Genetic analysis for a shared biological basis between migraine and coronary artery disease.

OBJECTIVE: To apply genetic analysis of genome-wide association data to study the extent and nature of a shared biological basis between migraine and coronary artery disease (CAD). METHODS: Four separate methods for cross-phenotype genetic analysis were applied on data from 2 large-scale genome-wide association studies of migraine (19,981 cases, 56,667 controls) and CAD (21,076 cases, 63,014 controls). The first 2 methods quantified the extent of overlapping risk variants and assessed the load of CAD risk loci in migraineurs. Genomic regions of shared risk were then identified by analysis of covariance patterns between the 2 phenotypes and by querying known genome-wide significant loci. RESULTS: We found a significant overlap of genetic risk loci for migraine and CAD. When stratified by migraine subtype, this was limited to migraine without aura, and the overlap was protective in that patients with migraine had a lower load of CAD risk alleles than controls. Genes indicated by 16 shared risk loci point to mechanisms with potential roles in migraine pathogenesis and CAD, including endothelial dysfunction (PHACTR1) and insulin homeostasis (GIP). CONCLUSIONS: The results suggest that shared biological processes contribute to risk of migraine and CAD, but surprisingly this commonality is restricted to migraine without aura and the impact is in opposite directions. Understanding the mechanisms underlying these processes and their opposite relationship to migraine and CAD may improve our understanding of both disorders.

The interleukin-1α gene C>T polymorphism rs1800587 is associated with increased pain intensity and decreased pressure pain thresholds in patients with lumbar radicular pain.

OBJECTIVES: Previous studies have suggested that many inflammatory cytokines, including interleukin (IL)-1α, may be associated with lumbar radicular pain after disk herniation. In the present study, we examined how variability of the IL-1α gene affects pain intensity and the pressure pain threshold (PPT) in patients with symptomatic disk herniation. MATERIALS AND METHODS: A total of 121 patients with lumbar radicular pain due to disk herniation were recruited from Oslo University Hospital, Norway, and followed up at 6 weeks and 12 months. The primary outcome measures were pain intensity scores for the lower back and legs using a visual analog pain scale (VAS) and PPT for the gluteal muscles. Genotyping was carried out using a predesigned TaqMan assay for IL-1α rs1800587. The effect of the IL-1α genotype on the VAS and PPT was analyzed by repeated measure analyses of variance. RESULTS: The IL-1α gene C>T polymorphism rs1800587 affected VAS and PPT scores in patients with symptomatic disk herniation. Patients with the CT/TT genotype reported a higher VAS leg pain intensity (P=0.002) and also a lower PPT in the gluteal muscles (left P=0.016; right P=0.016) compared with patients with the CC genotype during 1 year of follow-up. DISCUSSION: The present data show that the IL-1α CT/TT genotype rs1800587 may be associated with increased pain intensity and corresponding reduced PPT during the first year after disk herniation.

Urinary albumin excretion as a marker of endothelial dysfunction in migraine sufferers: the HUNT study, Norway.

OBJECTIVE: To investigate urine albumin leakage as a marker of endothelial dysfunction in migraine patients. DESIGN: A population-based health study. PARTICIPANTS: 303 patients with migraine, 1009 patients with non-migraine headache and 5287 headache-free controls. OUTCOMES: The association between urine albumin- to-creatine ratio (ACR) and headache status was investigated in the Nord-Trøndelag Health Study (HUNT-2). Patients were selected in two strata, based on either (1) self-reported hypertension/diabetes (morbid sample) or (2) a random sample. Analyses were performed using analysis of covariance. RESULTS: There was no association between headache status and ACR in the study population (p=0.23, mean ACR for migraine 1.66, 95% CI 1.31 to 2.01, for non-migraine headache 1.90, 95% CI 1.71 to 2.09 and for no headache 1.73, 95% CI 1.64 to 1.81) after relevant adjustments. Similarly, no association between headache status and ACR was seen when the analysis was stratified for morbid and random samples, or for migraine with and without aura. CONCLUSIONS: We found no evidence of increased urine albumin leakage in migraine sufferers when compared with headache-free controls. This could indicate that systemic endothelial dysfunction is not a prominent feature of migraine.

The MMP1 rs1799750 2G allele is associated with increased low back pain, sciatica, and disability after lumbar disk herniation.

OBJECTIVES: Previous studies indicate that genetic variants in genes encoding proteins like matrix metalloproteinase (MMP) enzymes may affect degeneration of the intervertebral disk. One such genetic variant is a single nucleotide polymorphism insertion in the promoter region of the MMP1 gene, that is, the MMP1 rs1799750 2G allele, which increases the MMP1 expression in vitro. In this study, we examined whether the MMP1 rs1799750 2G allele might be associated with disk degeneration and clinical outcome after lumbar disk herniation. MATERIALS AND METHODS: A total of 260 patients with lumbar disk herniation and sciatic pain were included in this study and genotyped for the MMP1 rs1799750 2G allele. RESULTS: The present data showed no differences in the frequency of the MMP1 2G allele in patients recently diagnosed with disk herniation compared with pain-free controls. Moreover, in the patients, the MMP1 2G allele was not directly related to the disk degeneration. However, our data demonstrated that the MMP1 2G allele was associated with both pain and disability, that is, increased visual analog scale score, McGill Pain Questionnaire score, and Oswestry Disability Index score. Clearly, the patients homozygous for the 2G allele had more pain and reduced function compared with those carrying the 1G allele. DISCUSSIONS: Our findings suggest that the MMP1 rs1799750 2G/2G genotype may contribute to low back pain, sciatica, and disability after lumbar disk herniation.

Induction of the perceptual correlate of human long-term potentiation (LTP) is associated with the 5-HTT genotype.

The purpose of the present study was to examine how genetic variability in the promoter of the SLC6A4 gene encoding the serotonin transporter (5-HTT) may influence induction of long-term potentiation (LTP). The genotyping of the 53 healthy volunteers was performed by a combination of TaqMan assay and gel electrophoresis. Based on the transcription rates, the subjects were divided in 3 groups; 5-HTT SS, 5-HTT SL(G)/L(A)L(G)/SL(A) and 5-HTT L(A)L(A). The intensity of pain to test stimuli was rated on a visual analog scale (VAS). High frequency stimulation (HFS) conditioning applied to one arm was used to induce LTP. Only a minor change in pain was observed following the HFS conditioning evoked by electrical test stimuli delivered through the conditioning electrode. Moreover, the change in pain evoked by test stimuli delivered through the conditioning electrode was not related to the 5-HTT genotype. However, we observed a clear increase in pain following the HFS conditioning evoked by mechanical pin-prick test stimuli delivered at the skin adjacent to the conditioning. Also, the 9 individuals with the 5-HTT SS genotype reported more pain than individuals with 5-HTT SL(G)/L(A)L(G)/SL(A) genotype following HFS conditioning on mechanical pin-prick test stimuli. Thus, the present data show that induction of the perceptual correlate of human LTP is associated with the genetic variability in the gene encoding the 5-HTT. Taken together, this suggests that the expression of 5-HTT, may be important for induction of LTP in humans.

Catechol-O-methyltransferase (COMT) inhibition reduces spinal nociceptive activity.

Several variants of the catechol-O-methyltransferase (COMT) gene have recently been linked to pain sensitivity. In the present study, electrophysiological field potential recordings from the dorsal horn in rats were used to examine the spinal effect of reduced COMT activity. The data demonstrated that 30 mg/kg of the COMT inhibitor OR 486 reduced spinal nociceptive responses to painful stimuli (p

Spinal cord long-term potentiation (LTP) is associated with increased dorsal horn gene expression of IL-1beta, GDNF and iNOS.

Previous data show that spinal cord long-term potentiation (LTP) can be induced by electrical high-frequency stimulation (HFS) conditioning applied to the sciatic nerve. It has been suggested that the cellular events leading to this form of plasticity may contribute to central hyperalgesia. In the present study, extracellular recordings from single dorsal horn neurons and quantitative real-time reverse-transcriptase polymerase chain reaction (RT-PCR) on rat dorsal horn tissue were used to examine whether maintenance of spinal LTP is associated with changes in gene expression of the proinflammatory interleukin-1beta (IL-1beta), glial cell-line derived neurotrophic factor (GDNF), inducible nitric oxide synthase (iNOS), p38 mitogen-activated protein kinase (p38 MAPK), cyclooxygenase 2 (COX2) and tumor necrosis factor alpha (TNFalpha). The data demonstrated that the HFS conditioning induced a robust increase in the dorsal horn C-fibre responses, which outlasted the duration of the experiments of 6h (p<0.05, HFS vs. control). Moreover, a significant increase in the expression of mRNA for IL-1beta, GDNF and iNOS were observed 6h following the HFS conditioning (p<0.05, HFS vs. control). For the first time we show that spinal cord LTP is associated with an increased dorsal horn expression of the genes for IL-1beta, GDNF and iNOS.

Metabolic plasticity in the supraspinal pain modulating circuitry after noxious stimulus-induced spinal cord LTP.

It has been suggested that spinal cord long-term potentiation (LTP) may contribute to hypersensitivity and hyperalgesia. We have investigated if noxious stimulus-induced spinal cord LTP might have a long lasting effect on supraspinal neuronal activity. First, we verified that spinal LTP was induced by electrical high frequency stimuli (HFS) conditioning applied to the sciatic nerve. The C-fibre response in the dorsal horn reached a twofold increase 150 min after HFS (t-test, p<0.01, n=6). Then, to study the metabolic supraspinal activity following the same stimulation protocol, we used small animal positron emission tomography (PET) and the glucose analog [(18)F]-fluorodeoxyglucose (FDG). With this combined approach we measured changes in regional supraspinal activity at two time points in HFS conditioned and in sham animals; acute (immediately after HFS/sham, n=4) and late phase (150 min after HFS/sham, n=10). Comparisons between HFS and sham groups revealed that induction of spinal LTP was followed by an acute metabolic response in the primary somatosensory cortex (S1), but also various slower metabolic adaptations in brain regions involved in modulation of nociceptive signaling and descending inhibition, i.e., amygdala, periaqueductal gray (PAG), rostral ventromedial medulla (RVM), and the dorsolateral pontomesencephalic tegmentum (DLPT) (t-test, p<0.05). The study demonstrates that PET may be used as an in vivo method to study regional brain metabolic activity between different conditions. It is concluded that noxious sciatic stimuli which induce spinal cord LTP also affect supraspinal metabolic activity. We suggest that these changes might illustrate a supraspinal maladaptive dysfunction involved in pain hypersensitivity and hyperalgesia.