Migraine is a frequent debilitating neurological disorder that is considered to be genetically complex with a multifactorial mode of inheritance. It has a high prevalence with approximately 18% of women and 6% of men suffering from the disorder. Migraine is characterized by severe head pain with associated nausea, emesis, photophobia, phonophobia, and neurological disturbances. The International Headache Society (IHS) has classified various types of migraine according to their clinical features. The two main subtypes of migraine are migraine without aura (MO), occurring in ~70-75% of migraineurs, and migraine with aura (MA) which occurs in ~25% of migraineurs. Some people experience both types of attack in their lives. While the precise pathogenesis of migraine is unknown, it is widely accepted that short-term alterations in neuronal activity occur in relation to the attack, along with temporary changes in the cerebral vasculature. Trigeminal nerve activation is also considered pivotal to progression of a migraine attack. Neurotransmitters, especially serotonin (5-hydroxytryptamine, 5-HT), platelet activation and sympathetic hyperactivity all appear to play a part, whether as part of the primary triggering event, or as a response mechanism. Migraine imparts a significant burden on society, both socially and financially. The World Health Organization has identified migraine among the world's top 20 leading causes of disability, with an impact that extends far beyond individual suffering. There is significant evidence from family and twin studies to indicate a strong genetic component to migraine. The current understanding of migraine is that it is a polygenic multifactorial disorder. It has been postulated that genetic factors set the individual migraine threshold, with environmental influences playing a modulating role. It is likely that many genes may provide an important although moderate contribution to an individuals migraine susceptibility. The identification of migraine susceptibility genes has been the focus of substantial research to date and could eventually lead to improved treatments and greater understanding of the disorder. Several loci have shown promise, although these need to be followed up by both replication and functional studies to determine a definitive causative role. This research investigated the role of both hormonal and vascular related genes as candidate genes that may play a role in migraine susceptibility due to the well-known role of hormones and vascular changes in some migraineurs. The estrogen receptor (ESR) and progesterone receptor (PGR) genes are potential migraine candidates due to the recognized hormonal influence on migraine susceptibility. Migraines in women frequently occur during the childbearing years and are often influenced by significant hormonal milestones. The fluctuating hormone levels of the menstrual cycle have been implicated in migraine but a definitive role is yet to be established. It has been suggested that factors additional to circulating hormone levels may be at play. This research considered that variation in the ESR 1 and PGR genes may confer an increased migraine risk. To investigate the potential role of these genes in migraine, association studies investigating variants in ESR 1 and PGR were undertaken in two independent casecontrol cohorts. This was followed up by mutation screening and gene expression analysis in an effort to elucidate a functional role for these genes in the pathogenesis of migraine. Vascular genes also represent likely migraine candidates as alterations in both vascular function and cerebral blood flow are well known in migraine. Furthermore, cortical spreading depression (CSD), a depolarization wave that propagates across the brain cortex and has been speculated to cause the neurological symptoms that present in MA, has also been linked to vascular dysfunction. The methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MTRR) genes both play a role in vascular functioning and were thus considered potential migraine candidates for this study. Both are involved in the pathway of homocysteine metabolism. Impaired activity of these enzymes can lead to mild hyperhomocysteinemia which is believed to lead to oxidative arterial damage. This may in turn impact on migraine susceptibility, possibly through the activation of trigeminal fibres. The MTHFR 677T allele results in an amino acid change in the catalytic domain of the enzyme leading to mild hyperhomocysteinemia. This particular variant has been implicated in migraine in four separate studies. One of these studies also suggested a role for the MTHFR 1298C allele in migraine. This allele also results in an amino acid change and reduced enzyme activity. Similarly, the MTRR 66G allele results in an amino acid change and has been associated with reduced activity of MTRR and increased plasma homocysteine concentration. To investigate the role of the ESR 1, PGR, MTHFR and MTRR genes in migraine, samples from two large independent case control cohorts were investigated. Cohort 1 was comprised of 275 migraineur samples and 275 age, sex and ethnicity matched controls while cohort 2 comprised 300 cases and 300 matched controls. All individuals were collected at the Genomics Research Centre with migraine diagnosis undertaken by HIS criteria and migraine affected individuals designated as MO or MA. Results of analysis of ESR 1 indicated a positive association with migraine in the two large independent cohorts for the exon 8 G594A polymorphism (P = 0.003; P = 8x10-6). Similarly, the PGR analysis showed a positive association with migraine for the PROGINS allele (P = 0.02; P = 0.003). Results also showed that individuals with both ESR 1 and PGR susceptibility alleles were 3.2 times more likely to suffer migraine those those with no susceptibility alleles. As the ESR 1 variant is synonymous, a mutation analysis was undertaken in a small sub-sample of individuals carrying the susceptibility allele, but no mutations were detected in these particular samples. Detailed mutation analysis of ESR 1 in a larger study group may be warranted. An ESR 1 and PGR expression analysis by RT-PCR was undertaken to examine if there were any notable expression level changes in migraineurs versus controls and additionally whether the susceptibility genotypes influenced gene expression. Altered expression levels may point to a functional change in the gene. Although results did not show any significant difference in expression levels in the case/control group, nor any influence in gene expression conferred by the specific susceptibility genotypes, ESR 1 expression did appear to be down-regulated in the migraine group and more specifically in the migraine susceptibility genotype subgroup. A larger study group may therefore be warranted to detect any potential genuine changes in gene expression. Overall, these results suggested that these hormonal genes appear to play a role in migraine susceptibility, although further studies are needed to define this. Results of the MTHFR 677 analysis showed that the TT genotype was significantly associated with the MA subgroup in a joint analysis of the two independent cohorts (P = 0.004). Results of analysis of MTHFR 1298, which is tightly linked to the 677 locus, showed a significant association in female migraineurs (P = 0.009). Similarly, results of the MTRR analysis also showed a significant difference between the female case and control groups with the G allele over-represented in female migraineurs (P = 0.022) These results may indicate that a significant gender effect appears in this locus as well as the MTHFR 1298 locus although results may also be due to a larger number of female migraineurs conferring increased statistical power to the gender subgroup. Interaction analysis of the MTHFR 1298 locus and the MTRR locus showed that females who carried both variants under a recessive model were 5 times more likely to suffer migraine those those with no susceptibility genotypes. Overall these results indicated that these vascular genes appear to play a role in migraine susceptibility. The final study focused on 6 genetic variants that had shown a positive association with migraine and/or MA in the same large association population analysed in this research. The aim of this study was to provide preliminary data on the potential role of genetic profiling in migraine. Using the genotypic data to create vascular and hormonal risk profiles based on positive association and interaction of MTHFR 677 T and ACE D alleles, and MTHFR 1298 AA and MTRR GG genotypes as vascular variants; and positive association and interaction of ESR 1 594 A and PGR PROGINS as hormonal variants, this study was able to demonstrate the relevance of genetic risk profiling to migraine. Results showed a significantly higher proportion of individuals with at least one genetic risk profile in the migraine group compared to those in the control group (P = 6 x 10-6). Individuals who possessed either the vascular and/or hormonal genetic risk profile were 8.6 times more likely to suffer from migraine than those who possessed a no risk profile. This indicated a greater effect than the individual effect of each of these variants. Furthermore individuals who possessed a vascular or both risk profiles were more likely to suffer nausea, emesis, phonophobia and photophobia, and have a mother who also suffered migraine. Overall, the genetic profiling approach provided interesting preliminary data on migraine susceptibility and indicated that such an approach may prove very useful for migraine diagnosis, particularly when all migraine genes have been identified. In conclusion this study provided the first indication that hormone receptor genes play a role in migraine susceptibility. Hormones have long been considered to play a role in the disorder but this study has provided the first molecular evidence to support this premise. In addition, this study showed that vascular related genes also play a role in migraine susceptibility. Finally, this study has clearly shown that migraine is a complex disorder involving multiple genes. Although a number of studies have implicated neurotransmitter related genes in the disorder, the present study is the first to show that both vascular and hormonal genes also play a role in migraine susceptibility. Thus there now appear to be three classes of genes that affect migraine susceptibility and although this study has implicated new variants, the preliminary genetic profiling study has shown that not all predisposing variants involved in the disorder have been defined.
| Identifer | oai:union.ndltd.org:ADTP/194981 |
| Date | January 2007 |
| Creators | Colson, Natalie, n/a |
| Publisher | Griffith University. School of Medical Science |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | http://www.gu.edu.au/disclaimer.html), Copyright Natalie Colson |
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