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.

Shorter telomere length in peripheral blood cells associated with migraine in women

Objective To evaluate relative telomere length of female migraine patients. Background Migraine is a debilitating disorder affecting 6-28% of the population. Studies on the mechanisms of migraine have demonstrated genetic causes but the pathophysiology and subcellular effects of the disease remain poorly understood. Shortened telomere length is associated with age-related or chronic diseases, and induced stresses. Migraine attacks may impart significant stress on cellular function, thus this study investigates a correlation between shortening of telomeres and migraine. Methods Relative telomere length was measured using a previously described quantitative polymerase chain reaction method. A regression analysis was performed to assess differences in mean relative telomere length between migraine patients and healthy controls. Results The leukocyte telomeres of a cohort of 142 Caucasian female migraine subjects aged 18-77 years and 143 matched 17-77-year-old healthy control Caucasian women were examined.A significantly shorter relative telomere length was observed in the migraine group compared with the control group after adjusting for age and body mass index (P = .001). In addition, age of onset was observed to associate with the loss of relative telomere length, especially at early age of onset (<17 years old). No association was observed between relative telomere length and the severity and frequency of migraine attacks and the duration of migraine. Conclusion Telomeres are shorter in migraine patients and there is more variation in telomere length in migraine patients.

Genome-wide association study identifies new multiple sclerosis susceptibility loci on chromosomes 12 and 20

To identify multiple sclerosis (MS) susceptibility loci, we conducted a genome-wide association study (GWAS) in 1,618 cases and used shared data for 3,413 controls. We performed replication in an independent set of 2,256 cases and 2,310 controls, for a total of 3,874 cases and 5,723 controls. We identified risk-associated SNPs on chromosome 12q13-14 (rs703842, P = 5.4 x 10(-11); rs10876994, P = 2.7 x 10(-10); rs12368653, P = 1.0 x 10(-7)) and upstream of CD40 on chromosome 20q13 (rs6074022, P = 1.3 x 10(-7); rs1569723, P = 2.9 x 10(-7)). Both loci are also associated with other autoimmune diseases. We also replicated several known MS associations (HLA-DR15, P = 7.0 x 10(-184); CD58, P = 9.6 x 10(-8); EVI5-RPL5, P = 2.5 x 10(-6); IL2RA, P = 7.4 x 10(-6); CLEC16A, P = 1.1 x 10(-4); IL7R, P = 1.3 x 10(-3); TYK2, P = 3.5 x 10(-3)) and observed a statistical interaction between SNPs in EVI5-RPL5 and HLA-DR15 (P = 0.001).

Principal component and linkage analysis of cardiovascular risk traits in the Norfolk isolate

OBJECTIVE(S): An individual's risk of developing cardiovascular disease (CVD) is influenced by genetic factors. This study focussed on mapping genetic loci for CVD-risk traits in a unique population isolate derived from Norfolk Island. METHODS: This investigation focussed on 377 individuals descended from the population founders. Principal component analysis was used to extract orthogonal components from 11 cardiovascular risk traits. Multipoint variance component methods were used to assess genome-wide linkage using SOLAR to the derived factors. A total of 285 of the 377 related individuals were informative for linkage analysis. RESULTS: A total of 4 principal components accounting for 83% of the total variance were derived. Principal component 1 was loaded with body size indicators; principal component 2 with body size, cholesterol and triglyceride levels; principal component 3 with the blood pressures; and principal component 4 with LDL-cholesterol and total cholesterol levels. Suggestive evidence of linkage for principal component 2 (h(2) = 0.35) was observed on chromosome 5q35 (LOD = 1.85; p = 0.0008). While peak regions on chromosome 10p11.2 (LOD = 1.27; p = 0.005) and 12q13 (LOD = 1.63; p = 0.003) were observed to segregate with principal components 1 (h(2) = 0.33) and 4 (h(2) = 0.42), respectively. CONCLUSION(S): This study investigated a number of CVD risk traits in a unique isolated population. Findings support the clustering of CVD risk traits and provide interesting evidence of a region on chromosome 5q35 segregating with weight, waist circumference, HDL-c and total triglyceride levels.

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.

No role for estrogen receptor 1 gene intron 1 Pvu II and exon 4 C325G polymorphisms in migraine susceptibility

Background We have previously reported an association between the estrogen receptor 1 (ESR1) gene exon 8 G594A polymorphism and migraine susceptibility in two independent Australian cohorts. In this paper we report results of analysis of two further single nucleotide polymorphisms (SNPs) in the ESR1 gene in the same study group, the T/C Pvu II SNP in intron 1 and the C325G SNP in exon 4, as well as results of linkage disequilibrium (LD) analysis on these markers. Methods We investigated these variants by case-control association analysis in a cohort of 240 migraineurs and 240 matched controls. The SNPs were genotyped using specific restriction enzyme assays. Results were analysed using contingency table methods incorporating the chi-squared statistic. LD results are presented as D' statistics with associated P values. Results We found no evidence for association of the Pvu II T/C polymorphism and the C325G polymorphism and migraine susceptibility and no evidence for LD between these two SNPs and the previously implicated exon 8 G594A marker. Conclusion We have found no role for the polymorphisms in intron 1 and exon 4 with migraine susceptibility. To further investigate our previously implicated exon 8 marker, we suggest the need for studies with a high density of polymorphisms be undertaken, with particular focus on markers in LD with the exon 8 marker.

Phenotypical characterisation of the isolated Norfolk Island population focusing on epidemiological indicators of cardiovascular disease

Objectives Only 193 people from Pitcairn Island, all descended from 9 ‘Bounty’ mutineers and 12 Tahitian women, moved to the uninhabited Norfolk Island in 1856. Our objective was to assess the population of Norfolk Island, several thousand km off the eastern coast of Australia, as a genetic isolate of potential use for cardiovascular disease (CVD) gene mapping. Methods A total of 602 participants, approximately two thirds of the island’s present adult population, were characterized for a panel of CVD risk factors. Statistical power and heritability were calculated. Results Norfolk Islander’s possess an increased prevalence of hypertension, obesity and multiple CVD risk factors when compared to outbred Caucasian populations. 64% of the study participants were descendents of the island’s original founder population. Triglycerides, cholesterol, and blood pressures all had heritabilities above 0.2. Conclusions The Norfolk land population is a potentially useful genetic isolate for gene mapping studies aimed at identifying CVD risk factor quantitative trait loci (QTL).

The role of vascular and hormonal genes in migraine susceptibility

Migraine is a primary headache disorder that involves both genetic and environmental components. Migraine is considered to be a polygenic disorder with a number of susceptibility genes having a minor but nonetheless significant impact on susceptibility. Migraine candidate gene studies have concentrated mainly on genes involved in neurotransmitter pathways, however evidence also exists for a role for alterations in vascular and hormonal function in migraine susceptibility. We present here a mini-review of genetic studies, investigating the potential role of vascular and hormonal gene variants, and discuss how vascular and hormonal dysfunction may impact on migraine susceptibility. We propose that the potential role of vascular and hormonal genes in this disorder warrants further investigation.

The Politics of Sex Trafficking : a Moral Geography

This book offers a unique insight into the moral politics behind the making of human trafficking policy in Australia and the United States of America. As governments around the world rush to meet their international obligations to combat human trafficking, a heated debate has emerged over the rights, wrongs, and harms of prostitution, and its relationship to sex trafficking. The Politics of Sex Trafficking identifies and challenges intrinsic notions of moral harm that have pervaded trafficking discourse and resulted in a distinctly anti-prostitution agenda in trafficking policy in recent decades. Including rare interviews with key political actors, this book charts the competing perspectives of feminist, faith-based, and sex-worker activists, and their efforts to influence policy-makers. This critical account of the creation of anti-trafficking policy challenges the sex trafficking narrative dominant in US Congressional and Australian Parliamentary hearings, and demonstrates the power of a moral politics in shaping policy. This book will appeal to academics across the fields of criminology, criminal justice, law, human rights and gender studies, as well as policy-makers.

Investigation of hormone receptor genes in migraine

Migraine is a common neurological condition with a complex mode of inheritance. Steroid hormones have long been implicated in migraine, although their role remains unclear. Our investigation considered that genes involved in hormonal pathways may play a role in migraine susceptibility. We therefore investigated the androgen receptor (AR) CAG repeat, and the progesterone receptor (PR) PROGINS insert by cross-sectional association analysis. The results showed no association with the AR CAG repeat in our study group of 275 migraineurs and 275 unrelated controls. Results of the PR PROGINS analysis showed a significant difference in the same cohort, and in an independent follow-up study population of 300 migraineurs and 300 unrelated controls. Analysis of the genotypic risk groups of both populations together indicated that individuals who carried the PROGINS insert were 1.8 times more likely to suffer migraine. Interaction analysis of the PROGINS variant with our previously reported associated ESR1 594A variant showed that individuals who possessed at least one copy of both risk alleles were 3.2 times more likely to suffer migraine. Hence, variants of these steroid hormone receptor genes appear to act synergistically to increase the risk of migraine by a factor of three.

The estrogen receptor 1 G594A polymorphism is associated with migraine susceptibility in two independent case/control groups

Migraine is a painful and debilitating disorder with a significant genetic component. Steroid hormones, in particular estrogen, have long been considered to play a role in migraine, as variations in hormone levels are associated with migraine onset in many sufferers of the disorder. Steroid hormones mediate their activity via hormone receptors, which have a wide tissue distribution. Estrogen receptors have been localized to the brain in regions considered to be involved in migraine pathogenesis. Hence it is possible that genetic variation in the estrogen receptor gene may play a role in migraine susceptibility. This study thus examined the estrogen receptor 1 (ESRα) gene for a potential role in migraine pathogenesis and susceptibility. A population-based cohort of 224 migraine sufferers and 224 matched controls were genotyped for the G594A polymorphism located in exon 8 of the ESR1 gene. Statistical analysis indicated a significant difference between migraineurs and non-migraineurs in both the allele frequencies (P=0.003) and genotype distributions (P=0.008) in this sample. An independent follow-up study was then undertaken using this marker in an additional population-based cohort of 260 migraine sufferers and 260 matched controls. This resulted in a significant association between the two groups with regard to allele frequencies (P=8×10−6) and genotype distributions (P=4×10−5). Our findings support the hypothesis that genetic variation in hormone receptors, in particular the ESR1 gene, may play a role in migraine.

A typical migraine susceptibility region localizes to chromosome 1q31

Migraine (with and without aura) is a prevalent neurovascular disease that shows strong familial aggregation, although the number of genes involved and the mode of inheritance is not clear. Some insight into the disease has been gained from genetic studies into a rare and very severe migraine subtype known as familial hemiplegic migraine (FHM). In this study, we took a family-based linkage and association approach to investigate the FHM susceptibility region on chromosome 1q31 for involvement in typical migraine susceptibility in affected Australian pedigrees. Initial multipoint ALLEGRO analysis provided strong evidence for linkage of Chrlq31 markers to typical migraine in a large multigenerational pedigree. The 1-LOD* unit support interval for suggestive linkage spanned approximately 18 cM with a maximum allele sharing LOD* score of 3.36 obtained for marker D1S2782 (P=0.00004). Subsequent analysis of an independent sample of 82 affected pedigrees added support to the initial findings with a maximum LOD* of 1.24 (P=0.008). Utilising the independent sample of 82 pedigrees, we also performed a family-based association test. Results of this analysis indicated distortion of allele transmission at marker D1S249 [global chi2 (5) of 15.00, P=0.010] in these pedigrees. These positive linkage and association results will need further confirmation by independent researchers. However, overall they provide good evidence for the existence of a typical migraine locus near these markers on Chrlq3l, and reinforce the idea that an FHM gene in this genomic region may also contribute to susceptibility to the more common forms of migraine.

Evidence for allelic association of the dopamine β-hydroxylase gene (DBH) with susceptibility to typical migraine

Migraine is a debilitating neurological disorder characterized by recurrent attacks of severe headache. The disorder is highly prevalent, affecting approximately 12% of Caucasian populations. It is well known that migraine has a strong genetic component, although the type and number of genes involved is not yet clear. However, the calcium channel gene, CACNA1A, on chromosome 19 contains mutations responsible for familial hemiplegic migraine, a rare and severe subtype of migraine. There is also evidence to suggest that serotonin- and dopamine-related genes may be involved in the pathogenesis of migraine. This study employed a linkage and association approach to investigate neurotransmitter-related migraine candidate genes. Polymorphisms within the dopamine beta-hydroxylase (DBH) gene, serotonin transporter gene (SERT), and dopamine receptor gene (DRD2) were tested in 177 unrelated Caucasian migraineurs and 182 control individuals. In addition, an independent sample of 82 families affected with migraine was examined. Unrelated case-control association analysis of a DBH intragenic dinucleotide polymorphism indicated altered allelic distribution between migraine and control groups (L2=16.53, P=0.019). Furthermore, the transmission/disequilibrium test, which was implemented on the family data, also indicated distortion of allele transmission for the same DBH marker (L2=4.44, P=0.035). Together, these results provide evidence for allelic association of the DBH gene with typical migraine susceptibility (Fisher's combined P value=0.006) and indicate that further research into the role of the DBH gene in the etiology of migraine is warranted.

Saliva-derived DNA performs well in large-scale, high-density single-nucleotide polymorphism microarray studies

As of June 2009, 361 genome-wide association studies (GWAS) had been referenced by the HuGE database. GWAS require DNA from many thousands of individuals, relying on suitable DNA collections. We recently performed a multiple sclerosis (MS) GWAS where a substantial component of the cases (24%) had DNA derived from saliva. Genotyping was done on the Illumina genotyping platform using the Infinium Hap370CNV DUO microarray. Additionally, we genotyped 10 individuals in duplicate using both saliva- and blood-derived DNA. The performance of blood- versus saliva-derived DNA was compared using genotyping call rate, which reflects both the quantity and quality of genotyping per sample and the “GCScore,” an Illumina genotyping quality score, which is a measure of DNA quality. We also compared genotype calls and GCScores for the 10 sample pairs. Call rates were assessed for each sample individually. For the GWAS samples, we compared data according to source of DNA and center of origin. We observed high concordance in genotyping quality and quantity between the paired samples and minimal loss of quality and quantity of DNA in the saliva samples in the large GWAS sample, with the blood samples showing greater variation between centers of origin. This large data set highlights the usefulness of saliva DNA for genotyping, especially in high-density single-nucleotide polymorphism microarray studies such as GWAS.