DBH activity shown positively correlated with migraine severity. It is plausible that the functional promoter variant of DBH may play a role in the migraine disorder.

Study of leukemia inhibitory factor polymorphism within an Australian multiple sclerosis population

OBJECTIVE: To examine a polymorphism within the 3' untranslated region of the leukemia inhibitory factor gene for an association with multiple sclerosis within an Australian case-control population. METHODS: A test group of 121 unrelated multiple sclerosis patients, of Caucasian origin, and 121 controls, matched for ethnicity, sex and age (+/-5 years) were included in the study. The LIF 3' UTR StuI polymorphism was genotyped by restriction fragment length polymorphism analysis. Statistical analysis of genotype and allele frequencies included Hardy-Weinberg law and conventional contingency table analysis incorporating the standard chi-squared test for independence. RESULTS: Allelic and genotype frequencies did not demonstrate a significant association between the case and control groups for the tested LIF 3' UTR StuI polymorphism. CONCLUSION: The results indicate that the LIF 3' UTR StuI polymorphism is not associated with multiple sclerosis, however we cannot exclude the hypothesis that other polymorphic alleles of LIF could be implicated in MS susceptibility.

Predictors of mental health in post-menopausal women : results from the Australian healthy aging of women study

Objective: To examine the extent to which socio-demographics, modifiable lifestyle, and physical health status influence the mental health of post-menopausal Australian women. Methods: Cross-sectional data on health status, chronic disease and modifiable lifestyle factors were collected from a random cross-section of 340 women aged 60-70 years, residing in Queensland, Australia. Structural equation modelling (SEM) was used to measure the effect of a range of socio-demographic characteristics, modifiable lifestyle factors, and health markers (self-reported physical health, history of chronic illness) on the latent construct of mental health status. Mental health was evaluated using the Medical Outcomes Study Short Form 12 (SF-12®) which examined and Center for Epidemiologic Studies Depression Scale (CES-D). Results: The model was a good fit for the data (χ2=4.582, df=3, p=0.205) suggesting that mental health is negatively correlated with sleep disturbance (β = -0.612, p <0.001), and a history of depression (β = -0.141, p = 0.024).While mental health was associated with poor sleep, it was not correlated with most lifestyle factors (BMI, alcohol consumption, or cigarette smoking) or socio-demographics like age, income or employment category and they were removed from the final model. Conclusion: Research suggests that it is important to engage in a range of health promoting behaviours to preserve good health. We found that predictors of current mental health status included sleep disturbance, and past mental health problems, while socio-demographics and modifiable lifestyle had little impact. It may be however, that these factors influenced other variables associated with the mental health of post-menopausal women, and these relationships warrant further investigation.

Prevalence and correlates of sleep disturbance in post-menopausal Australian women : the Healthy Aging of Women (HOW) study

Background: Sleep disturbance in midlife women has been studied extensively, although less is known about sleep after menopause. This study examined the relative impact of socio-demographics, modifiable lifestyle factors, and health status on sleep disturbance in post-menopausal women from Queensland, Australia. Methods: The longitudinal Healthy Aging of Women (HOW) study examines health-related quality of life (HRQOL measured by SF-12©), chronic illness, modifiable lifestyle factors such as physical activity, alcohol consumption, smoking, and sleep disturbance (General Sleep Disturbance Scale, GSDS ≥ 43 represent poor sleep) in midlife and older women from low and high socio-economic, rural and urban areas of South-East Queensland, Australia. This paper presents cross-sectional data from the 322 women, aged 60-70 years, participating in the HOW study in 2011. Results: For women in this study, sleep disturbance was relatively common, with 23% (n = 83) reporting poor sleeping (GSDS ≥ 43). Sleep disturbance scores were strongly correlated with being unemployed or on a disability support pension (β = 18.69, P < 0.01), sedentary lifestyle (β = 23.84, P < 0.01), and lower mental (β = -0.60, P <0.01) and physical health-related quality of life scores (β = -0.32, P = 0.01), and these variables explained almost one third of variance in sleep disturbance scores (ηρ² = 29%). Conclusions: Multivariable analysis revealed that sleep disturbance was correlated with physical and mental health-related quality of life, disability, and sedentary lifestyle, but not other lifestyle and socio-demographic characteristics. It may be however, that modifiable lifestyle factors may indirectly impact on sleep by influencing health status.

Investigation between the S377G3 GATA-4 polymorphism and migraine

Migraine is a common and painful neurological disorder, with genetic and environmental components. Several conditions have been shown to be comorbid with migraine, notably a cardiac malformation affecting the interatrial septum and leading to patent foramen ovale (PFO). Mutations in the development regulatory gene GATA-4, located on human chromosome 8p23.1-p22, have been found to be responsible for some cases of congenital heart defects including PFO. To determine whether the GATA-4 gene is involved in migraine, the present study performed an association analysis of a common GATA-4 variant that results in a change of amino acid (S377G), in a large case/control population (275 unrelated Caucasian migraineurs versus 275 control individuals). The results showed that there was no significant association for this polymorphism between migraine and controls (χ² = 0.84, P = 0.66). Thus it appears that the GATA-4 (S377G) mutation does not play a significant role in common migraine susceptibility.

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 ε (GABRE) and type θ (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.

Allelic variation investigation of the estrogen receptor within an Australian multiple sclerosis population

Multiple Sclerosis (MS) is a central nervous system (CNS) chronic inflammatory demyelinating disease leading to various neurological disabilities. The disorder is more prevalent for women with a ratio of 3:2 female to male. Objectives: To investigate variation within the estrogen receptor 1 (ESR1) polymorphism gene in an Australian MS case-control population using two intragenic restriction fragment length polymorphisms; the G594A located in exon 8 detected with the BtgI restriction enzyme and T938C located in intron 1, detected with PvuII. One hundred and ten Australian MS patients were studied, with patients classified clinically as Relapsing Remitting MS (RR-MS), Secondary Progressive MS (SP-MS) or Primary Progressive MS (PP-MS). Also, 110 age, sex and ethnicity matched controls were investigated as a comparative group. No significant difference in the allelic distribution frequency was found between the case and control groups for the ESR1 PvuII (P = 0.50) and Btg1 (P = 0.45) marker. Our results do not support a role for these two ESR1 markers in multiple sclerosis susceptibility, however other markers within ESR1 should not be excluded for potential involvement in the disorder.

Gene expression studies in multiple sclerosis

Multiple sclerosis (MS) is a serious neurological disorder affecting young Caucasian individuals, usually with an age of onset at 18 to 40 years old. Females account for approximately 60x of MS cases and the manifestation and course of the disease is highly variable from patient to patient. The disorder is characterised by the development of plaques within the central nervous system (CNS). Many gene expression studies have been undertaken to look at the specific patterns of gene transcript levels in MS. Human tissues and experimental mice were used in these gene-profiling studies and a very valuable and interesting set of data has resulted from these various expression studies. In general, genes showing variable expression include mainly immunological and inflammatory genes, stress and antioxidant genes, as well as metabolic and central nervous system markers. Of particular interest are a number of genes localised to susceptible loci previously shown to be in linkage with MS. However due to the clinical complexity of the disease, the heterogeneity of the tissues used in expression studies, as well as the variable DNA chips/membranes used for the gene profiling, it is difficult to interpret the available information. Although this information is essential for the understanding of the pathogenesis of MS, it is difficult to decipher and define the gene pathways involved in the disorder. Experiments in gene expression profiling in MS have been numerous and lists of candidates are now available for analysis. Researchers have investigated gene expression in peripheral mononuclear white blood cells (PBMCs), in MS animal models Experimental Allergic Encephalomyelitis (EAE) and post mortem MS brain tissues. This review will focus on the results of these studies.